8th PSK Medichem Workshop by Fei Xiang

Schedule

6월 20일 (수)

Program 11:30 – 12:50! ! 12:50 – 13:00 !!

등록, 포스터 부착 및 숙소 Check-In 개회사 (장영동 교수, 약품화학분과학회 회장)

Invited Lectures ! 13:00 – 13:30 !! 13:30 – 14:00! ! 14:00 – 14:30 !! 14:30 – 14:40 !!

! 좌장: 신계정 교수 - 가톨릭대 이규양 박사 (한국화학연구원 신약연구본부) 백경업 박사 (ILP국제특허법률사무소 대표변리사) 배애님 박사 (한국과학기술연구원(KIST) 뇌의약연구단장) Coffee Break

Young Scientist Presentation 14:40 – 15:40! ! Session 1 (YS 01~ 06)! 좌장: 최원준 교수 (동국대) 15:40 – 16:40 !! Coffee Break, 분과학회 총회, 포스터 발표 16:40 – 17:50 !! Session 2 (YM 01~ 07)! 좌장: 이지연 교수 (서울대) Closing Ceremony 18:00 – 18:20 !! 구두발표 및 포스터발표 시상식, Closing Remark Workshop Dinner & Party 19:00 – 20:00 !! 저녁식사

6월 21일 (목) 20:00 – 22:00 !! 22:00 – 24:00 !!

장기자랑 및 시상식 친목의 시간

07:00 – 09:00 !! 09:00 – 11:00 !! 11:00 – 12:00 !!

아침 식사 분과학회 총회 및 토론 숙소 Check-Out

Invited Lectures

YSS: Organic Synthesis 좌장 : 최원준 교수 (동국대 약대)

좌장 : 신계정 교수 (가톨릭대 약대) 13:00-13:30

YS-1

이규양 박사 (한국화학연구원 신약연구본부)

(14:40 ~14:50)

Discovery of Drug Candidates for Cardiovascular Diseases Employing Benzopyran Scaffold

13:30-14:00

YS-2

백경업 박사 (ILP국제특허법률사무소 대표변리사)

(14:50 ~15:00)

“연구논문과 특허출원”

YS-3 14:00-14:30

배애님 박사 (한국과학기술연구원 (KIST) 뇌의약연구단장)

(15:00 ~15:10)

“Novel Mitochondrial Function Modulators for Treatment of Alzheimer’s Disease” YS-4 (15:10 ~15:20)

Chiral 2-Aminobenzimidazole Bifunctional Organocatalysts: Effect of di-CF3 and TFA on Catalytic Mechanisms Myungmo Lee1, Lei Zhang1, Yohan Park2, and Hyeung-geun Park1* 1Research Institute of Pharmaceutical Science and College of Pharmacy, Seoul National University, Seoul 151-742, Korea, 2College of Pharmacy, Inje University, 607 Obang-dong, Gimhae, Gyeongnam 621-749, Korea Synthesis of 12-Oxobenzo[c]phenanthridinones and 4-Substituted 3 Arylisoquinolones via Vilsmeier-Haack Reaction Daulat Bikram Khadka, Su Hui Yang, Chao Zhao, Yifeng Jin, Won-Jea Cho* College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, Korea Pd-Catalyzed Decarboxylative Coupling of Propioli Acids: One-Pot Synthesis of 1,4-Disubstituted 1,3-Diynes via Sonogashira-Homocoupling Sequence Jihye Park and In Su Kim* College of Pharmacy, Kyung Hee University, Seoul 130-701, Korea Stereoselective Synthesis of (+)-α-Conhydrine and its Pyrrolidine Analogue Tian Jin1, Yu Mu1, Sung-Soo Kim1, Sung-Il Huh1, Won-Hun Ham1* 1School of Pharmacy, SungKyunKwan University, Suwon, 440-746, Republic of Korea, E-mail: whham@skku.edu

Total Synthesis of D-Fagomine and 6-Deoxyfagomine Using CSI-mediated Stereoselective Amination (15:20 Im Suk Min, Sook Jin Park, A Reum Baek and Young Hoon Jung* ~15:30) School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Korea YS-5

Stereoselective Synthesis of Fluoro-homoneplanocin A as a Potential Antiviral Agent YS-6 Girish Chandra, Ji Yee Lee, Akshata Nayak, Yang Won Moon, Mahesh S. (15:30 Majik, and Lak Shin Jeong* ~15:40) College of Pharmacy and Department of Bioinspired Science, Ewha Womans University, Seoul 120-750, Korea. *Correspondence to: lakjeong@ewha.ac.kr

iii

YSM: Medicinal Chemistry 좌장 : 이지연 교수 (서울대 약대)

6월 20일 (수)

YM-1 (16:40 ~16:50)

YM-2 (16:50 ~17:00)

YM-3 (17:00 ~17:10)

YM-4 (17:10 ~17:20)

Identification of The Allosteric Communication of GPCR Using Network Analysis Yoonji Lee and Sun Choi* National Leading Research Lab (NLRL) of Molecular Modeling & Drug Design, College of Pharmacy, Division of Life and Pharmaceutical Sciences, and National Core Research Center for Cell Signaling and Drug Discovery Research, Ewha Womans University, Seoul 120-750, Korea Design, Synthesis, and Evaluation of 3,5-Disubstituted 7-Azaindoles as Trk inhibitors with Anticancer and Antiangiogenic Activities Jinhee Kima, Seunghee Honga, Ju Hyeon Seob, Kyung Hee Jungb, Soon-Sun, Hongb*, and Sungwoo Hong a* aDepartment of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 305- 701, Korea,bDepartment of Biomedical Sciences, College of Medicine, Inha University, Incheon, 400-712, Korea. Synthesis and Biological Activity of Norlignans, Hinokiresinol and Nyasol, as Potential Anti-Ischemic Agents Jinsun Kwon, Yongseok Choi Department of Biotechnology, School of Life Sciences and Biotechnology, Korea University, Seongbuk-gu, Seoul 136-713, Korea Synthesis and Biological Evaluation of Hydroxylated 2,4,6-Triphenyl Pyridine Compounds as Potent Topoisomerase Inhibitor and StructureActivity Relationship Study Radha Karki, Pritam Thapa, Han Young Yoo, Tara Man Kadayat, Youngjoo Kwon,Eung-Seok Leea* College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Republic of Korea, aCollege of Pharmacy, Division of Life & Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750, Republic of Korea

Poster Presentations P-1

Chiral 2-Aminobenzimidazole Bifunctional Organocatalysts: Effect of di-CF3 and TFA on Catalytic Mechanisms Myungmo Lee a, Lei Zhang a, Yohan Park b, and Hyeung-geun Parka* aResearch Institute of Pharmaceutical Science and College of Pharmacy, Seoul National University, Seoul 151-742, Korea, bCollege of Pharmacy, Inje University, 607 Obang-dong, Gimhae, Gyeongnam 621-749, Korea

P-2

Halogenation of Simplied Resiniferatoxin TRPV1 Agonists Showed Enhanced Antagonism to Capsaicin Hyejin Yoon1, Dong Wook Kang, Yong Sung Cho, Peter M. Blumberg2, Jeewoo Lee* 1Laboratory of Medicinal Chemistry,College of Pharmacy, Seoul National University,Seoul 151-742, Korea, 2Laboratory of Cellular Carcinogenesis and Tumor Promotion, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892,USA

P-3

2-(4-Methylsulfonylaminophenyl) Propanamide TRPV1 Antagonists-Structure Activity Relationships in the C-regions Tran Phoung Thao1, Tae-Hwan Ha1, Sang-Uk Kang1, Hyung-Chul Ryu1, Mi-Kyoung Jin1, Hyun-Kyung Choi1, Yongsung Cho1, Myeong Seop1, Wei Sun1, Rahul S. Bhondwe1, Shivaji A. Thorat1, Jeewoo Lee1* Peter M. Blumberg2 1College of Pharmacy, Seoul National University, Seoul 151-742, Korea, 2Laboratory of Cancer Biology and Genetics, NCI, NIH, Bethesda, MD 20892, USA Email: jeewoo@snu.ac.kr

P-4

Halogenation of Resiniferatoxin TRPV1 Agonists Myeong Seop Kim, Kwang Soo Lim, Dong Wook Kang, Peter M. Blumberg2, Jeewoo Lee Laboratory of Medicinal Chemistry, College of Pharmacy, Seoul National University, Seoul 151-742, Korea, 2Laboratory of Cellular Carcinogenesis and Tumor Promotion, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA

P-5

N-4-t-Butylbenzyl 2-(4-methylsulfonylaminophenyl) Propanamide TRPV1 Antagonists: Structure Activity Relationships in the A-regions Jihyae Ann1, Ho-Shin Kim1, Yongsoo Kim1, Min-Jung, Kil1, Sang-Uk Kang1, Hyun-Kyung Choi1, HyungChul Ryu1, Yeon-Sil Choi1, Sook-Hyun Cho1, Jin Hee Lee2, Sun Choi2, Peter M. Blumberg3, Jeewoo Lee1* 1College of Pharmacy, Seoul National University, Seoul 151-742, Korea College of Pharmacy,Ewha Womans University, Seoul 120-750, Korea, 2Laboratory of Cancer Biology and Genetics, NCI, NIH, Bethesda, MD 20892, USA

P-6

Studies on Synthesis and Modes of Action of Mitomycin Dimer That Contains a 1,2-Dithiolane Linker Hyoung Rae Kim, Jae Jin Kim, Jung Jae Park, and Sang Hyup Lee* College of Pharmacy, Duksung Women`s Universty Seoul 132-714, Korea

6월 20일 (수) 6월 20일 (수)

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Abtracts

Abtracts Abstracts For Invited Lectures

[IL-1, 13:00~ 13:30]

Discovery of Drug Candidates for Cardiovascular Diseases Employing Benzopyran Scaffold Kyu Yang Yi

Division of Drug Discovery Research, Korea Research Institute of Chemical Technology, Daejeon 305-600, Korea, E-mail: kyyi@krict.re.kr

The benzopyran ring system is one of the most important privileged structures which has valuable and diverse biological properties. The different positions of the benzopyran ring have been variously substituted permitting the optimal activity to be correlate with a specific set of structural characteristics and stereochemical features in the molecule. In connection with research program based on benzopyran ring system, we have discovered drug candidates for cardiovascular diseases. We discovered SKP-450, a new K-channel opener as a potential anti-hypertensive agent including an acetal moiety at the 2-position of benzopyran ring which imparted a new chiral center. Next, we discovered KR-31378 having a cyanoguanidine moiety at the 4-position of benzopyran ring with enhance selectivity toward the ischemic myocardium over vasorelaxion. KATP openers have shown protective properties in ischemia-reperfusion injury both in heart and brain, presumably through â&#x20AC;&#x2DC;ischemic preconditioningâ&#x20AC;&#x2122;, an endogenous protective mechanism. Finally, 4-(N-imidazol-2-ylmethyl)amino benzopyran compound, KR-31831, showed strong anti-angiogenic effects. Because formation and growth of new blood vessels play a major role in the disease pathogenesis of wet AMD, KR-31831 has the potential to be a useful therapeutics for AMD. The topically delivered KR-31831 as eye drops exhibited good ocular pharmacokinetics and reach the back of the eye in sufficient concentrations for the treatment of AMD.

[IL-2, 13:30~ 14:00]

Research Paper and Patent Application Kyong-Up Baik ILP International Patent & Law Firm

A development of a medicine corresponds to a fruit of the convergence between biological engineering technology and fine chemistry technology and a success in the development of a medicine enables the securement of an intellectual property right as well as high value products. Therefore, a development of medicines may contribute to high value technology and product exports, as well as achieving an import substitution. In the meantime, the Republic of Korea is currently experiencing an imbalance between quantitative results and qualitative results of R&D investment. The Republic of Korea ranked 12th worldwide in the number of SCI (Science Citation Index)-level papers, but an average of R&D productivity (royalty/ invested research expense) of the Republic of Korea is merely 1.3%, which is lower than 5.6% of the United States and 7.7% of Germany. Accordingly, a search for prior arts related to papers and patents through a 3P (Paper-Patent-Product) analysis from a beginning stage of research, an objectoriented R&D plan through a survey of demand in industry technology, etc., R&D progress, and a strategy for filing patent applications have been emphatically demanded above all. The contents of the presentation are necessary for enabling research results related to the development of medicines to take a role as a patent right having strong domestic/international competitiveness in technology and business, and this presentation introduces a patent system related to medicines, how to utilize patent information, how to draw up research notes, how to draft a patent specification, and court precedents, and discusses a strategy for presenting a paper on medicine-related research results and filing a patent application for the research results.

translocation of CypD to the mPTP and results in mPTP opening. After the mPTP opening, cytosolic solutes influx into the mitochondrial matrix, and then mitochondrial swelling causes cell death. Therefore, blockage of CypD or PBR can be an effective therapeutic strategy in Alzheimer's disease. Based on the pharmacophore-based virtual screening, we identified novel scaffolds KST013033 and KST013418, and the synthesis and biological evaluations of those compounds were performed. The optimizations of novel mPTP blockers are now in progress.

[IL-3, 14:00~ 14:30]

Novel Mitochondrial Function Modulators for the Treatment of Alzheimer's Disease Tae Hoon Kim1, 2, Ha Yeon Yang1, 4, Beoung-Geon Park1, 3, Mohammad Neaz Morshed1, 2, Yong Seo Cho1, Eun Joo Roh1, Sun-Joon Min1, Seung Hoon Baek1, Jiyoun Lee1, Ja-Hyun Baik2, Jin Sung Tae4, Moon Yong Cha5, Inhee Mook-Jung5,

Organic Synthesis

Ae Nim Pae1, * 1Korea

Institute of Science and Technology, PO Box 131, Seoul130-650, South Korea. University of Science and Technology, 52, Eoeun-dong, Yuseonggu, Daejon 305-333. 3School of Life Sciences and Biotechnology, Korea University, Seoul Korea. 4Department of Chemistry, Yonsei University, Seodaemun-gu, Seoul 120-749, Korea. 5School of Medicine, Seoul National University, Seoul, South Korea 2Korea

Alzheimer's disease (AD) is a late-onset, progressive, age-dependent neurodegenerative disorder, characterized clinically by the impairment of cognitive functions and changes in behavior and personality. Mitochondrial dysfunction, or a problem with the cellular exchange of energy, is an early event observed in Alzheimer's disease. Amyloid-β peptide has deleterious effects on mitochondrial function and contributes to energy failure, respiratory chain impairment, neuronal apoptosis, and generation of reactive oxygen species in Alzheimer's disease. The mechanisms underlying amyloid-β induced mitochondrial stress remain unclear. Emerging evidence indicates that mitochondrial permeability transition pore (mPTP) is important for maintenance of mitochondrial and neuronal function in aging and neurodegenerative disease. CypD, adenin nucleotide translocator (ANT), voltage-dependent anion channel(VDAC), and benzodiazepine receptor(PBR) compose the mitochondrial permeability transition pore(mPTP). The interaction of Aβ with CypD enhances the

[YS-1, 14:40 ~ 14:50]

neutral condition and non-substituted 2-aminobenzimidazole catalysts in cocatalyst (TFA) condition give high chemical yield and enantioselectivity.

Chiral 2-Aminobenzimidazole Bifunctional Organocatalysts:Effect of di-CF3 and TFA on Catalytic Mechanisms Myungmo Lee1, Lei Zhang1, Yohan Park2, and Hyeung-geun Park1, * 1Research

Institute of Pharmaceutical Science and College of Pharmacy, Seoul National University, Seoul 151-742, Korea 2College of Pharmacy, Inje University, 607 Obang-dong, Gimhae, Gyeongnam 621-749, Korea

Chiral amine conjugated thioureas have been used as chiral bifunctional organocatalysts capable of simultaneously activating both nucleophiles and electrophiles in asymmetric reactions due to their Brønsted/Lewis acidic (thiourea moiety) and basic (chiral amine moiety) functionalities. Among the disclosed thiourea based catalysts, the N-5,7-bis(trifluoromethyl)phenyl group substituted catalysts have been widely used as chiral bifunctional catalysts. The electronwithdrawing CF3 group not only increases N–H acidity, but also contributes to the conformational rigidity of the catalyst by polarizing the adjacent H atoms and inducing an intramolecular hydrogen bonding interaction with the sulfur atom in the thioureas. Since the 2-aminobenzimidazole group is conformationally more rigid and can potentially serve as new Brønsted/Lewis acid catalysts, we recently reported new 2-aminobenzimidazoles conjugated with cinchona alkaloid and successfully applied to enantioselective Michael additions. In this presentation, we report the synthesis and application of (S,S)-transcyclohexanediamine-5,7-di-CF3-benzimidazole as a new efficient chiral bifunctional organocatalysts and successfully applied to Michael addition of diethylmalonate to nitroolefins (up to 99%, 97% ee) under neutral condition. We also investigated the catalytic mechanism of chiral 2-aminobenzimidazole type bifunctional organocatalysts at different reaction conditions. Systematic investigation on the catalytic mechanism revealed that the role of the guanidine moiety and the dimethylamine moiety in catalysts might be reversed with respect to Brønsted/Lewis acidic or basic functionalities, depending on the reaction conditions. Generally, di-CF3 group substituted 2-aminobenzimidazole catalysts in

[YS-2, 14:50 ~ 15:00]

Synthesis of 12-Oxobenzo[c]phenanthridinones and 4-Substituted 3-Arylisoquinolones via Vilsmeier-Haack Reaction Daulat Bikram Khadka, Su Hui Yang, Chao Zhao, Yifeng Jin, Won-Jea Cho* College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, Korea Isoquinolones are an important class of compounds that comprise a large variety of natural and synthetic products which express a wide spectrum of pharmacological activities. Isoquinolones with substituents at various positions exhibit different therapeutic properties. Apart from this, different functional groups at the same position also impart unique biological functions. In addition to exhibiting potent biological properties, the isoquinolone moiety (more precisely 3-arylisoquinolone) is the chief precursor for synthesis of several classes of alkaloids and potent antitumor agents like indeno[1,2-c]isoquinoline, isoindolo[2,1-b]isoquinolines and dibenzo[c,h][1,6]naphthyridines which work primarily by inhibiting human topoisomerase I (topo I). Synthesis of 3-arylisoquinolines as topo I inhibitors involves conversion of the flexible 3-arylisoquinoline core into constrained tetracyclic structure with increased ability to cease the activity of topo I. Based on the fact that the isoquinolone skeleton with varied substitution at the same position can manifest clinically useful properties and rigidification of 3-arylisoquinoline can improve topo I inhibition and cytotoxicity, a variety of 4-substituted 3-arylisoquinolones and 12-oxobenzo[c] phenanthridinones were synthesized. The synthetic approach was principally centered in formation of versatile 4-formylated isoquinolone by Vilsmeier-Haack reaction. The aldehyde obtained as end product of Vilsmeier-Haack reaction and the alcohol formed after reduction of the aldehyde were converted into 12-oxobenzo[c]phenanthridinones, 4-alkoxymethyl-3-arylisoquiolones, 3-aryl-4-phenoxymethylisoquinolones, 4-aminomethyl-3-arylisoquinolone and 3-isoquinolinyl-2-phenyl-acrylonitrile utilizing different synthetic strategies.

disubstituted 1,3-diynes by cross-coupling of two different 3-substituted propiolic acids is described.

[YS-3, 15:00 ~ 15:10]

Reference 1. Park, J.; Park, E.; Kim, A.; Park, S.-A.; Lee, Y.; Chi, K.-W.; Jung, Y. H.; Kim, I. S. Pd-Catalyzed Decarboxylative Coupling of Propiolic Acids: One-Pot Synthesis of 1,4-Disubstituted 1,3-Diynes via Sonogashira- Homocoupling Sequence. J. Org. Chem. 2011, 76, 2214-2219.

Pd-Catalyzed Decarboxylative Coupling of Propiolic Acids:One-Pot Synthesis of 1,4Disubstituted 1,3-Diynes via SonogashiraHomocoupling Sequence Jihye Park and In Su Kim* College of Pharmacy, Kyung Hee University, Seoul 130-701, Korea

Conjugated 1,3-diynes are very crucial materials in the fields of chemistry, biology and material science, because they have been used in the preparation of natural products, organic/inorganic composites, pharmaceuticals, and Ď&#x20AC;conjugated polymers as well as the molecular recognition process. Traditional method for the construction of symmetric 1,3-diynes is oxidative homocoupling reactions of terminal alkynes, reported by Glaser, via the treatment of Cu(I) salt in the presence of aqueous ammonia followed by air oxidation. Later related modified methods to improve the disadvantage of the original reaction condition were developed by Chodkiewicz-Cadiot, Yu, and Lei. However, these methodologies present intrinsic drawbacks, namely the need for prefunctionalization of both coupling partners. For examples, in the case of homocoupling of terminal alkynes, the preparation of terminal alkynes through Sonogashira reaction between haloarenes and metal(Si, Sn, etc)-substituted acetylenes and subsequent reductive hydrogenation were often required. Moreover, the methods for the synthesis of unsymmetrical 1,3-diynes have required the prefunctionalization to prepare haloalkynes or propiolic acids as well as terminal alkynes. The multi-step syntheses required for the preparation of such reagents can pose additional barriers to their use. Therefore, it is highly desirable to develop more efficient methodologies saving synthetic steps and avoiding waste formation for synthesizing conjugate 1,3-diynes. Herein, we demonstrate one-pot direct synthesis of symmetrical 1,4-disubstituted 1,3-diynes from iodoarenes and propiolic acid via Sonogashira reaction followed by Pd-catalyzed decarboxylative homocoupling. Furthermore, one-pot synthesis of unsymmetrical 1,4-

5. Meng-Yang Chang, Yung-Hua Kung and Shui-Tein Chen, Tetrahedron, 2006, 62, 10843-10848

[YS-4, 15:10 ~ 15:20]

Stereoselective Synthesis of (+)-α-Conhydrine and its Pyrrolidine Analogue Tian Jin1, Yu Mu1, Sung-Soo Kim1, Sung-Il Huh1, Won-Hun Ham1, * 1School

of Pharmacy, SungKyunKwan University, Suwon, 440-746, Republic of Korea, E-mail: whham@skku.edu

Alkaloid mimics with a nitrogen in the ring, especially those α-substituted by a 1-hydroxyalkyl side chain, constitute a framework frequently encountered in natural alkaloids. Conhydrine is one of the alkaloids of the hemlock, isolated from the seeds and leaves of the poisonous alkaloids plant Conium maculatum, whose extracts were used in the ancient Greece for execution of criminals. Structure of conhydrine was elucidated in 1933. A number of total syntheses of αconhydrine have been established. Various methods for the asymmetric synthesis of α-conhydrine mainly based on auxiliary-supported or chiral pool approaches have been documented in the literature. However, many of the reported methods either make use of chiral building blocks or involve longer reaction sequences, often accompanied by low product selectivity. A key feature is highly diastereoselective chelating-controlled hydride reduction of the amino ketone to give the anti-amino alcohol directly, and intramolecular ring-closing methesis. References 1. Van-Thoai Pham, Jae-Eun Joo, Yong-Shou Tian, Yong-Hyun Kim, KeeYoung Lee, Chang-Young Oh, Jin-Hyun Jeong, and Won-Hun Ham. Heterocycles, 2008, 75, 2817-2823 2. Yong-Shou Tian, Jae-Eun Joo, Bae-Soo Kong, Van-Thoai Pham, Kee-Young Lee, and Won-Hun Ham, J.Org. Chem. 2009, 74, 3962-3965 3. Andrew G. Jamieson and Andrew Sutherland, Org. Lett., 2007, 9, 1609-1611 4. Subba Rao V. Kandula and Pradeep Kumar, Tetrahedron: Asymmetry, 2005, 16, 3268-3274

[YS-5, 15:20 ~ 15:30]

Total Synthesis of D-Fagomine and 6Deoxyfagomine Using CSI-mediated Stereoselective Amination Im Suk Min, Sook Jin Park, A Reum Baek and Young Hoon Jung* School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Korea

Polyhydroxylated piperidine alkaloids have been frequently reported in nature and received considerable attention as potential medical agents because of their interesting pharmacological properties, such as, viral infections, cancer, malaria, insecticides and diabetes. Consequently, The Synthesis of Polyhydroxylated piperidine alkaloids, their stereoisomers, and analogs have attracted considerable attention, and a number of methods have been developed. D-Fagomine and 6-deoxyfagomine are piperidine alkaloids isolated from Lycium chinense root. Among them, D-fagomine has inhibitory activity toward mammalian Îą-glycosidase and Î˛-galactosidase, and potent antihyperglycemic effect. Recently, we reported the regioselective and diastereoselective allylic amination of various allylic ethers using chlorosulfonyl isocyanate(CSI), and its application to the various biologically active piperidine, pyrrolidine, pyrrolizidine, and indolizidine alkaloids including DAB1 as important components of glycosidase inhibitors. Herein we describe a straightforward asymmetric synthesis of D-fagomine and 6-deoxyfagomine with use of CSI. The synthesis of the title compounds start from D-Lyxose and key steps in this route are the regioselective hydroboration and oxidation and the diastereoselective amination of allylic ether using our CSI methodology.

(2) and homoneplanocin A (3). Herein, we report the stereoselective synthesis of fluoro-homoneplanocin A (4), using the enyne ring-closing metathesis (RCM), stereo- and regioselective opening of the epoxide with fluoride, and simultaneous oxidation-elimination as key steps.

[YS-6, 15:30 ~ 15:40]

Stereoselective Synthesis of Fluorohomoneplanocin A as a Potential Antiviral Agent

RESULTS AND DISCUSSION First, the glycosyl donor 11 was synthesized from D-ribose (5) via the key intermediate 7 and then condensed with the purine base under the Mitsunobu conditions. D-Ribose (5) was converted to enyne 6, using the reaction of the lactol with trimethylsilyl diazomethane in the presence of strong base as a key step. Enyne ring-closing metathesis (RCM) reaction of 6 afforded the key intermediate 7, which can be served as a versatile intermediate for the synthesis of carbocyclic nucleosides. Regio- and stereoselective nucleophilic fluorination to an epoxide 9 provided the corresponding fluorodiol 10, which underwent simultaneous oxidation-elimination to give the glycosyl donor 11. Condensation of glycosyl donors, 8 and 9 with 6-chloropurine and further manipulation of corresponding condensed nucleosides gave the final compounds 3 and 4, respectively.

Girish Chandra, Ji Yee Lee, Akshata Nayak, Yang Won Moon, Mahesh S. Majik, and Lak Shin Jeong* College of Pharmacy and Department of Bioinspired Science, Ewha Womans University, Seoul 120-750, Korea Email : lakjeong@ewha.ac.kr

ABSTRACT Fluoro-homoneplanocin A (4) was synthesized from D-ribose, via the enyne ring-closing metathesis of 6, the stereoselective opening of epoxide 9 with fluoride, and a simultaneous oxidation-elimination reaction.

CONCLUSION

INTRODUCTION

We have accomplished the stereoselective synthesis of fluoro-homoneplanocin A (4) along with the synthesis of homoneplanocin A (3) from D-ribose, using the enyne ring-closing metathesis, the regio- and stereoselective opening of the epoxide with fluoride, and a simultaneous oxidation-elimination reaction as key steps. The key intermediate 8 is expected to serve as an excellent template for the synthesis of carbocyclic nucleosides

Neplanocin A (1) is one of the representative carbocyclic nucleosides that inhibit S-adenosylhomocysteine (SAH) hydrolase, which plays a key role in the formation of the capped methylated structure at the 5â&#x20AC;&#x2122;-terminus of viral mRNA. Thus, SAH hydrolase is an attractive target for the development of broadspectrum antiviral agents. Neplanocin A showed potent antiviral activities against several RNA and DNA viruses but could not be further developed as a clinical agent because of high cytotoxicity due to the phosphorylation by adenosine kinase. On the basis of the structure of 1, fluoroneplanocin A (2) was designed and synthesized as a mechanism-based inhibitor of SAH hydrolase. Compound 2 was found to inhibit the enzyme through both mechanism-based irreversible inhibition and mechanism-based reversible cofactor (NAD+)-depletion. Homoneplanocine A (3), a one-carbon homologated analog of 1 was reported to exhibit potent inhibitory activity against SAH hydrolase and showed potent antiviral activity against hepatitis B virus (HBV) without apparent cytotoxicity. Based on these results, it was of great interest to synthesize fluorohomoneplanocin A (4), which combines the properties of fluoro-neplanocin A

Medicinal Chemistry

[YM-1, 16:40 ~ 16:50]

Complex systems are constructed by the networks of interactions among the system components. Through analyzing this network, which consists of a set of points (i.e., “nodes”) and a set of lines (i.e., “edges”) connecting pairs of points, the characteristics of the whole system and its individual components can be identified. The network analysis method was first developed by social network analysis researchers, and now is a common technology in many disciplines including statistical physics, particle physics, computer science, economics, and biology. Protein structures can also be represented as networks where amino acid residues are the nodes and their interactions are the edges. We applied the network analysis to identify key residues for the allosteric communication of GPCR. The residues with high centralities consist of the physically connected sparse network linking from the ligand binding site to G-protein binding site. In addition, they included the several micro-switch residues which are reported as important residues for GPCR function. Here, we introduced the intra-molecular network analysis method, which is simple but extremely powerful way to identify key residues for the allosteric communication, and the detailed results will be presented.

[YM-2, 16:50 ~ 17:00]

Design, Synthesis, and Evaluation of 3,5Disubstituted 7-Azaindoles as Trk inhibitors with Anticancer and Antiangiogenic Activities Jinhee Kima, Seunghee Honga, Ju Hyeon Seob, Kyung Hee Jungb, Soon-Sun, Hongb, *, and Sungwoo Hong a, * aDepartment

of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 305- 701, Korea, bDepartment of Biomedical Sciences, College of Medicine, Inha University, Incheon, 400-712, Korea.

Tropomyosin-related kinase A (TrkA) is considered a promising target in the development of a therapeutic treatment of cancer and pain. In this study, we designed and synthesized a series of novel 7-azaindole-based Trk kinase inhibitors through the structure-based design strategy. By varying the functional groups at the 3 and 5 positions of a 7-azaindole scaffold, we studied the structure-activityrelationship (SAR) profiles and identified a series of potent Trk inhibitors. Representative derivatives showed desirable acivity in cellular proliferation and apoptosis assays. Moreover, these inhibitors exhibited noteworthy antiangiogenic activity.

[YM-3, 17:00 ~ 17:10]

Synthesis and Biological Activity of Norlignans, Hinokiresinol and Nyasol, as Potential AntiIschemic Agents Jinsun Kwon, Yongseok Choi Department of Biotechnology, School of Life Sciences and Biotechnology, Korea University, Seongbuk-gu, Seoul 136-713, Korea

Cerebral ischemic injury is a major leading cause of death and chronic disability in adults. Since multiple cytotoxic pathways including excitotoxicity, oxidative stress, and inflammatory responses are engaged to ischemic neuronal injury, the development of drug with multi-factorial anti-ischemic activities draws much attention to develop the improved clinical therapy. In the present study, we conducted synthesis of natural norlignans and investigated the potential therapeutic effects of cis-hinokiresinol and its trans-isomer in in vitro as well as in vivo ischemic/hypoxic models. The synthesis of (Âą)-nyasol and (Âą)-hinokiresinol has been achieved from readily available 4-hydroxy benzaldehyde and 4-iodo phenol as starting materials via regiospecific epoxide opening and partial hydrogenations using Lindlarâ&#x20AC;&#x2122;s catalyst. The synthesized norlignans exerted significant, but stereo-specific neuroprotective effects against ischemic injury, through differential anti-oxidant but comparable anti-inflammatory activities. Detailed delineation of antiischemic mechanism of norlignans will be presented as a better strategy to develop efficacious regimen for cerebral ischemic stroke.

[YM-4, 17:10 ~ 17:20]

Synthesis and Biological Evaluation of Hydroxylated 2,4,6-Triphenyl Pyridine Compounds As Potent Topoisomerase Inhibitor and StructureActivity Relationship Study

Radha Karki, Pritam Thapa, Han Young Yoo, Tara Man Kadayat, Youngjoo Kwon, Eung-Seok Leea, * College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Republic of Korea. aCollege of Pharmacy, Division of Life & Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750, Republic of Korea A series of hydroxylated 2,4,6-triphenyl pyridines were designed and synthesized which contain hydroxyl groups at ortho, meta or para position of 2-, 4and/or 6- phenyl rings attached to the central pyridine. They were evaluated for topoisomerase I and II inhibitory activity, and cytotoxicity against several human cancer cell lines for the development of novel anticancer agents. Generally, di-hydroxylated and tri-hydroxylated 2,4,6-triphenyl pyridines exhibited stronger topoisomerase II inhibitory activity, and cytotoxicity compared to mono-hydroxylated compounds. Interestingly, it was observed that introduction of hydroxyl moiety increases the topoisomerase II inhibitory activity and further increase in the number of hydroxyl group enhances the activity. Positive correlation between topoisomerase II inhibitory activity and cytotoxicity was observed for several compounds. Keywords: hydroxylated 2,4,6-triphenyl pyridines, topoisomerase I, topoisomerase II, cytotoxicity, anticancer agents

[YM-5, 17:20 ~ 17:30]

Discovery, Structure Activity Relationships and Pharmacological Studies of 3,5-Dichloropyridine Derivatives As Novel P2X7 Receptor Antagonists Won-Gil Lee†, So-Deok Lee†, Joong-Heui Cho†, Younghwan Jung†, Jeong-hyun Kim†, Tran T. Hien‡, Keon-Wook Kang‡, Hyojin Ko§, and Yong-Chul Kim†, §, * †School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 500-712, Korea, ‡College of Pharmacy, Seoul National University, Seoul, Korea, §Graduate Program of Medical System Engineering, Gwangju Institute of Science and Technology, Gwangju 500-712, Korea

Screening of a library of chemical compounds showed that the 3,5dichloropyridine based analog 9 was a novel P2X7 receptor antagonist. To optimize its activity, we assessed the structure-activity relationships (SAR) of 9, focusing on the hydrazide linker, the dichloropyridine skeleton and the hydrophobic acyl (R2) group. We found that the hydrazide linker and the chlorides at C3 and C5 positions in the pyridine skeleton were critical for P2X7 antagonistic activity and that the presence of hydrophobic polycycloalkyl groups at the R2 position optimized antagonistic activity. On the ethidium bromide uptake assay in hP2X7-expressing HEK293 cells, the optimized antagonists, 51 and 52, had IC50 values of 4.9 and 13 nM, respectively. The antagonistic effects of 51 and 52 were paralleled by their ability to inhibit of the release of the proinflammatory cytokine, IL-1β! by LPS/IFN-γ/BzATP stimulation of THP-1 cells (IC50 = 1.3 and 9.2 nM, respectively). In addition, 52 strongly inhibited iNOS/COX-2 expression and NO production in THP-1 cells, further indicating that this compound blocks inflammatory signaling and suggesting that the dichloropyridine analogs may be useful in developing P2X7 receptor targeted anti-inflammatory agents.

[YM-6, 17:30 ~ 17:40]

Remodeling of Narylsulfonylimidazolones to Narylsulfonylpyrimidones as Anti-cancer agent Santhosh Subramanian, Vinay Kumar Sharma, EedaVenkateswara Rao, Ki-Cheul Lee, Manickam Manoj, Hyun-sun Yang, Sang-Hun Jung* College of Pharmacy and Institute of Drug Research and Development, Chungnam National University, Daejeon 305-764, Republic of Korea Email : jungshh@cnu.ac.kr Tubulin inhibitors like colchicine, combretastatin, paclitaxel, epothilone A and vinblastine exhibit anticancer properties by interfering with the dynamics of tubulin polymerization and depolymerisation resulting in mitotic arrest. However, the clinical use of all these antitubulin agents is associated with problems of drug resistance, toxicity, and bioavailability. In our earlier study we have explored that N-arylsulfonylimidazolones are potent antitubulin agents. The current investigation is on the modification of the N-arylsulfonylimidazolones to N-arylsulfonylpyrimidones and N-arylsulfonyltetrahydropyrimidones as anticancer agents. Based on investigation, we found that 1-(indolin-5-ylsulfonyl)-4phenylpyrimidin-2(1H)-one and 4-phenyl-1-(1-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroquinolin-6-ylsulfonyl)py rimidin-2(1H)-one showed moderate activity against human cancer cell lines namely, ACHN, HCT15, MDA-MB-231, NCI-H23, NUGC-3 and PC-3. Some critical points were elicited from these results. Compared to Narylsulfonyltetrahydropyrimidones, N-arylsulfonylpyrimidones showed better activity, whereas solubility of the N-arylsulfonylpyrimidones compounds has to be improved by introducing some hygrophilicity on the indoline or the quinolone ring. Their planarity of pyrimidone and bulky N-arylsulfonyl group of N-arylsulfonylpyrimidones are crucial for their anticancer activity. The other regioisomers were found during synthesis such as 2arylsulphonyltetrahydropyrimidones, which are not active.

[YM-7, 17:40 ~ 17:50]

RAGE inhibitory activities was partly elucidated by SPR analysis, the results of which supported the hypothesis that the direct binding of the inhibitor with RAGE contributed to its RAGE-inhibitory activities. In addition, the binding mode of the inhibitors with RAGE was predicted by a docking study of the inhibitors on the RAGE V-domain.

Ligand-based Design, Synthesis and Biological Evaluation of a Novel Series of RAGE (Receptor for Advanced Glycation End Products) Inhibitors Young Taek Hana, Gyeong-In Choi a, Do-Hyun Sonb, Nam-Jung Kim b, Hwayoung Yun a, Sunjin Lee a, Dong Jo Chang a, Hyun-Seok Hong c, Hyun-Ju Park b, Jeewoo Lee a, and Young-Ger Suh,a,* aCollege

of Pharmacy, Seoul National University, 599 Gwanak-ro, Gwanak-gu, Seoul 151-742, Korea, bSchool of Pharmacy, Sungkyunkwan University, Suwon 440-746, Korea, cMedifron DBT, Sandanro 349, Danwon-Gu, Ansan-City, Gyeonggi-Do, 425-839, Korea; E-mail: ygsuh@snu.ac.kr

Alzheimer’s disease (AD) is the most common neurodegenerative disease in elderly individuals. According to “β-amyloid (Aβ) hypothesis”, Aβpeptide is central to the pathological cascade involved in the pathogenesis of AD. Aβ is produced mostly in somatic cells through the proteolysis of amyloid precursor protein (APP), and the entry of Aβ into the brain and subsequent accumulation is essential for the pathogenesis of AD. Receptor for advanced glycation end products (RAGE)-Aβ interaction not only promotes the transport of Aβ into the brain, but also activates NF-κB, a transcription factor that plays a crucial role in various inflammatory responses. In this context, the inhibition of the RAGE-Aβ interaction has been recognized as more preclusive and curative AD treatment strategy. In connection with the development of novel RAGE inhibitors as potential AD therapeutics, we designed and synthesized on the structural basis of a monomeric advance glycation end product (AGE). Subsequently, we identified a novel pyrimidine scaffold for RAGE-inhibitory activity. We also established the structure-activity relationship of the inhibitors based on the in vitro RAGE inhibition. In particular, one of the analogs resulted in the significant inhibition of Aβ accumulation in the brain and in a noticeable improvement in cognitive function in AD model mice after oral administration. The mechanism of the

[P-1]

Chiral 2-Aminobenzimidazole Bifunctional Organocatalysts: Effect of di-CF3 and TFA on Catalytic Mechanisms

Poster Presentations

Myungmo Lee a, Lei Zhang a, Yohan Park b, and Hyeung-geun Parka* aResearch

Institute of Pharmaceutical Science and College of Pharmacy, Seoul National University, Seoul 151-742, Korea, bCollege of Pharmacy, Inje University, 607 Obang-dong, Gimhae, Gyeongnam 621-749, Korea

tions. Generally, di-CF3 group substituted 2-aminobenzimidazole catalysts in neutral condition and non-substituted 2-aminobenzimidazole catalysts in cocatalyst (TFA) condition give high chemical yield and enantioselectivity.

[P-2]

tigate how the halogenation on the aromatic A-region of our potent agonists modulates their functional activity. In this presentation, we describe the syntheses, receptor activities and the analysis of structure activity relationships of 5 and 6-halogenated analogues of our lead agonists.

Halogenation of Simplied Resiniferatoxin TRPV1 Agonists Showed Enhanced Antagonism to Capsaicin Hyejin Yoon1, Dong Wook Kang, Yong Sung Cho, Peter M. Blumberg2, Jeewoo Lee* 1Laboratory

of Medicinal Chemistry, College of Pharmacy, Seoul National University, Seoul 151-742, Korea, 2Laboratory of Cellular Carcinogenesis and Tumor Promotion, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA

TRPV1 is a member of the transient receptor potential (TRP) superfamily; the TRP family proteins form non-voltage activated cation channels and share a structural characteristic of six transmembrane segments. TRPV1 functions as a molecular integrator of nociceptive stimuli expressed predominantly on unmyelinated pain-sensing nerve fibers (C-fibers) and small A fibers in the dorsal root, trigeminal, and nodose ganglia. It is activated by protons, heat, endogenous substances such as anandamide and lipoxygenase products, by vanilloids such as capsaicin (CAP) and resiniferatoxin (RTX), or indirectly by bradykinin. Since TRPV1 is a non-selective cation channel with high Ca2+ permeability, its activation by these agents leads to an increase in intracellular Ca2+ that results in excitation of the primary sensory neurons. Previously, we have demonstrated that so-called simplified RTX analogues, N-(3-pivaloyloxy-2-benzylpropyl)-Nâ&#x20AC;&#x2122;-(4hydroxy-3-methoxybenzyl)thioureas or N-(3-pivaloyloxy-2-benzylpropyl)-2-(4hydroxy-3-methoxyphenyl) acetamide, possess potent TRPV1 agonism with high affinity in rat TRPV1 heterologously expressed in Chinese hamster ovary (CHO) cells and excellent analgesic activities. Recently it was reported that the halogenation of the aromatic A-ring of agonists shifted the agonism of the ligands toward antagonism. Two leading examples are 5-iodoresiniferatoxin and 6-iodononivamide, iodinated products of the agonists RTX and nonivamide, which showed potent antagonism, respectively. The result prompted us to inves-

[P-3]

ture activity relationships of the C-region in a series of 2-(4methylsulfonylaminophenyl) propanamide TRPV1 antagonists.

of Pharmacy, Seoul National University, Seoul 151-742, Korea 2Laboratory of Cancer Biology and Genetics, NCI, NIH, Bethesda, MD 20892, USA Email: jeewoo@snu.ac.kr

TRPV1 antagonists have attracted much attention as promising drug candidates for inhibiting the transmission of nociceptive signaling from the periphery to the CNS and for blocking other pathological states associated with this receptor. They have thus emerged as novel and promising analgesic and antiinflammatory agents, particularly for chronic pain and inflammatory hyperalgesia. The number of antagonists reported continues to increase and their clincal development has been in progress. P r e v i o u s l y, w e h a v e r e p o r t e d t h a t a s e r i e s o f N - 4 (methylsulfonylaminobenzyl) thiourea analogues were effective antagonists of the action of capsaicin on rat TRPV1. In order to further optimize the antagonistic activities of thiourea leads and avoid the potential toxicity associated with the thiourea functionality, we explored the amide B-region surrogates of parent thiourea antagonists in a series of simplifed RTX and reported that the propanamide B-region surrogates showed stereospecific high binding affinities and potent antagonisms. As a continuation of our effort to optimize the 4-methylsulfonamide TRPV1 antagonists, we have investigated a series of 2-(4-methylsulfonylaminophenyl) propanamide analogues as TRPV1 antagonists. In this paper, we report the struc-

[P-4]

Halogenation of Resiniferatoxin TRPV1 Agonists Myeong Seop Kim, Kwang Soo Lim, Dong Wook Kang, Peter M. Blumberg2, Jeewoo Lee Laboratory of Medicinal Chemistry, College of Pharmacy, Seoul National University, 2 Seoul 151-742, Korea, Laboratory of Cellular Carcinogenesis and Tumor Promotion, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA

Resiniferatoxin (RTX), isolated from Euphorbia resinifera, is an extremely potent irritant tricyclic diterpene which is structurally related to phorbol-related diterpenes except for its homovanillyl ester group at C-20. RTX has proven to function pharmacologically as an ultrapotent agonist for the transient receptor potential vanilloid 1 (TRPV1) channel, displaying 103- to 104-fold greater potency than the prototypic agonist capsaicin. Structure-activity relations for RTX derivatives have been investigated employing partial modifications starting from RTX or ROPA (resiniferonol orthophenylacetate) based on the three structural regions including the A-region (4-hydroxy-3-methoxyphenyl), B-region (C20 ester), and C-region (diterpene). In the SAR of the A-region of RTX (4hydroxy-3-methoxyphenyl), any modifications on the phenolic hydroxyl, such as methylation and 2-aminoethylation, led to the reduction in binding affinity and agonism in rat DRG. However, 5-Iodo RTX, prepared semisynthetically from RTX by iodination, displayed good potency in rat and human TRPV1 and shifted the activity from agonism to antagonism. Previously, we and other groups reported that the halogenation of the aromatic A-ring of TRPV1 agonists also shifted the agonism of the ligands toward antagonism. On the basis of this SAR analysis, we have investigated the halogenated RTX analogues in which 5 position of the 4-hydroxy(or 4-amino)-3-methoxyphenyl group was halogenated with fluoro, chloro and bromo atoms, respectively. In this presention, the synthesis, receptor activities and SAR analysis of halogenated RTX will described.

tion of rTRPV1 but also of stimulation by temperature and pH. Conversely, the 3-methoxy derivative 3 showed a shift to partial agonism (Ki = 51 nM, 17% ago and 84% antago in rTRPV1/CHO) while the binding affinity remained unaffected. As a continuation of our effort to optimize the 4-methylsulfonamide TRPV1 antagonists, we have investigated a series of 2-(4methylsulfonylaminophenyl) propanamide analogues as TRPV1 antagonists. In this poster, we report the structure activity relationships of A-region in a series of N-4-t-butylbenzyl 2-(4-methylsulfonylaminophenyl) propanamide TRPV1 antagonists. Further biological characterization and molecular modeling of key antagonist will also be presented.

[P-5]

N-4-t-Butylbenzyl 2-(4methylsulfonylaminophenyl) Propanamide TRPV1 Antagonists: Structure Activity Relationships in the A-regions Jihyae Ann1, Ho-Shin Kim1, Yongsoo Kim1, Min-Jung, Kil1, Sang-Uk Kang1, Hyun-Kyung Choi1, HyungChul Ryu1, Yeon-Sil Choi1, Sook-Hyun Cho1, Jin Hee Lee2, Sun Choi2, Peter M. Blumberg3, Jeewoo Lee1* 1College

of Pharmacy, Seoul National University, Seoul 151-742, Korea College of Pharmacy,Ewha Womans University, Seoul 120-750, Korea 2Laboratory of Cancer Biology and Genetics, NCI, NIH, Bethesda, MD 20892, USA

The transient receptor potential V1 (TRPV1) receptor is a molecular integrator of nociceptive stimuli, including protons, heat, inflammatory mediators such as anandamide and lipoxygenase products, and vanilloids such as capsaicin (CAP) and resiniferatoxin (RTX). The receptor functions as a non-selective cation channel with high Ca2+ permeability and its activation leads to an increase in intracellular Ca2+ that results in excitation of primary sensory neurons and ultimately the central perception of pain. Thus TRPV1 antagonism has been promising drug mechanism for the development of novel analgesic, particulary for neuropathic pain. P r e v i o u s l y, w e h a v e r e p o r t e d t h a t a s e r i e s o f N - 4 (methylsulfonylaminobenzyl) thiourea analogues were effective antagonists of the action of capsaicin on rat TRPV1. A prototype antagonist (1) showed high binding affinity and potent antagonism (Ki = 63 nM and Ki(ant) = 54 nM in rTRPV1/CHO). We further found that 3-substitutents of the 4(methylsulfonylamino)phenyl group in the A-region affected the extent of agonism/antagonism. Thus, the 3-fluoro derivative 2 (Ki = 53.5 nM, Ki(ant) = 9.2 nM in rTRPV1/CHO) was a potent antagonist not only of capsaicin stimula-

[P-6]

Mitomycins are known to be DNA alkylating agents that constitute a class of potent antitumor agents with representative example, mitomycin C (MMC). Recently, disulfide mitomycins that contain a disulfide unit were found to display improved pharmacological properties. So, our study focused on the mitomycin dimer connected by the unique structural motif, a 5-membered cyclic disulfide (a 1,2-dithiolane). We have synthesized the target mitomycin dimer and reference diol mitomycin dimer using mitomycin A (MMA) and corresponding intermediates. Mode of action studies by checking the methanolysis (activation) rate showed that the activation rates of target disulfide mitomycin with phosphine nucleophile were much faster than those of reference diol mitomycin. We also found that in the presence of phosphine nucleophile the target mitomycin provided much higher levels of DNA interstrand cross-links (DNA ISC) than the reference mitomycin. Taken together, it was found that the target mitomycin of our interest underwent faster activation and provided more efficient DNA-ISC formation than reference mitomycin, and that the disulfide unit lies at the core of the mitomycin activations.

[P-7]

Receptor-Based Discovery of Novel and Highly Selective ERRγ Inverse Agonists Su Hui Yanga, Yifeng Jina, Daulat Bikram Khadkaa, Hueng-Sik Choib, Won-Jea Choa* aCollege

of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, Korea, b School of Biological Sciences and Technology, Chonnam National University, Gwangju 500-757, Korea

Estrogen-related receptors (ERRs) are orphan nuclear receptors closely related to estrogen receptors (ERs), and ERRγ is a third subtype receptor of ERRs. ERRγ is highly expressed in a number of adult human tissues, including the brain, kidney, pancreas, and placenta. Interestingly, its various biological functions have been reported; for example, ERRγ-positive status in breast cancer cells may indicate a favorable prognosis in human breast cancer. Due to its potential roles in cancers, ERRγ has been of great interest and there have been several attempts to develop agonists or inverse agonists toward ERRγ. However, considering the limited selectivity and specificity of the developed ligands, it is essential to identify selective small-molecule ligands for ERRγ in order to explore the specific functions of ERRγ in a biological system. With the goal of discovering an ERRγ inverse agonist with enhanced selectivity over ER, receptor-based virtual screening was applied by using chemical library through docking algorithm, SurflexDock. The new lead, CWJ-SIR1, showed strong inhibition effect on ERRγ with dose-dependency and specifically inhibited not other nuclear receptors, ER, and even ERR or ERRβ but rather well inhibited ERRγ. In addition, computational docking study demonstrated that the lead CWJ-SIR1 has two hydrogen bonds for strong binding affinity and occupies the bulky binding pocket of ERRγ for increased selectivity, providing a new insight into the rational design of selective ERRγ inverse agonists. All findings suggest that CWJ-SIR1 can be a potential lead for development of novel and highly selective ERRγ inverse agonists

[P-8]

Discovery and Synthesis of New JAK2 Inhibitors Chao Zhao, Su Hui Yang, Daulat Bikram Khadka, Suk Hee Cho, Yi Feng Jin, Won-Jea Cho* College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, Korea

JAK2 is a member of the Janus kinases (JAKs), which are intracellular nonreceptor protein tyrosine kinases including Jak1, Jak2, Jak3, and Tyk2. JAK2 phosphorylates specific tyrosine and serine residues of the JAK2 receptor, creating docking sites for the signal transducers and activators of transcription (STATs). Then, STATs bind the receptor, allowing JAK2 in turn to phosphorylate STATs. Finally, phosphorylated STATs are dissociated from the receptor, form dimers, and translocate into the nucleus, where gene transcription is regulated. Structurally diverse ninety-one compounds containing the nicotinamides, bis-amides and quinazolines were tested for JAK2 inhibition. The strongest compounds, WJ042 and WJ023, were further investigated for inhibition effect on STAT3 phosphorylation and target gene expression, and they strongly reduced JAK2 activation, subsequent STAT3 phosphorylation, and anti-apoptotic protein levels. Intriguingly, these compounds showed strong cytotoxicity in a dosedependent manner. This good correlation between JAK2/STAT3 inhibition and cytotoxic effect of the compounds demonstrates the nicotinamides and bisamides would be potential leads for developing inhibitors of JAK2/STAT3 signaling pathway as antitumor agents.

[P-9]

A Facile Route to Isoflavone Quinones via the Direct Cross-Coupling of Chromone and Quinones Youngtaek Moon, and Sungwoo Hong* Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 305-701, Korea

The family of isoflavone quinones has been extensively investigated due to its broad range of remarkable biological activities. Isoflavone quinone scaffolds are useful and versatile building blocks and, therefore, provide target systems for synthetic chemists. Despite significant synthetic efforts, existing methods for preparing the scaffolds suffer from multiple steps, and harsh reaction conditions. In view of the high synthetic utility of isoflavone quinone derivatives, the most straightforward method for synthesizing the compounds would involve a direct cross-coupling of chromones with quinones via C-H bond functionalization. We developed an efficient method for preparing isoflavone quinones via a palladium-catalyzed direct C-C coupling reaction. This approach provides facile and affordable access to isoflavone quinone structural motifs, which are privileged and prevalent structures in many biologically active compounds. The beneficial effects associated with the use of AgOAc were clearly observed in this cross-coupling reaction. This method represents an unprecedented example of the direct coupling of chromones with quinones and a significant advance over existing methods.

[P-10]

Synthesis and Biological activities of 2,3Dihydronaphtho[1,2-b]furan-2-carboxamide Derivatives Young Sik Hwang, Da Young Kim, Jae-Hwan Kwak, Sri Hari G., Minho Choi, Hyeju Jo, Jae Young Lim, Jae-Kyung Jung and Heesoon Lee* College of Pharmacy and Medical Research Center (MRC), Chungbuk National University, Cheongju 361-763, Korea

Nuclear facter-kB (NF-kB) is one of important transcription factors, because it is relaterd to the regulation of immune, inflammatory responses, and diverse human diseases. Therefore, NF-kB has been considered as one of the major targets for anti-inflammatory agents and antitumor agents. During the search for compound can inhibit NF-kB in our previous study, it was found that benzofuran- or 2,3-dihydrobenzofuran-2-carboxylic acid N-(subsituted)phenylamide derivatives inhibited NF-kB activation. In this study, based on structure-activity relationship (SAR), benzofuran skeleton of the lead compound was modified to a 2,3-dihydronaphtho[1,2-b]furan ring system. Hence, we synthesized that combine several aniline group with 2,3-dihydronaphtho[1,2-b]furan moiety, and evaluated the NF-kB inhibition activity of new compounds.

[P-11]

1-Step enantioselective Synthesis of (+)Tetrabenazine Lim Jae Young, Kwak Jae-Hwan, Choi Minho, Jo Hyeju, Hwang Young Sic, Kim Da Young, Lee Heesoon, Jung Jae-Kyung* College of Pharmacy and Medical Research Center(MRC), Chungbuk National University, Cheongju 361-763, Korea

Tetrabenazine is an only drug used for the treatment of Huntington's chorea and other hyperkinetic movement disorders. The primary pharmacological action of TBZ is to deplete levels of monoamines (e.g. dopamine, serotonin, and norepinephrine) by binding to the central, presynaptic, intravesicular portion of the vesicular monoamine transporter2 (VMAT2). This transporter is predominantly expressed in the brain and translocates monoamines from cytoplasm into synaptic vesicles, where they are both stored and protected from metabolism prior to their synaptic release. Herein, 1-step enantioselective synthesis of (+)TBZ is reported, which use asymmetrical organic catalyst.

[P-12]

Synthesis and Biological Evaluation of Pheophorbide-a Conjugates as Potential Cancer Diagnostic and Therapeutic Agents Hyun You,1 Sung-Min Kwon, 3 Jung-Hoon Yoon,3 Hyojin Ko1 and YongChul Kim1,2 1Department

of Medical System Engineering (DMSE), of Life Science, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea, 3Department of Pathology and Research Center for Oral Disease Regulation for the Aged, School of Dentistry, Chosun University, Gwangju, Republic of Korea

2School

Pheophorbide-a, a chlorine based photosensitizer known to be selectively accumulated in cancer cells, was conjugated with anticancer drugs, doxorubicin and paclitaxel in the purpose of selective cancer diagnosis and therapy. Pheophorbide-a was conjugated with anticancer drugs via directly and by the use of selective cleavage linkers in cancer cell. The fluorescence of pheophorbide-a and doxorubicin conjugate was greatly diminished possibly by the energy transfer mechanism between two fluorescent groups. However, upon treatment in cancer cells, the conjugate showed to be cleaved to restore each fluorescence of pheophorbide-a and doxorubicin after 48 h of incubation. Also, pheophorbide-a conjugates either with doxorubicin and paclitaxel inhibited the growth of various cancer cells more potently than pheophorbide-a, which displayed very weak inhibitory activity. And tumor growth was delayed by the conjugates with intratumoral dose of the drug. The results indicated that the pheophorbide-a conjugates with anticancer drugs could be utilized for selective cancer therapy as well as for the fluorescence detection of cancer.

[P-13]

Design, Synthesis, and Evaluation of 3,5Disubstituted 7-Azaindoles as Trk inhibitors with Anticancer and Antiangiogenic Activities Jinhee Kima, Seunghee Honga,Ju Hyeon Seob, Kyung Hee Jungb, Soon-Sun, Hong b*, and Sungwoo Hong a* aDepartment

of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 305- 701, Korea, bDepartment of Biomedical Sciences, College of Medicine, Inha University, Incheon, 400-712, Korea.

[P-14]

Synthesis of pyrimidineylimidazole scaffold as novel B-Raf Kinase Inhibitors based on SBDD Minjung Kim, Hyangmi Kim, Kyungjin Jung, Jung-Mi Hah* Department of Pharmacy, College of Pharmacy, Hanyang University 1271 Sa 3-Dong, Sangnok-gu, Ansan-si, Gyunggi-do 426-791, Korea

The ‘Ras/Raf/Mek/Erk pathway’ is a well-known cell signaling network for cell survival, growth, and proliferation. The Ras proteins are membrane-bound small G-protein, whereas Raf, Mek, and Erk are cytosolic protein kinases that compose a sequential signaling cascade. Out of these complicated cascade, Raf kinase has been the most studied drug target since mutations of the Raf protein were found in approximately 7% of human cancers with particularly high frequency in melanoma (50–70%), ovarian (35%), thyroid (30%), and colorectal (10%) cancers. The discovery of the most frequent V600E (>85%) B-Raf mutations in 50% of melanoma have raised the expectation for targeted therapy. The V600E B-Raf mutations show a 500-fold increase in catalytic activity, providing cancer cells with both proliferation and survival signals. Therefore, B-Raf V600E is a high-interest therapeutic target for the treatment of human cancers. Generally, in addition to the ATP binding site, Type II inhibitors also utilize additional allosteric site made possible by the DFG (Asp-Phe-Gly) residues of the activation loop being folded away in an inactive conformation of kinase. Since the amino acids in this secondary pocket are less similar with those in the ATP binding pocket between kinases, type II kinase inhibitors can achieve selectivity. X-ray crystal structure of V600E B-Raf kinase and sorafenib showed that the inhibitor held the activation segment in an inactive conformation, preventing ATP binding and subsequent kinase reaction. we designed a novel scaffold for bRaf inhibitor that occupies the unique secondary hydrophobic pocket in inactive conformation of kinase domain as a Type II inhibitor. Pyrimidineylimidazole derivatives, which designed based on this rationality and synthesized

[P-15]

Synthesis of a Class of Indole Derivatives as Modulator of Human Stem Cells Guanghai Jin, Yan Xia, Hyunkyung Choi, Ravi Naik, Xuezhen Xu, Seohyun Son, Kyeong Lee* College of Pharmacy, Dongguk University-Seoul, Korea

Small molecules that modulate specific signaling pathways and epigenetic modifications have been a major focus to control stem cell fate and function, especially for the maintenance and/or reacquisition of pluripotency and differentiation. Identifying small molecules effective for somatic cell reprogramming and/or supporting hESC/hiPSC pluripotency would provide a better understanding of pluripotency and improve reprogramming technology that, if coupled with scalable, defined, and safe culture conditions, would result in a higher quality yield of hiPSCs. Here we present a novel and effective indole derivatives that facilitates the maintenance of pluripotent hESCs and hiPSCs as well as functions as a potent chemical booster for human somatic cell reprogramming via improving reprogramming efficiency and kinetics.

[P-16]

Synthesis of 5-(Substituted benzylidene) thiazolidine-2,4-dione Derivatives and Antimelanogenesis Yu Min Song, Yun Jung Park, Young Mi Ha, Daeui Park, Ji Young Park , Hye Jin Lee, Ji Yeon Lee, Pusoon Chun1, Hyung Ryong Moon* and Hae Young Chung* College of Pharmacy, Pusan National University, Busan 609-735, Korea, 1College of Pharmacy, Inje University, Gimhae, Gyeongnam 621-749, Korea

In continuing our search for novel tyrosinase inhibitors, a series of 5(substituted benzylidene)thiazolidine-2,4-diones were rationally designed and synthesized, and their inhibitory effects on mushroom tyrosinase activity were evaluated. Twelve target compounds 2a–2l were designed and synthesized based on the structural characteristics of N-phenylthiourea, a tyrosinase inhibitor, and tyrosine and L-DOPA, the natural substrates of tyrosinase. Among them, (Z)-5-(4-hydroxybenzylidene)thiazolidine-2,4-dione (2a) and (Z)-5-(3hydroxy-4-methoxybenzylidene)thiazolidine-2,4-dione (2f) exhibited much higher tyrosinase inhibitory activities, with IC50 values of 13.36 and 9.87 µM, respectively, than kojic acid (IC50 = 24.72 µM). Kinetic analysis of tyrosinase inhibition revealed that 2a and 2f are competitive inhibitors of mushroom tyrosinase. In addition, through prediction of the potato catechol oxidase tertiary structure and simulation of docking with compounds 2a and 2f using DOCK6, we found that these inhibitors likely bind to the active site of the enzyme. Docking simulation results suggested that 2a and 2f have high binding affinities with potato catechol oxidase. In addition, compounds 2a and 2f effectively inhibited tyrosinase activity and reduced melanin levels in B16 -melanocyte-stimulating hormone (α-MSH). These data stronglycells treated with suggest that compounds 2a and 2f suppress the production of melanin via the inhibition of tyrosinase activity.

tyrosinase and its transcription factor, MITF, through cAMP, which regulates protein kinase A. This study strongly indicates that the depigmenting effect of MHY384 results from the downregulation of MITF and tyrosinase through direct tyrosinase inhibition. Our findings suggest that MHY384 can be an effective skin-whitening agent.

[P-17]

Synthesis of (2RS, 4R)-2-(2,4-Dihydroxyphenyl) thiazolidine-4-carboxylic acid (MHY384) as a Novel Tyrosinase Inhibitor Yu Min Song, Yun Jung Park, Yu Kyeong Han, Young Mi Ha, Daeui Park, Ji Yeon Lee, Jeong Hyun Yoon, Pusoon Chun1, Hyung Ryong Moon* and Hae Young Chung* College of Pharmacy, Pusan National University, Busan 609-735, Korea, of Pharmacy, Inje University, Gimhae, Gyeongnam 621-749, Korea

1College

We synthesized (2RS,4R)-2-(2,4-dihydroxyphenyl)thiazolidine-4-carboxylic acid (MHY384) as a potential tyrosinase inhibitor and investigated its antityrosinase activity. The structure of MHY384 was established using 1H and 13C NMR spectroscopy and mass spectral analyses. To investigate dual mechanisms of action of MHY384 for the inhibition of melanin synthesis, we confirmed the inhibitory effect of tyrosinase catalytic activity of MHY384. Then, we confirmed the inhibitory effect of MHY384 on transcription of tyrosinase mRNA through alpha-MSH-induced cAMP–PKA–MITF signaling. In addition, we supported the inhibitory mechanism of MHY384 against tyrosinase using a kinetic study and docking programs. To determine how MHY384 regulates melanogenesis, we measured melanin levels and expression of the genes for microphthalmia-associated transcription factor (MITF) and tyrosinase in αmelanocyte-stimulating hormone (α-MSH)-induced B16F10 melanoma cells. MHY384 potently inhibited tyrosinase activity and melanin production in B16F10 melanoma cells. Through docking models, we were able to construct the tertiary structure of mushroom tyrosinase and simulate its docking with MHY384. The result supports that MHY384 strongly interacts with tyrosinase residues in the active site and it can directly inhibit tyrosinase. To investigate additional mechanisms of action of MHY384, we confirmed that the inhibition of tyrosinase activity was found to be due to the modulation of the expression of

[P-18]

Design and Synthesis of Novel Dihydrobenzofuro [4,5-b][1,8] naphthyridin-6-one Derivatives as Potent Anticancer Agents Ji Yeon Lee, Jin-Ah Kang, Zunhua Yang, Umasankal De, Ji Young Park, Hye Jin Lee, Yun Jung Park, Pusoon Chun1, Hyung Sik Kim, Lak Shin Jeong2 and Hyung Ryong Moon* College of Pharmacy, Pusan National University, Busan 609-735, Korea, 1College

of Pharmacy, Inje University, Gimhae, Gyeongnam 621-749, Korea,

2College

of Pharmacy, Ewha Womans University, Seoul 120-750, Korea

On the basis of the chemical structures of psorospermin with a xanthone template and acronycine derivatives with an acridone template, rac-1 and rac-2 constructed on an 1,2-dihydrobenzofuro[4,5-b][1,8]naphthyridin-6(11H)-one scaffold were designed and synthesized as potential anticancer agents. The plausible protonated nitrogen atoms at 10- and/or 11-positions of rac-1 and -2 bearing an oxiranyl substituent as a potential electrophile in biological pH might increase the binding affinity with the DNA helix. Anticancer activities of rac-1 and rac-2 were evaluated against human prostate cancer cell lines (LNCaP, DU145 and PC3) and breast cancer cell lines (MCF-7 and doxorubicin-resistant MCF-7/ ADR). Rac-2 showed similar anticancer activity to doxorubicin and rac-1 exhibited even higher anticancer activity against LNCaP (IC50 = 0.14 µM), DU145 (IC50 = 0.15 µM), PC3 (IC50 = 0.30 µM) and MCF-7 (IC50 = 0.26 µM) cancer lines than doxorubicin and rac-2. Also, rac-1 revealed very potent anticancer activity (IC50 = 0.15 µM) against MCF-7/ADR cell (doxorubicin-resistant breast cancer cell) lines. Moreover, we examined the effect of rac-1 and rac-2 on regulation of cell cycles against MCF-7/ADR cell lines with Flow cytometry. Rac-1 was found to induce G2/M phase arrest of the cell cycle in MCF-7/ADR cells.

[P-19]

Synthesis of 2-(Substituted phenyl)thiazolidine-4carboxylic acid Derivatives and Their Evaluation for Antityrosinase Activity Yu Min Song, Yun Jung Park, Young Mi Ha, Ji Yeon Lee, Daeui Park, Yeon Ja Choi, Ji Young Park, Hye Jin Lee, Pusoon Chun1, Hyung Ryong Moon* and Hae Young Chung* College of Pharmacy, Pusan National University, Busan 609-735, Republic of Korea, 1College of Pharmacy, Inje University, Gimhae, Gyeongnam 621-749, Korea

Herein we describe the design, synthesis and biological activities of 2(substituted phenyl)thiazolidine-4-carboxylic acid derivatives as novel tyrosinase inhibitors. The target compounds 2a–2j were designed and synthesized from the structural characteristics of N-phenylthiourea, tyrosinase inhibitor and tyrosine, and L-DOPA, the natural substrates of tyrosinase. Among them, (2R/ S,4R)-2-(2,4-dimethoxyphenyl)thiazolidine-4-carboxylic acid (2g) caused the greatest inhibition 66.47% at 20 µM of L-DOPA oxidase activity of mushroom tyrosinase. Kinetic analysis of tyrosinase inhibition revealed that 2g is a competitive inhibitor. We predicted the tertiary structure of tyrosinase, and simulated the docking of mushroom tyrosinase with 2g. These results suggest that the binding affinity of 2g with tyrosinase is high. Also, 2g effectively inhibited tyrosinase activity and reduced melanin levels in B16 cells treated with α-MSH. These data strongly suggest that 2g can suppress the production of melanin via the inhibition of tyrosinase activity.

[P-20]

Rapid and Facile Synthesis of Îą-1, 2, 3Triazoloamide Derivatives on Solid Support Doohyun Lee1, Young-Dae Gong2, and Taeho Lee1* 1College

and

of Pharmacy, Kyungpook National University, Daegu 702-701, Korea of Chemistry, Dongguk University, Seoul 100-715, Korea

2Department

Solid-phase organic synthesis has emerged as a powerful technique in generating combinatorial libraries of small organic molecules useful for drug discovery. Recently, Sharpless and co-workers have reported remarkable high-yielding syntheses of 1,2,3-triazoles with excellent regioselectivity using a Cu(I)-catalyzed [3+2] cycloaddition reaction. This reaction has become a powerful method for generating combinatorial libraries and has found increasing applications in lead discovery and lead optimization. Herein, we describe recent progress on the first solid-phase synthetic protocol for the preparation of Îą-1,2,3triazoloamides, which is applicable to high throughput construction of drug-like compound libraries. The strategy allows for a ready access to a large library and is potentially applicable to the preparation of other 1,2,3-triazole derivatives.

[P-21]

Solid-Phase library synthesis of Quinolinone Derivatives Seung hwa Kwak1, Hyun You2, Hyojin Ko2, Yong-Chul Kim1, 2 1School

of Life Science, 2Department of Medical System Engineering (DMSE), Gwangju Institute of Science and Technology, Gwangju 500-712, Republic of Korea

Chemical synthesis of quinolinone is flexible and can be easily adapted to new structure so we tried to synthesis of novel quinolinone derivatives with use of solid phase synthesis. 3,5 - substituted quinolinone which was prepared from 2-amino-6-nitro benzoic acid has been loaded to the 4-formyl-3,5dimethoxyphenoxy(PL-FDMP) resin with high efficiency of reductive amination. Various amine and acid chloride were used for the reaction affording the 3,5-substituted position of the quinolinone compound in a high purity which was analysis by mass. Library of novel quinolinone derivatives will be tested for the various target molecules for finding a new drug.

[P-22]

Synthesis and Biological Evaluation of Hydrid analogs of Chalcone and Chromone as Inhibitors of interleukin-5 Eeda Venkateswararao1, Vinay Kumar Sharma1, Hyun-sun Yang1, Manickam Manoj1, Ki-Cheul Lee1, Hoon-Seok Yoon2, Young-Soo Kim2, SangHun Jung1,* 1

College of Pharmacy and Institute of Drug Research and Development, Chungnam National University, Deajeon 305-764, Korea, 2College of Pharmacy, Chungbuk National University, Cheongju 361-763, Korea

Asthma disease is mainly characterized by airway obstruction, bronchial inflammation, which is affecting ocer 15 million people in the United States. Activated T cells produce Interleukin(IL)-4, (IL)-5, monocyte chemotactic protein (MCP)-1, (MCP)-2, Whereas IL-5 is responsible for growth, differentiation, activation and survival of eosinophils. Several studies show that increased accumulation of eosinophils on blood and inflamed tissues is a characteristic feature of the major allergic disease such as bronchial asthma, rhinitis and atopic dermatitis. It was observed that IL-5 antibodies have confirmed the key role of IL-5 in the process of eosinophilia, inflammation, and/or tissue alterations in response to an allergic challenge, this suppression or antagonism of proallergic cytokines may represent a viable approach for the treatment of asthma. Since in our previous study we found the IL-5 inhibitory activity in chalcones and chromones, we designed and synthesized the hydrid of chalcone and chromones and studied their structural acticity relationship for the IL-5 inhibition.

[P-23]

Synthesis and Anticancer activity of Peroxiredoxin inhibitors through a ROS-mediated mechanism Jail Goo,a Seong Chen Lee,a Yeon Ju Yang,b Jin Young Baek,b Sun Hee Han,b Tong-Shin Changb,* Yongseok Choia* aCollege

of Life Sciences and Biotechnology, Korea University, Seoul, Korea. bDivision of Life & Pharmaceutical Sciences and Center for Cell Signaling & Drug Discovery Research, Ewha Womans University, Seoul, Korea

Most cancer cells exhibit an increase in reactive oxygen species (ROS) generation, which enable to maintain their malignant phenotypes. Cancer cells, under oxidative stress associated with increased metabolic activity and production of ROS, are highly dependent on antioxidant system for survival and thus more susceptible to oxidative insults by ROS-stressing agents than normal cells. Peroxiredoxin (Prx), the novel H2O2 eliminating enzyme, is known to be elevated in a variety of human cancers. Recent studies have suggested that this biochemical property of Prxs in cancer cells can be exploited for therapeutic benefits. In our search for novel anticancer agents to inhibit Prx I, it was found that N-(3-acetylphenyl)-4-(biphenyl-4-ylmethyl)piperidine-1-carboxamide effectively inhibits the reduction of Prx I from cysteine sulfenic acid to cysteine sulfhydryl acid through interruption of electron transfer from reducing system and causes severe ROS accumulation in cancer cells. Further biochemical study suggests that the Prx-mediated H2O2 elimination may serve as a novel therapeutic target for cancer intervention. Herein, the structure-activity relationships and biochemical study of the piperidine-1-carboxamide derivatives will be presented.

[P-24]

Synthesis of Benz-Annulated Tryptanthrins and Their Biological Properties Hyo Chang Cha 1, Jing Lu Liang1, So-Eun Park2, Youngjoo Kwon2, Yurngdong Jahng1,* 1College

of Pharmacy, Yeungnam University, Gyeongsan 712-749, Korea. 2College of Pharmacy & Division of Life & Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750, Korea

Althought tryptanthrin was first reported as a sublimation product of indigo, later was isolated as an alkaloid from the culture of the yeast Candida lipolytica and from the petroleum extract of dried and powdered fruit of Couroupita guaianensis Abul.. A variety of biological properties have been reported since the discovery. As a part of our interest in derivatization of simple alkaloids as well as in the effect of benzoannulation on the chemical and/or biological properties spurred us to prepare a series of benzo-annulated derivatives of tryptanthrin. Optical, redox, and biological properties of them were studied. Tryptanthrin and its benzo-annulated derivatives showed selective inhibitory activity on topo I with an increase of activity on topo II by benzo-annulation on quinazolin4(3H)-one moiety. Although the benzo-annulation on quinazolin-4(3H)-one ring did not affect significantly on the inhibitory activities against topo I and II, the benzoannulation on indolin-3-one ring affected the inhibitory activity very much especially by linear annulation. Cytotoxicities were not significantly changed upon benzoannulation, which were not directly related either to the inhibitory activities against topo I and II or to the reduction potentials.

tives having arylsulfones and the ionizale nitrogen was N-methyl piperazine. All the synthesized compounds were evaluated in vitro against the human recombinant 5-HT6 serotonin receptor. The functional efficacy of each compound was evaluated by measuring the cAMP level using HER 293 cells stably expressing the recombinant human 5-HT6 receptor. Some of the prepared compounds showed IC50 value of 1.02-5.03 ÂľM .

[P-25]

5HT6 Receptor Antagonists: Synthesis and Biological Evaluation of some Heterocyclic Compounds

Faisal Hayata, Hyewhon Rhimb, Darong Kima, Hea-Young Park Chooa aCollege

of Pharmacy & Division of Life & Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750, Republic of Korea. bCenter for Neuroscience, Korea Institute of Science & Technology, PO Box 131, Cheongryang, Seoul 130-650, Republic of Korea

The serotonin (5-HT) receptors have been subdivided into seven main classes (5-HT1-7). The 5-HT6 serotonin receptor is one of the most recent incorporations to this family. Its a G-protein-coupled receptor (GPCRa) predominantly expressed in the central nervous system (CNS). It has been demonstrated that antagonism of the 5-HT6 receptor modulates the release of a wide variety of neurotransmitters including elevating extracellular levels of both glutamate and acetylcholine in brain regions such as the medial prefrontal cortex (mPFC) and the hippocampal formation (HPC). Consequently, the predominant distribution of the 5-HT6 receptor population in the brain, combined with its high affinity for certain CNS drugs, has stimulated extensive research to discover new druggable targets and to elucidate a clearer picture of the role of the 5-HT6 receptor in cognition and learning as well as certain types of neuropsychological and neuropsychiatric diseases such as affective and eating disorders, schizophrenia, and Alzheimerâ&#x20AC;&#x2DC;sdisease. Based on the reported pharmacophore models, we designed two series of compounds. In first series of compounds, we synthesized 7 benzoisothiazole derivatives having the arylsulfonamides, in which an ionizable nitrogen was introduced as N,N-dimethylformimiamide. And in second series we synthesized 13 (Z)-(2-methyl-1H-indol-3-yl)-N-(4-methylpiperazin-1-yl)methanimine deriva-

[P-26]

Synthesis and Biological Evaluation of Novel Pyrimidine Derivatives as Potent GPR119 Agonists for the Treatment of Type 2 Diabetes Tuan-Anh N. Phama, Yuanying Fanga, Zunhua Yangab, and Haeil Parka aCollege

of Pharmacy, Kangwon National University, Chuncheon 200-701, Republic of Korea, bCollege of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang 330004, China

GPR119 is a G protein-coupled receptor predominantly express on pancreatic beta cells and intestinal enteroendocrine cells. Agonist to GPR119 stimulates glucose-dependent insuline secretion in vitro and lowers an evaluated blood glucose level in vivo. Additionally, they have been demonstrated to stimulate the release of the increatin (GLP-1 and GIP). Therefore, GPR119 agonist has emerged as a promising therapeutic approach for the treatment of type 2 diabetes. As a part continuing structural elaboration and searching more potent GPR119 agonists, we became interested in the pyrimidine derivatives 1 as a lead structure. A series of novel pyrimidine derivatives in which bicyclic scaffolds were replaced for the piperidine scaffold in 1 were synthesized and found to be potent agonists of human GPR119 receptor (hEC50 = 1.4 - 110.2 nM).

of sophoricoside is not needed for the activity. Highly effective antagonism of select JSH compound on asthma reaction in murine model comes through the anti-eosinophilic activity, which implies the possibility of this compound as a good candidate for anti-asthma medicine as an inhaler. Detail exploration of the stucture activity relationship of these isoflavones in the inhibition of IL-5 bioactivity will be discussed with in vivo study.

[P-27]

Study on the Pharmacophore of Isoflavonoid as Interleukin-5 Antagonist for Finding Novel AntiAllergic Agent Hyun-sun Yang 1, Ki-Cheul Lee1, Santhosh Subramanian1, Manickam Manoj1, Eeda Venkateswararao1, Sang-Hun Jung1, b* 1 College

of Pharmacy, Chungman National University, Deajeon 305-764, Korea

Interleukin (IL)-5 appears to be one of the main proinflammatory mediators among a growing number of cytokines and chemokines that induce eosinophilic inflammation. Interfering with the action of IL-5 represents one of the new immunomodulatory therapeutic atrategie in the treatment of allergic dieases including bronchial asthma. Compared to establiched immunosuppressive agents like corticosteroids, a major advantage of this strategy is the specificity of reducing eosinophilic inflammation, thus possibly acting nearly without side effects. However small organic compounds to inhibit IL-5 activity have been rarely found. Our screening effort with natural products resulted in identification of sophoricoside and its analogs isolated from Sopora japonica, a plant of Leguminosae family, as novel and selective inhibitors of interleukin (IL)-5 bioactivity with differential inhibition of IL-3 and GM-CSF bioactivities. However sophoricoside is chemically and metabolically unstable glycoside and thus is required to formation of stable analogs as a candidate. Therefore, structural requirements of this isoflavonone for its inhibitory activity against IL-5 were investigated by design and preparation of novel isoflavonones and their glycosides. The necessary structural features of these isoflavonone analogs conprise a planar chromen-4-one ring, the existence of hydrogen bonding acceptor at 4-position of B ring, and introduction of hydrophobic groups at 5 posotion, which might adjust permeability of these isoflavones. However, the glycopyranosyl moiety

regioisomers were found during synthesis such as 2arylsulphonyltetrahydropyrimidones, which are not active.

[P-28]

Tubulin inhibitors like colchicine, combretastatin, paclitaxel, epothilone A and vinblastine exhibit anticancer properties by interfering with the dynamics of tubulin polymerization and depolymerisation resulting in mitotic arrest. However, the clinical use of all these antitubulin agents is associated with problems of drug resistance, toxicity, and bioavailability. In our earlier study we have explored that N-arylsulfonylimidazolones are potent antitubulin agents. The current investigation is on the modification of the N-arylsulfonylimidazolones to N-arylsulfonylpyrimidones and N-arylsulfonyltetrahydropyrimidones as anticancer agents. Based on investigation, we found that 1-(indolin-5-ylsulfonyl)-4phenylpyrimidin-2(1H)-one and 4-phenyl-1-(1-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroquinolin-6-ylsulfonyl)py rimidin-2(1H)-one showed moderate activity against human cancer cell lines namely, ACHN, HCT15, MDA-MB-231, NCI-H23, NUGC-3 and PC-3. Some critical points were elicited from these results. Compared to Narylsulfonyltetrahydropyrimidones, N-arylsulfonylpyrimidones showed better activity, whereas solubility of the N-arylsulfonylpyrimidones compounds has to be improved by introducing some hygrophilicity on the indoline or the quinolone ring. Their planarity of pyrimidone and bulky N-arylsulfonyl group of N-arylsulfonylpyrimidones are crucial for their anticancer activity. The other

[P-29]

Asymmetric Synthesis of a Bioactive Substance from Zingiber cassumunar Roxb. via Highly Enantioselective Diels-Alder Reaction Yuanying Fang a, Zunhua Yang a, b, Byung-Soo Kim a and Haeil Park a a College

of Pharmacy, Kangwon National University, Chuncheon 200-701, Republic of Korea, b College of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang 330004, China

A novel bioactive phenylbutenoid dimer, (Âą)-trans-3-(4-hydroxy-3-methoxyphenyl)-4-[(E)-3,4-dimethoxystyryl] cyclohex-1-ene (A) was isolated from Zingiber cassumunar Roxb., the tropical ginger widely distributed in Southeast Asia. The extracted oil of this herb was known as Plai oil in Thailand and was used as massage oil by massage therapists. The phenylbutenoid dimer (A) was reported to possess anti-inflammatory and cytotoxic activities. Therefore, it has been an interesting target to develop an efficient synthetic pathway and conducting structure-activity relationship study for medicinal chemists. Inthis presentation, asymmetric synthesis of a bioactive substance (A) from Zingiber cassumunar Roxb. will be described. Optically active cyclohexene ring fragment was constructed via hignly enantioselective Diel-Alder reaction of chiral acryloyloxazolidin-2-one chiral auxiliary and TiCl4 lewis acid were used(100.0%e.e.). The bioactive compound A was achieved from the optically active Diel-Alder adduct in 2 steps.

[P-30]

Synthesis of Aurones as Acetylcholinesterase Inhibitors Young-Hun Lee, Sang-Min Oh, Jong-Hoon Ryu, and Yong-Sup Lee* Department of Life and Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul 130-701, Korea

Alzheimerâ&#x20AC;&#x2122;s disease, one of the most common forms of dementia, is a progressive neurodegenerative disorder symptomatically characterized by the decline in memory and cognitive abilities. One of the major causes of the memory impairments in Alzheimerâ&#x20AC;&#x2122;s disease patients is a deficit in cholinergic neurotransmission in the brain area caused by degeneration of cholinergic neurons. To date, the successful therapeutic strategy to treat Alzheimer's disease is to maintain the levels of acetylcholine by inhibiting acetylcholinesterase responsible to the degradation of neurotransmitter acetylcholine. A series of novel aurone derivatives linked with aminoalkyl moiety was synthesized and they were evaluated for acetylcholinesterase inhibitory activity. The ameliorating effects of aurones on scopolamine-induced memory impairments will be also presented.

[P-31]

Synthesis of Chiral Ru Complexe and their DNA Cleaving Activity Moinul Karim, Hasan, Fakhrul, Yurngdong Jahng* College of Pharmacy, Yeungnam University, Gyeongsan 712-749

Ruthenium complexes of polypyridines have long been of interest due to their potentials for various physicochemical and biological properties. However, studies on ruthenium complexes of tridentates are reletively limited due to the achirality of the RuL 2-type (L = tridentate) complexses. Chirality on ruthenium complexes of tridentates can be induced by either employing unsymmetriic tridenates for RuL 2 -type complexes or mixed complexes such as RuLL' (L = tridentates and L' = unsymmetric bidentates). We herein described synthesis of unsymmetric tridentates, chiral RuLL'-type complexes, O=RuLL'-typecomplexes, and their biological properties on DNA.

[P-32]

Synthesis of Norlignans and Inhibitory Effect of Antigen-Induced Degranulation Eonjeong Park and In Su Kim* College of Pharmacy, Kyung Hee University, Seoul 130-701, Korea

Norlignans are abundant in the heartwood of many coniferous trees and in some monocotyledonous plants, and possess a wide spectrum of biological activities such as anti-cancer/anti-inflammatory, anti-complement, anti-fungal activity, testosterone 5α–reductase inhibition, and cyclic AMP phosphodiesterase inhibition. Naturally occurring norlignan are a class of natural phenolic compounds with diphenylpentane carbon skeletons (C6–C5–C6). Hinokiresinol, the E-isomer of nyasol, is a typical example of such a norlignan. Hinokiresinol was first isolated from the heartwood of Chamaecyparis obtuse in 1965, and was found to display appreciable estrogen receptor binding activity and some antiplasmodial activity. We recently found that nyasol and its derivatives, isolated from Anemarrhena asphodeloides, act as powerful inhibitors of antigen-induced degranulation, and have the potential to be useful therapies for allergic disorders such as asthma and atopic dermatitis. In view of these interesting biological activities of norlignans, we report here the inhibitory activity of hinokiresionol derivatives including synthetic intermediates on antigen-induced degranulation.

and C-heteroatom unsaturated bonds, (e.g., C=O and C=N bonds), remain relatively unexplored. Herein we describe a rhodium-catalyzed oxidative acylation and intramolecular cyclization of primary benzamides with aryl aldehydes via direct sp2 C–H bond cleavage. In the presence of [Cp*RhCl2]2, AgSbF6, and silver carbonate as an oxidant, primary benzamides can be effectively carbonylated to 3Hydroxyisoindolin-1-ones in good to high yields.

[P-33]

Rh-Catalyzed Oxidative C-H Bond Functionalization of Benzamides with Aldehydes: 3Hydroxyisoindolin-1-ones Satyasheel Sharma and In Su Kim* College of Pharmacy, Kyung Hee University, Seoul 130-701, Korea

3-Hydroxyisoindolin-1-one is an important core structure of numerous natural products and artificially synthesized bioactive molecules, such as chilenine, a natural isoindolobenzazepine alkaloid isolated from Berberis empetrifolia, and fumadensine, an isoquinoline from Fumaria densiflora. Additionally, 3hydroxyisoindolin-1-one moieties have been found in other bioactive molecules such as a Raf kinase inhibitor, an MEK protein kinase inhibitor as well as an HIV integrase inhibitor. 3-Hydroxyisoindolin-1-ones are also useful precursors for synthesis of arylmethyleneisoindolin-1-one compounds, which are important privileged structures of many biological active molecules. In addition, the products of dehydration of 3-hydroxyisoindolin-1-ones have been found to be useful intermediates in the total synthesis of isoindolobenzazepine alkaloids such as lennoxamine. Transition metal-catalyzed direct transformation of inactive C–H bonds has emerged as a powerful tool for the facile production of structurally diverse organic molecules. Since the pioneering efforts of Murai, great progress has been made in transition metal-catalyzed C–H bond functionalization upon trapping with appropriate electrophiles or nucleophiles under oxidative or basic conditions, respectively. In particular, reactions involving the activation of C–H bonds by neighboring directing group have been extensively investigated. As results, the combination of transition metals and directing groups provides efficient conversion of C–H bonds to C–C, C–X, C–O, and C–N bonds. Although carbon–carbon bond formation reactions using unsaturated C=C or C≡C bonds as the coupling partners have been well established, the reactions of C–H bonds

[P-34]

A Concise Total Synthesis of Aerangis Lactone Ae Jin Kim and In Su Kim* College of Pharmacy, Kyung Hee University, Seoul 130-701, Korea

Lactones are important flavor and aroma constituents that are extensively used as additives in food and perfume. Many lactones exhibit interesting biological activities as attractants for pollination and seed germination stimulants. They also act as allergens, pheromones, antiseptics, and cardiotonic agents. In particular, δ-lactones appear as a ubiquitous structural motif in a number of natural products that display a wide range of biological activity. As representative examples of δ-lactones, cis-aerangis lactones and trans-aerangis lactones were first reported by Kaiser in 1993 as the main odoriferous components of the African moth orchids Aerangis confusa and Aerangis kirkii. Later, (–)-cis-aerangis lactone was found to be the sole stereoisomer present in the scent of living white flowering orchids (Aerangis confusa). All four stereoisomers were initially synthesized as a racemic mixture of cis- and trans-isomers through hydrogenation of dihydrojasmone and subsquent Bayer–Villiger oxidation of the cyclopentanone moiety. In this paper, we present a new catalytic strategy for the asymmetric total synthesis of (–)-cis-aerangis lactone and (+)-trans-aerangis lactone, that includes catalytic carbon-carbon bond formations, such as iridium-catalyzed diastereoselective and enantioselective carbonyl crotylation, ruthenium-catalyzed intermolecular or intramolecular metathesis reaction, and the organocatalytic Mitsunobu reaction.

[P-35]

Identification of Histone Methyltransferase G9a Inhibitors by Structure-Based Virtual Screening Jie Chen and Hyun-Ju Park* School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Korea *Corresponding author: hyunju85@skku.edu

G9a (EHMT2), a SET domain-containing mammalian histone methyltransferase, contributes to early embryogenesis, genomic imprinting, lymphocyte development, gene silencing and chromatin regulation through mono- or dimethylate lysine 9 and lysine 27 on histone H3. It is responsible for various human diseases including leukemia, cancer, drug addiction, mental retardation and maintenance of HIV-1 latency. Therefore, G9a has been emerging as a key target for therapeutics. We performed virtual screening of chemical database (ZINC) and in-house natural product database to discover novel G9a inhibitors. First, a 3D structural model of G9a was established, and the docking analysis for known G9a inhibitors was performed for validating reliability. After docking screening of about 9 million compounds, a total of 70 high-ranked compounds were selected. Bioactivities of these hitlist compounds were evaluated by in vitro G9a enzymatic assay and cytotoxicity (MTS) assay. This study resulted in the discovery of novel G9a inhibitors with sub-micromolar IC50 values.

[P-36]

Identification of Ligands for HIV-1 Stem-Loop RNA as Anti-frameshift Agents Youngju Kim, So-Jung Park,* and Hyun-Ju Park* School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Korea; *Corresponding author: sojung1024@gmail.com, hyunju85@skku.edu Programmed -1 ribosomal frameshifting (-1 RF) is an essential common strategy regulates protein expression at translational level in many RNA viruses. Human immunodeficiency virus type 1 (HIV-1) utilizes -1 RF to regulate the expression ratio of Gag to Gag-Pol, which is critical for the production of infectious virion particles. A stem-loop RNA structure is one of essential components of -1 RF site of HIV-1 and its stability and structure is an important in maintaining efficient -1 RF. Thus, small molecules interacting with HIV-1 RNA stem-loop may alter the -1 RF efficiency and have potential as anti-HIV agents. The aim of this study is to search small molecules which alter -1 RF efficiency upon binding to HIV-1 stem-loop RNA. We performed in silico virtual screening of chemical DB. First, the pharmacophore query for 3D database search was determined based on the NMR solution structure of HIV-1 RNA stem-loop in complex with known ligand RG501. The 3D search of ZINC database and in-house chemical and natural products database resulted primary focused compound library. Docking screening of the primary focused library was done by using automated docking programs, such as AutoDock_vina and DOCK6.4. Through docking score analysis, the final candidate compounds were selected, and their effects on HIV-1 -1 RF efficiency were tested by in vitro -1 RF assay.

[P-37]

Stereosynthesis of A-82768 Xiangdan Jin1, Yu Mu1, Won-Hun Ham1,* 1School

of Pharmacy, SungKyunKwan University, Suwon, 440-746, Korea, Email : whham@skku.edu

A-82768, also called as the Abbott amino diol, Which is a core unit as a peptide hydrolysis transition state mimetic, in these potent renin inhibitors like Zankien, Enalkien, etc. The presence of this dihydroxyethlene isostere unit showed an enhancement of oral activity and make the inhibitor the most potent to date. On the basis of our research , an efficient procedure for synthesizing was developed by the palldium(0) catalyzed intramolecular cyclization . We anticipated that might proceed with high stereo-selectivity . According to this , we provides highly enantiomerically and diastereomerically material.

[P-38]

Total Syntheses of (+)-Hyacinthacine A2 and 7Deoxyalexine Seok-Hwi Park, Sung-Soo Kim, Won-Hun Ham* School of Pharmacy, Sungkyunkwan University, Korea, Email : whham@skku.edu

Castanospermum australe, a rainforest tree found in Queensland, Australia, and Alexa leiopetala, a leguminous tree indigenous to Guyana, Surinam, Venezuela, and the Amazon basin, are rich sources of polyhydroxylated pyrrolizidine and indolizidine alkaloids. The alkaloidal components are powerful inhibitors of several glucosidaes, including mammalian intestinal sucrosidase and the glucosidase involved in lysomal glycoprotein procession. Furthermore, the wide variety of biological activities has drawn interest toward these alkaloids present in the pods and seeds of C. australe and A. leiopetala. (+)-Hyacinthacine A2 is a polyhydroxylated pyrrolizidine alkaloid and has continuous four stereocenters in its structure. 7-Deoxyalexine, not been reported as a member of the family of naturally occurring hydroxylated pyrrolizidines, is one of stereoisomers of (+)hyacinthacine A2. From our previous researches, we found highly stereoselective synthetic routes for oxazines using Pd0 catalyst. Their mechanisms are via Ď&#x20AC;-allyl Pd(II) complex intermediates, and Pd0-catalyzed intramolecular cyclizations of benzamides are formed. Several polyhydroxylated pyrrolizidines, including (+)-hyacinthacine A2 and 7-deoxyalexine, are anticipated to be synthesized through our researches.

[P-40] [P-39]

Synthesis and Biological Evaluation Of Rigid Analogues of 2,4,6-Trisubstituted Pyridines

Development of Anti-Coxsackievirus Agents Targeting 3C Protease

Pritam Thapa, Radha Karki, Hanyoung Yoo, Taraman Kadayat, Youngjoo Kwon1, Eung-Seok Lee*

Bo-Kyoung Kim, Na-Ri Kim, Jeong-Hyun Kim, Won-Gil Lee, So-Deok Lee, Yong-Chul Kim*

College of Pharmacy, Yeungnam University, kyongsan 712-749, Korea, of Pharmacy, Ewha Woman’s University, Seoul 120-750, Korea

1College

Life Sciences Gwangju Institute of Science and Technology, Oryong-dong, Bukgu, Republic of Korea

Over the past several years, our research group has been studying 2,4,6trisubstituted pyridine derivatives for their topoisomerase I & II inhibitory activity and cytotoxicity against several human cancer cell lines. These compounds were found to possess considerable topo I and II inhibitory activity as well as cytotoxicity against several human cancer cell lines. As we know, planar structure facilitates the intercalation of compound into DNA, it would be interesting to see the effect of rigidification on the anticancer activity of 2,4,6-trisubstituted pyridines. In addition, rigid structures are commonly considered to have little conformational entropy compared to flexible structures and can be more efficiently fitted into the active site of a receptor. On this basis, we have designed and synthesized compounds containing five or six-membered rigid structures such as benzofuro, chromenopyridine, dihydro-1,10-phenanthroline and dihydrothieno[2,3-h] quinoline. They were studied for their topo I and II inhibitory activity and cytotoxicity against several human cancer cell lines.

Peptidomimetic anti-viral agents against Coxsackievirus B3 (CVB3) were developed using a strategy involving the inhibition of 3C protease (CVB3 3Cpro), a target for CVB3-mediated myocarditis or pericarditis. In an attempt to improve the inhibitory activity against CVB3, a variety of hetero-aromatic groups were incorporated into the α,β-unsaturated ester as Michael acceptor moiety, which was interacted with the cysteine moiety in the P1’ active site of CVB3 3Cpro. Among these heter-oaromatic groups, the quinoline analogs 9c and 9e, with IC50 values 250 and 130 nM as determined from an enzyme assay, significantly inhibited the CVB3-mediated cell cytotoxicity, indicating parallel anti-viral activities. A comparison of the binding modes of the potent inhibitor 9e and the relatively weak inhibitor 9n was explored in a molecular docking study, which revealed that compound 9n lacked hydrogen bonds in its interactions with Gly129, 128, and 145.

Keywords: terpyridine, topoisomerase inhibitor, cytotoxicity, rigid structure

[P-41]

2,4,6-Triaryl Pyridines Containing Chlorophenyl and Phenolic Moiety and Evaluation for Antitumor Activity Han Young Yoo, 1 Minho Yun, 1 Pritam Thapa, 1 Radha Karki, 1 Tara Man Kadayat, 1 Nam Doo Kim, 2 Youngjoo Kwon, 3 and Eung-Seok Lee1, * 1College

of Pharmacy, Yeungnam University, Kyongsan 712-749, Korea Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 706-010, Republic of Korea 3College of Pharmacy & Division of Life & Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750, Korea

2New

Many phenolic or polyphenolic compounds have been reported to have a wide range of biological activities. In addition, previous work by our research group has provided evidence for the importance of the hydroxyl group in 2,4,6trisubstituted pyridines for topoisomerase (topo) inhibitory activity and cytotoxicity. Due to the ability to improve potency, blood brain barrier permeability, and metabolic and chemical stability, the insertion of halogen atoms is widely practiced in drug discovery optimization. In this study, forty-two 2,4,6-triaryl pyridines containing phenolic and chlorophenyl moiety were synthesized. They were evaluated for their topo I and II inhibitory activity and cytotoxicity against several human cancer cell lines. Most of the compounds showed significant topo II inhibitory activity. Structureactivity relationship study showed that furyl, thienyl and phenyl moieties are more important than pyridyl moiety for topoisomerase inhibitory activity. Molecular modeling study of the potent compound with topo I and II showed the similar binding pattern to that of topotecan and etoposide, respectively. Key words: topoisomerase I and II, phenolic, chlorophenyl, 2,4,6-triaryl pyridines, cytotoxicity

[P-42]

Synthesis of Hydroxychalcones as Potential Anti-Angiogenic Agent Taraman Kadayat, Radha Karki, Pritam Thapa, Han Young Yoo, Youra Kang, Jung-Ae Kim, Eung-Seok Lee* College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Republic of Korea

Angiogenesis is a fundamental process by which new blood vessels are formed from existing vessels. It is essential in reproduction, development and wound repair. However many diseases are driven by persistent unregulated angiogenesis such as tumor development, and formation of metastases. In the past decade, anti-angiogenic drug development has attracted more research interest. Hydroxychalcones, abundantly found in nature as the precursors of flavonoids and isoflavonoids, are reported to have several pharmacological activities including anticancer activity. In this study, we systematically designed and synthesized fifteen hydroxychalcones using Claisen-Schmidt condensation reaction where hydroxy group(s) was introduced at various positions (ortho, meta or para) of phenyl rings. These compounds were evaluated for their inhibitory effect on vascular endothelial growth factor (VEGF)-induced angiogenesis in vivo using chick chorioallantoic membrane (CAM). Structure-activity relationship was determined, and dihydroxychalcones were found to be potent antiangiogenic agents. Keywords: hydroxychalcones, vascular endothelial growth factor (VEGF), angiogenesis, chick chorioallantoic membrane (CAM).

[P-43]

Gold-Catalyzed Direct Synthesis of Trisubstituted Isoxazoles Doo-hee Song and Jae-Sang Ryu* Center for Cell Signaling and Drug Discovery Research, College of Pharmacy and Division of Life and Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750, Republic of Korea

The utilization of gold catalysts in the field of organic chemistry is one of the hot topics in current research. Most of these reactions are atom economical and are remarkably mild in most cases. Among these transformations, the intramolecular addition of heteroatom nucleophiles to carbon–carbon multiple bonds play an important role as powerful tool for the synthesis of various heterocycles. Especially, cycloisomerization of α,β-acetylenic oximes leading to isoxazoles has attracted chemists’ attentions due to their interesting biological activities. Thus, the development of new methods for the synthesis of the isoxazole skelcton is an area of considerable ongoing interest. We herein report novel gold-catalyzed cycloisomerization reaction leading to 3,4,5-trisubstituted isoxazoles.

[P-44]

Design and Synthesis of Novel Benzamide Derivatives as Potential Aurora Kinase Inhibitors Jooyeon Lee and Jae-Sang Ryu* Center for Cell Signaling and Drug Discovery Research, College of Pharmacy and Division of Life and Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750, Republic of Korea

Aurora kinases, which are key regulators of mitosis, play a pivotal role in onset and proliferation of cancer. Aurora A is a putative oncogene and responsible for the centrosome amplification and polyploidy. Aurora B is known to phosphorylate histone H3 during mitosis, which may play a role in chromosome condensation. Both are over-expressed in a number of human malignancies including colon, breast, pancreatic, and ovarian tumor. Currently, several aurora kinase inhibitors such as VX680/MK-0457, AZD1152, PHA-739358, and SNS-314 are on the clinical trials and are proved to have an effect on cancer treatment. Herein, we report design and synthesis of new benzamide derivatives tethered to various hinge binders as potential Aurora kinase inhibitors.

[P-45]

Design and Synthesis of New (+)-Decursin Derivatives with Potent Inhibitory Activity of Wnt/βCatenin Pathway Yu-Seok Oh, Jee Hyun Lee, Soo-Hyun Cho, Gyu-Yong Song* College of Pharmacy, Chungnam National University, Daejeon 305-764, Korea

Wnt/β-catenin pathway has a critical role in carcinogenesis. Abnormal subcellular localization and aberrant accumulation of β-catenin are often observed in human cancers, including colorectal cancer. The cellular levels of β-catenin protein are regulated by the ubiquitin-proteasome system and Phosphorylation of β-catenin by GSK3β is essential for the ubiquitination of β-catenin. Initiation of Wnt signaling leads to inhibition of GSK3β-dependent phosphorylation and degradation of β-catenin, activating the β-catenin transcriptional pathway. Aberrant activation of Wnt signaling is common in colorectal cancer. (+)-Decursin is a pyranocoumarin isolated from Angelica gigas, and has been traditionally used not only to treat primarily anemia but also as a sedative reagent. Recently, (+)-Decursin has been known to have antitumor activity. For the development of more effective agents with inhibitory Wnt/β-catenin pathway, the six series of (+)-decursin derivatives were synthesized and evaluated for their antitumor activity. Among them, SLC-B034, which was substituted 3,4dihydroxy cinnamoyl group in secondary alcohol of (+)-decursinol, showed the strongest inhibitory activity (99.5%) for Wnt/β-catenin pathway and antagonized dose-dependently in Wnt-3a CM-induced CRT. Furthermore, SLC-B034 inhibited perfectly PC3 tumor growth at 100mg/kg and inhibited over 80% at 50mg/kg in vivo test of athymic mude mice bearing established s.c. PC3 xenograft tumors. And all mice tolerated the treatment without observable signs of toxicity.

[P-46]

Synthesis and Biological Evaluation of α, βUnsaturated Lactones as Potent Immunosuppressive Agents Sun-mi Leea, Won-Gil Leeb, Yong-Chul Kima, b, Hyojin Koa* a Department

of Medical System Engineering (DMSE), Gwangju Institute of Science and Technology (GIST), Gwangju 500-712, Republic of Korea, b School of Life Science, Gwangju Institute of Science and Technology(GIST), Republic of Korea

α,β-Unsaturated lactone moieties display a variety of biological activities, including in the context of HIV, as protein phosphatase inhibitors, as antioxidants, as antiprotozoals, as antibacterials and as anticancer agents. Because the pharmacological effects of α,β-unsaturated lactones have not been fully established, many research groups have tested both natural and unnatural α,βunsaturated lactones for as-yet undiscovered biological properties. We synthesized α,β-unsaturated lactones with various substituents at the δ-position and studied their immunosuppressive effects, that is, the inhibition of Interleukin-2 (IL-2) production. Among the compounds synthesized, the benzofuransubstituted α,β-unsaturated lactone 4h showed the best inhibitory activity toward IL-2 production in Jurkat e6-1 T lymphocytes (IC50 = 66.9 nM) without cytotoxicity at 10 µM. The results indicated that 4h may be useful as a potent immunosuppressive agent, as well as in IL-2-related studies.

[P-47]

A Facile Stereoselective Synthesis of α-(–)Conhydrine and its Pyrrolidine Analogue Seung Min Hong, Guang Ri Dong, Hye Ran Yang and Young Hoon Jung* School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Korea

Naturally occurring polyhydroxylated indolizidine, pyrrolizidine, pyrrolidine, piperidine and nortophane had attracted a lot of attentions from the synthetic community because of their interesting structures and glycosidase inhibitory activities. Glycosidase inhibitors are known to be used for treating diabetes, viral diseases(HIV and influenza), bacterial infections, cancer and immunological disorders. Representative examples of 2-(1-hydroxyalkyl)-piperidine, (+)-αconhydrine (1a) and (–)-β-conhydrine (1d), were first isolated from the seeds and leaves of the poisonous plant Conium maculatum L. in 1856 . As part of an ongoing research program aimed at developing asymmetric total syntheses of biologically active compounds, we recently reported a facile strategy for the construction of (–)-lentiginosine and its analogs based on the regioselective and diastereoselective allylic amination of polybenzyl ethers using chlorosulfonyl isocyanate (CSI). In connection with our previous work on the regioselective and diastereoselective allylic amination of polybenzyl ethers using CSI, we became interested in developing an efficient synthetic route for the preparation of (–)-α-conhydrine (1b) and its pyrrolidine analogue. Herein, we describe a facile total synthesis of 1b and 2, starting from readily available D-erythronolactone. Key steps in the syntheses include region and diastereoselective amination of dibenzyl ether using chlorosulfonyl isocyanate, intramolecular olefin metathesis leading to piperidine ring skeleton formation, and regioselective decarbamate reaction through potassium hydroxide.

show the synthesis of amino cyclic pentitols which can be obtained from intermediates of (+)-Neplanocin A. The key steps in the synthesis include intramolecular olefin metathesis leading to carbocyclic ring skeleton formation by the second generation of Grubbsâ&#x20AC;&#x2122; catalyst and regio- and stereoselective amination of polybenzyl ethers using Chlorosulfonyl Isocyanate CSI).

[P-48]

Asymmetric Synthesis of (+)-Neplanocin A and its derivatives Seung In Kim 1, Yeon Ju Hong1, Sung Gwan Lee and Young Hoon Jung1, * School of pharmacy, sungkyunkwan University, Suwon 440-746, Korea

Carbocyclic nucleosides are biologically interesting materials that sometimes display important antitumor or antiviral activities. Because of the absence of a true glycosidic bond, carbocyclic nucleosides are chemically more stable and not subject to the action of the enzymes that cleave this linkage in conventional nucleosides. A remarkable change in the biological activity of some of these pseudonucleosides occurs when the cyclopentane ring in modified into a cyclopentene ring. This structural change is usually accompanied by an increase in the biological potency and specificity of the unsaturated compounds when compared to the corresponding saturated carbocyclic analogues. (-)-Neplanocin A is naturally occurring carbocyclic nucleoside produced by Ampullariella regular and it has been shown to posess potent antitumor and antiviral activity and is a powerful inhibitor of S-adenosylhomocystein hydrolase. It has pronounced in vivo antileukemic activity and low toxicity and is more potent against vesicular stomatitis than the reversible SAH hydrolase inhibitor 3-deazaneplanocin(ID50 = 0.07 and 0.3 Âľg/ml, respectively). However, it is also important to synthesized (+)-Neplanocin A via enantioselective methods from a synthetic point of view. Recently, we reported the regioselective and diastereoselective allylic amination of various allylic ethers using chlorosulfonyl isocyanate (CSI) and its application to the synthesis of various bioactive alkaloids. Nowadays, we developed CSI reaction in the allylic ring systems and various cyclic allylic ethers were converted into the corresponding N-alkylcabamates. In this thesis, we describe the total synthesis of (+)-Neplanocin A from readily available benzyl protected D-galactose through 10 steps. Moreover, we also

[P-49]

Stereoselective Synthesis of Tubuphenylalanine (Tup), a Component of Tubulysin D Mikyung Sim and Jae-Sang Ryu* Center for Cell Signaling and Drug Discovery Research, College of Pharmacy and Division of Life and Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750, Republic of Korea

Tubulysins are tetrapeptides, secondary metabolites produced from myxobacteria species, Archangium gephyra and Angiococcus disciformis. They were first isolated from myxobacterial culture broths and their structures were identified by Florenz Sasse and Hans Reichenbach. Tubulysins are potential anticancer agents having exceptionally potent cell growth inhibitory activity that exceeds the epothilones, vinblastine, and taxol by a factor of 20- to 1000-fold. The most potent member, tubulysin D exhibits pico-molar GI50 value against NCI60 cancer cell-line by inhibiting tubulin polymerization. Tubulysin D is composed of four amino acid fragments, N-methyl-D-pipecolic acid (D-Mep), Lisoleucine (L-Ile), tubuvaline (Tuv), and tubuphenylalanine (Tup). Among these four amino acids, the stereoselective synthesis of the unusual amino acid, Tup, would be essential for an effective synthesis of tubulysins. We report herein an efficient method for the stereoselective synthesis of Tup.

[P-50]

Modification of trans-Stilbenoids as Potent and Selective Inhibitors for Human Cytochrome P450 1B1 Wonyoung Jang, Chaemin Lim, In Jinkyung, Heemin Park, and Sanghee Kim* College of Pharmacy, Seoul National University, Republic of Korea

CYP1B1 has received considerable attention as a new drug target. Among CYP1A Familiy, CYP1B1 is a major enzyme for the 4-hydroxylation of 17estradiol (E2) to produce a carcinogenic metabolite, 4-hydroxyestradiol (4OHE2). And it was reported that various trans-stilbene compounds are inhibitors of CYP. So we designed and systhesized 3,5-dimethoxyphenyl moiety based on natural trans-stilbenes through solution phase synthetic pathway, and their inhibitory activities were evaluated on human cytochrome P450s (CYP) 1A1, 1A2, and 1B1 to find a potent and selective CYP1B1 inhibitor. Among the compounds tested, the most selective and potent CYP1B1 inhibitor was 2,3â&#x20AC;&#x2122;, 4,5â&#x20AC;&#x2122;-tetramethoxystilbene. Moreover we found that 2-methoxy group in stilbene plays crucial role for discriminating between CYP1As and CYPB1. Based on this studies, we also prepared 2,4-dimethoxy group containing stilbenes with the ultimate goal of identifying a potent and selective CYP1B1 inhibitor. Molecular modeling was performed to determine the key molecular interactions with the CYP1B1 and CYP1A2 structures.

[P-51]

Synthesis and Evaluation of a 3-Deoxy Analogue of α-Galcer Jae Hyun Kim, Jurim Jang, Seokwoo Lee, Changhun Kim and Sanghee Kim* College of Pharmacy, Seoul National University, Republic of Korea

α-GalCer is the most potent agonistic antigen of the T cell receptor (TCR) of natural killer T (NKT) cells. From the limited availability of SAR results and the hydrogen-bonding network in the crystal structure, it was perceived that the 3-hydroxyl group of phytosphingosine played an important role in activating NKT cells and that the 4-hydroxyl group was less crucial. However, the analogue lacking only the 3-hydroxyl group on the phytosphingosine had not been synthesized and assessed to disclose the individual roles of the 3- and 4hydroxyl groups on NKT cell activation. We report here the synthesis and biological activity of the 3-deoxy analogue of α-GalCer.

[P-52]

Olefin Cross-Metathesis for the Determination of Double Bond Positions Yongseok Kwona, Hyun-Ji Lee, Hongjun Jeon, Hong-gu Lee, Dong-chan Ohb, * and Sanghee Kima* aCollege

bNatural

of Pharmacy, Seoul National University, Korea Products Research Institute, College of Pharmacy, Seoul National University, Korea

Accurately determining the double bond positions in the unsaturated long chain compounds still remains challenging. The chemical derivatization has been utilized to obtain the specific mass information on the double bond positions. However, this prior chemical derivatization approach has some drawbacks; extra steps are required and interferences of other functional groups on the analyte are possible. We envisioned that novel chemical derivatization of unsaturated long chains with Grubbs catalyst and simple olefin would afford the compounds with specific information. Depending on the simple olefin used, the produced CM fragments have distinct physicochemical properties that are suitable for chromatographic-mass spectrometric analysis. The position of double bond can be easily deduced by comparing and analyzing the m/z changes. In addition, the method is operationally simple and applicable at a sub-miligram scale.

[P-53]

An Improved High-Yielding One-pot Synthesis of 4-Acyl-1, 2, 3-Triazoles via Triisopropylsilyl (TIPS)-protected Ynones Soonho Hwang, Sumin Kim, Hyunkyung Cho, Jihee Cho, Yu Shuai, Hoon Bae, Sanghee Kim* College of Pharmacy, Seoul National University, Republic of Korea

1-substituted 4-acyl-1H-1,2,3-triazoles have various interesting biological activities such as tuberculosis inhibition, HIV protease inhibition, and antibacterial activity. Herein, we developed an improved and convenient one-pot process for the synthesis of 1-substituted 4-acyl-1,2,3-triazoles. The first step of one-pot process was the Sonogashira cross-coupling of acid chlorides with triisopropylsilyl (TIPS)-acetylene to generate TIPS-protected ynones. The next two steps were the in situ AgF-mediated desilylation to give terminal ynones and subsequent Cu-catalyzed Huisgen cycloaddition. We employed TIPS protecting group instead of the previously applied TMS group. The increased chemical stability of bulky TIPS-protected ynones allowed high-yielding one-pot process. In this study, we investigated an improved and convenient one-pot process and condition for the synthesis of 1-substituted 4-acyl-1,2,3-triazoles. This one-pot process can be applied to various substrates and should be of general utility for the synthesis of a wide range of triazole compounds. In addition, we could generate libraries of heterocyclic compounds, which are potentially useful as a scaffold for drug development.

[P-54]

Studies on the Immunosuppressive Effects of Subglutinol Derivatives Won-Gil Leea, Woo-Seok Kima, Sung-Gyoo Parka, Hyoungsu Kimb, SeokYong Leec, Jiyong Hongd, Hyojin Koa, Yong-Chul Kima aDepartment

of Life Science, Gwangju Institute of Science and Technology, Gwangju 500-712, Korea, bCollege of Pharmacy, Ajou University, Suwon 443749, Republic of Korea, cSchool of Medicine, Duke University, Durham, NC 27708, USA, dDepartment of Chemistry, Duke University, Durham, NC 27708, USA

The existing immunosuppressive drugs, cyclosporin A and FK 506, are widely used to treat autoimmune or non-autoimmune diseases, but they have serious side effects including gingival hyperplasia, kidney and liver toxicity. Thus diverse approaches to identify small organic molecules or natural products that can modulate T cell mediated immune disorders without severe adverse effects have been done. Synthetic intermediates of subglutinol A and B, which are diterpenoid pyrone class of natural immunosuppressive agents isolated from Fusarium Subglutinans, were investigated for the functional mechanism of immune modulation. Subglutinol A and its methyl-g-pyrone derivative, 8 significantly suppressed IL-2 production in stimulated Jurkat T cells or human and murine CD4+ primary T cells. These compounds also efficiently inhibited the expression of T-cell activation markers, CD25 and CD69. In the analysis of the effect at Kv1.3 channel, only compound 8 showed a moderate inhibition of the channel activity. The results indicated that subglutinol structure could be utilized to design new immunosuppressive agents.

[P-55]

Discovery, Structure−Activity Relationships and Pharmacological Studies of 3,5-Dichloropyridine Derivatives as Novel P2X7 Receptor Antagonists Won-Gil Lee†, So-Deok Lee†, Joong-Heui Cho†, Younghwan Jung†, Jeonghyun Kim†, Tran T. Hien‡, Keon-Wook Kang‡, Hyojin Ko§, and Yong-Chul Kim*,†,§

†Department of Life Science, Gwangju Institute of Science and Technology, Gwangju 500-712, Korea, ‡College of Pharmacy, Seoul National University, Seoul, Republic of Korea, §Graduate Program of Medical System Engineering, Gwangju Institute of Science and Technology (GIST), Gwangju 500-712 Screening of a library of chemical compounds showed that the 3,5dichloropyridine based analog 9 was a novel P2X7 receptor antagonist. To optimize its activity, we assessed the structure-activity relationships (SAR) of 9, focusing on the hydrazide linker, the dichloropyridine skeleton and the hydrophobic acyl (R2) group. We found that the hydrazide linker and the chlorides at C3 and C5 positions in the pyridine skeleton were critical for P2X7 antagonistic activity and that the presence of hydrophobic polycycloalkyl groups at the R2 position optimized antagonistic activity. On the ethidium bromide uptake assay in hP2X7-expressing HEK293 cells, the optimized antagonists, 51 and 52, had IC50 values of 4.9 and 13 nM, respectively. The antagonistic effects of 51 and 52 were paralleled by their ability to inhibit of the release of the proinflammatory cytokine, IL-1β? by LPS/IFN-γ/BzATP stimulation of THP-1 cells (IC50 = 1.3 and 9.2 nM, respectively). In addition, 52 strongly inhibited iNOS/COX-2 expression and NO production in THP-1 cells, further indicating that this compound blocks inflammatory signaling and suggesting that the dichloropyridine analogs may be useful in developing P2X7 receptor targeted anti-inflammatory agents.

[P-56]

Diyne Diols as Novel Cancer Chemoprevetive Agents and their Structrue-Activity Realtionship Chang-Yong Lee, Ju-Eun Park, Young-Ae Cho, and Dongyun Shin* College of Pharmacy, Gachon University

â&#x20AC;&#x153;Chemopreventionâ&#x20AC;? strategy is mainly used to suppress, delay, or reverse carcinogenic processes using natural or synthetic substances having anti-cancer activities. Therefore, this approach might be highly beneficial to patients in that it could reduce medical costs and improve the quality of life. In our previous publication, structure-activity relationship of diyne triols derived from natural gymnasterkoreayne G was revealed by our previous research (Bioorg. Med. Chem. Lett., 2010). Here, we communicate design and synthesis of novel diyne-based chemopreventive agents and their chemopreventive activityies. 35 Diyne compounds was designed, of which various alkyl alcohols were introduced on one side and substituted benzyl alcohols on the other side. Syntheses of desired products were successfully carried out in mostly five step sequences starting from bis(trimethylsilyl)buta-1,3-diyn. Cancer chemopreventive activities, Chemopreventive index (CI), for the prepared compounds were measured by quinone reductase induction activity and cell viability. Form the result, significant structure-activity relationship of novel diynes was revealed. Some derivative exhibited more potent chemopreventive activities than sulforaphane.

[P-57]

Synthesis and Biological evaluation of Peripheral benzodiazepine receptor (PBR) ligands for the treatment of Alzheimer’s disease Ha Yeon Yang a,*, and Ae Nim Paeb,* aDepartment

of Chemistry, Yonsei University, Seodaemun-gu, Seoul 120-749, Korea bNeuro-Medicine Center, cDoping Control Center, Korea Institute of Science and Technology(KIST), P.O. Box 131, Cheongryang, Seoul 130-650, Korea

The benzodiazepine receptors can be divided, from the point of view of their cellular localization, into two groups: central benzodiazepine receptors (CBR) and peripheral ones (PBR). A peripheral benzodiazepine receptor is localized in many types of tissues, on the surface of the mitochondrial membranes (IMMOMM). This receptor mediates various mitochondrial functions, including cholesterol transport and steroid hormone synthesis, mitochondrial respiration, mitochondrial permeability transition (mPT) pore opening and cell proliferation and apoptosis. Initial clinical trials have indicated that PBR ligands might be valuable in the treatment of psychiatric disorders and neurological desease such as alzheimer’s desease. Therefore, the PBR is targeted to develop alzheimer’s disease drug. As part of discovering novel PBR ligands, we designed and synthesized 38 compounds. The synthesized compounds were biologically evaluated against PBR. The detailed design, synthesis and biological evaluation of PBR ligands as alzheimer’s disease drugs will be presented.

[P-58]

Identification of a Novel Protease-Activated Receptor 2 Antagonist Using a Virtual Screening Approach Nam-Chul Choa,b, Ji Hyoun Chaa,c, Hye Jin Taka, Yun Kyung Kima, Kyung-Tae Leed, Kyoung Tai Nob, and Ae Nim Paea a

Center for Neuro-Medicine, Korea Institute of Science and Technology, Seoul 130-650, Korea. b Department of Biotechnology, Yonsei University, Seoul 120749, Korea c Department of Chemistry, Inha University, Nam-gu, Incheon 402751, Korea d Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, 1 Hoegi-dong, Dongdaemun-gu, Seoul 130-701, Republic of Korea

Protease-activated receptor 2 (PAR2), a family of G-protein-coupled receptor, is activated by serine protease such as trypsin and tryptase and play a key role in inflammatory disease like arthritis and cancers. The inhibition of PAR2 activation by small molecule antagonists may provide a pharmacological basis for interfering with these acute processes. In the present work, we have generated a pharmacophore model for PAR2 antagonist to identify novel compounds. The pharmacophore model was comprised of 4 hydrophobic feature, one hydrogen bond acceptor and one hydrogen bond donor. This model was virtually screened to the databases of 2.1 million compounds and hits subsequently were filtered by 8 criteria such as fitvalue, drug properties and in silico ADMET tests. Consequently, two compounds were found by cell-based PAR2 assay and antiinflammatory test as specific PAR2 antagonist. Moreover, these compounds can be raised into a potential anti-inflammatory drug candidate after optimizing and passing several phases of clinical trials.

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Synthesis and Biological Evaluation of the Mitochondrial Permeability Transition Pore Inhibitors for the Treatment of Alzheimer’s disease Tae Hoon Kima,b, Beoung Geon Parka,c, Ji Youn Leed, Ae Nim Paea a

Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, Seongbuk-Gu, Seoul 130-650, Korea , bUniversity of Science and Technology, Yuseong-Gu, Daejon 305-350, Korea, c School of Life Science and Biotechnology, Korea University, Seongbuk-Gu, Seoul 136-740, Korea, d Department of Gobal Medical Science, Sungshin Women's University , Gangbuk-gu, Seoul 142-732, Korea

β-Amyloid peptide(Aβ) is produced from transmembrane amyloid precursor protein(APP) by sequential actions of β- and γ-secretase. Aβ is implicated in the pathogenesis of Alzheimer’s disease(AD) by interaction of Aβ with cyclophilin D(CypD). CypD, adenin nucleotide translocator(ANT), voltage-dependent anion channel(VDAC), and benzodiazepine receptor(PBR) compose the mitochondrial permeability transition pore(mPTP). The interaction of Aβ with CypD enhances the translocation of CypD to the mPTP and results in mPTP opening. After the mPTP opening, cytosolic solutes influx into the mitochondrial matrix, and then mitochondrial swelling causes cell death. Therefore, blockage of CypD or PBR can be an effective therapeutic strategy in Alzheimer’s disease. Based on the pharmacophore-based virtual screening, we identified numerous novel scaffolds, and the synthesis and biological evaluations of those compounds were performed. The detailed synthesis and biological evaluation of mPTP inhibitors as Alzheimer’s disease drugs will be presented.

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Design, Synthesis and Biological Evaluation of Protease-Activated Receptor 2 (PAR2) Antagonists for The Treatment of Arthritis Ji Hyoun Cha*, Nam Chul Cho b*, and Ae Nim Paec* aDepartment

of Chemistry, Inha University, Nam-gu, Incheon 402-751, Korea of Biotechnology, Yonsei University, Seodaemun-gu, Seoul 120749, Korea cCenter for Neuro-Medicine, Korea Institute of Science and Technology(KIST), P.O. Box 131, Cheongryang, Seoul 130-650, Korea bDepartment

Protease-activated receptor 2 (PAR2) is the second number of a novel family of seven-transmembrane G-protein-coupled receptors, PARs. They are mainly expressed in platelets, but also on endothelial cells, myocytes and neurons. Activation of PAR2 is initiated through a proteolytic cleavage of serine proteases such as trypsin or Î˛-tryptase from mast cells, exposing a tethered ligand domain which binds and activates the cleaved receptor. This receptor regulates various physiological functions including vasoregulation, arteriolar dilation, degranulation of mast cells and cell growth to inflammation. Initial observations of PAR2 knock-down mice indicated that the receptors may be useful therapeutic agents for the treatment of human diseases such as arthritis. Therefore, PAR-2 is targeted to develop as inflammatory joint disease drug. A novel series of quinazoline derivatives was designed and synthesized as PAR2 antagonist. The synthesized 6-methoxy-quinazoline compounds showed reasonable inflammatory inhibition activity against various inflammatory cell lines. The detailed design, synthesis and biological evaluation of PAR2 antagonists as inflammatory joint disease drugs will be presented.

[P-61]

TSPO (translocator protein) deficient cells are resistant to the opening of mitochondrial permeability transition pore induced by Aβ1-42 peptides Beoung-Geon Park 1, 2, Dong Won Lee1, Ja-Hyun Baik2, Ae Nim Pae1, Seung Hoon Baek1* and Jiyoun Lee1,* 1Center

for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, Seoul, Korea ; 2School of Life Sciences and Biotechnology, Korea University, Seoul, Korea.

Amyloid beta (Aβ) plays a critical role in the pathophysiology of Alzheimer's disease. However, the effects of Aβ toxicity on mitochondria have not yet been fully understood. Recent studies suggested that the formation of mitochondrial permeability transition pore (mPTP) might be involved in Aβ-mediated mitochondrial dysfunction. The translocator protein (TSPO) is a transmembrane domain that is localized primarily in the outer mitochondrial membrane and interacting with mPTP indicating its involvement in the control of mPTP opening. In particular, it has been reported that the TSPO may activate the mPTP to open and cause transition of the mitochondrial membrane potential (ΔΨm), leading to the initiation of mitochondrial apoptotic pathway. Here, we have made a stable TSPO knockdown cell line by using shRNA technique, and were able to assess mitochondrial potential (ΔΨm), cytosolic Ca2+ concentrations, and ATP production under Aβ1-42 treatment. Our results demonstrated that the TSPO deficient cell line showed lower level of cytosolic Ca2+, slightly higher level of ATP production and higher cell viability upon treatment of Aβ1-42 compared to control cell lines, indicating that the TSPO deficient cells are more resistant to the opening of mPTP.

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6-chloropyridazine with allyl mercaptan and sodium methoxide. A series of synthesized alkylselenoallylthiopyridazine derivatives was synthesized for the development of new antitumor agents.

Synthesis of Sulfur and Selenium Analogues of Pyridazine Via Diselenylation and Allylthioltion Ji-Hee Lee, Sun-Hee Lee, Myung-Sook Park* College of Pharmacy, Duksung Women's University, Seoul 132-724, Korea.

Many organoselenium compounds are useful reagents or synthons in organic synthesis. Over the past few years, a few synthetic strategies for the seleniumcontaining higher heterocycles, such as 5-deoxy-5-selenopyanose sugars, and novel selenium analogs of an important antioxidant, Îą-tocopherol, have been reported. The main component of the volatile oil is sulfur compounds of especially allicin. Allicin is responsible for the typical odor of garlic, but is unstable and converts readily into other compounds. A number of sulfur compound of garlic have been shown to posses anticarcinogenic and antimutagenic activities. The results of a drug design, allylthio group as pharmacologically active group was introduced into pyridazine ring that was more stable. We synthesized new alkylselenoallylthiopyridaizine derivatives were expected to retain anticancer activity. Synthetic route for the final alkylselenoallylthiopyridazines was proceeded with diselenation, hydrolysis, dechlorination and allylthiolation from aryl halide. The allylthio group and alkylseleno group as pharmacologically active group was introduced into pyridazine ring in order to prepare new organoselenium compouds. Dichloropyridazinyl diselenide was prepared from the diselenide anion using synthetic route of Bhasin. Also dichloropyridazinyl diselenide can be reduced to 3-chloropyridazinyl selenolate anion using hydrazine hydrate at room temperature in the presence of sodium hydroxide in tetrahydrafuran. The anion thus formed reacts readily with alkyl halide to give the 3-alkylseleno-6chloropyridazine. These reactions were carried out presence of phase-transfer catalyst NH4Cl (or TBAB), in an effort to improve the efficiency of the reaction. The 3-alkylseleno-6-allylthiopyridazine was prepared from 3-alkylseleno-

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Efficient Synthetic Method of Psammaplin A Suckchang Hong1, Myungmo Lee1, Myunggi Jung1, Yohan Park2, Mi-hyun Kim1, Hyeung-geun Park1* 1Research

Institute of Pharmaceutical Sciences and College of Pharmacy, Seoul National University, Seoul 151-742, Korea, 2 College of Pharmacy, Inje University, 607 Obang-dong, Gimhae, Gyeongnam 621-749, Korea

Psammaplin A was originally isolated from the Psammaplysilla sponge in 1987. Psammaplin A has a unique symmetrical structure of bromotyrosinederived disulfide dimmer. Biological activity studies revealed that Psammaplin A has various bioactivities. Recently, the Psammaplin A was also isolated from an unidentified sponge collected from the south region of Korea, and confirmed significant cytotoxicity against the leukemia cell-line. As one of our research programs for the development of new therapeutics for the treatment of cancer, we needed to develop very concise and efficient synthetic methods of Psammaplin A and its analogues. Nicolaou group reported an efficient combinatorial synthetic method of Psammaplin A and its analogues for systematic SAR study as antibacterial agents. But, the synthesis starts from or via amino acids that are somewhat limited in diversity because of the limitation of their commercial availability. In this poster, we present a new efficient and concise synthetic method of Psammaplin A developed via Knovenagel condensation and direct nitrosation as key steps (50% yield in 9 steps). Since the newly developed method can use ethyl acetoacetate and various commercially available aldehydes or alkyl halides as starting materials, it might be a very efficient method to construct a more diverse library of Psammaplin A type analogues. The preparation of Psammaplin A analogues by our new synthetic method and the systematic SAR studies on cytotoxicity are now under investigation.

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Highly Enantioselective Total Synthesis of (+)Isonitramine Cheonhyoung Park†, Yohan Park‡, Young Ju Lee†, Suckchang Hong†, Myungmo Lee† and Hyeung-geun Park† †Research

Institute of Pharmaceutical Sciences and College of Pharmacy, Seoul National University, Seoul 151-742, Korea, ‡College of Pharmacy, Inje University, 607 Obang-dong, Gimhae, Gyeongnam 621-749, Korea

Nitraria alkaloids, (+)-isonitramine, have chiral quaternary carbon centers on the 2-azaspiro[5,5]undecane-7-ol skeletons. Recently, it was reported that the extract of Nitraria plants have antiproliferative effects on cancer cell lines through the apoptosic pathway. A new efficient enantioselective synthetic method of (+)-isonitramine is reported. (+)-Isonitramine could be obtained in 12 steps (98% ee and 43% overall yield) from δ-valerolactam via enantioselective phase-transfer catalytic alkylation, Dieckman condensation and diastereoselective reduction as key steps. Both the high enantioselectivity and chemical yield make this approach a practical route for the large scale synthesis of 2azaspirocycles.

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butoxycarbonylbutyrolactone and a-tert-butoxycarbonylvalerolactone under phase-transfer catalytic conditions (50% CsOH, toluene, -60 ºC) in the presence of (S,S)-3,4,5-trifluorophenyl-NAS bromide (5 mol %) afforded the corresponding a-alkyl-a-tert-butoxycarbonyllactones in very high chemical yields (up to 99%) and optical yields (up to 99% ee). Furthermore a-benzylated a-tertbutoxycarbonylbutyrolactone was converted to the corresponding amide by ammonolysis, followed by hofmann rearrangement and hydrolysis provided unnatural amino acid.

Highly Enantioselective Phase-Transfer Catalytic α-Alkylation of α-tert-Butoxylcarbonyllactones Min Woo Ha 1, Yohan Park2, Hee Jin Lee1, Hye Young Lee1, Suckchang Hong1, Myungmo Lee1, Hyeung-geun Park1* 1Research

Institute of Pharmaceutical Science and College of Pharmacy, Seoul National University, Seoul 151-742, Korea,2College of Pharmacy, Inje University, 607 Obang-dong, Gimhae, Gyeongnam 621-749, Korea

Malonate type compounds are one of the most fundamental synthetic starting materials for C-C bond formation in organic synthesis. In addition, chiral asubstituted malonate type compounds including a-carboxylactones and acarboxylactams, have been quite popularly employed for the construction of chiral quaternary carbon centers of biologically active natural products and pharmaceuticals. Although construction of chiral quaternary carbon centers by enantioselective a-alkylation of carbonyl systems, β-ketoester systems and chiral induction of b-position to malonate by asymmetric conjugate addition or palladium-catalyzed allylation of malonates have been popularly developed, to date, the enantioselective direct a-alkylation of malonate type compounds have not yet been extensively studied. Recently, we reported a new synthetic method for chiral a-mono-alkylmalonamide esters, a-alkyl-a-tertbutoxycarbonyllactams, and a,a-dialkylmalonates in high chemical and optical yields by asymmetric PTC a-alkylation. Based on a series of our previous studies, we attempted to extend the PTC alkylation to a-carboxylactone system. Here we developed a new and highly efficient enantioselective a-alkylation of a-carboxylactones under phase-transfer catalytic condition. It is because that in case of lactone there are no systematic studies on the asymmetric a-alkylation of lactones with high enantioselectivity. Only a few cases were reported as a part of studies, such as a-substitution of a-tert-butylcarboxybutyrolactone with cyclic sulamidate and a-fluorination of a-tert-butylcarboxylactones via chiral Pd(II)-bisphospine catalysis. In this poster, a new enantioselective α-alkylation of a-tert-butoxycarbonyllactones was reported. a-Alkylation of a-tert-

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more potent agonistic scaffolds for the treatment of metabolic disorders such as fatty liver diseases.

N-Methylthioureas as New Agonists of Retinoic Acid Receptor-Related Orphan Receptor α Yohan Park,1 Churlwoo Kim,2 Suckchang Hong,2 Myungmo Lee,2 Hyojun Jung,2 Won-Jea Cho,3 Eun-Jin Kim,4 Ho-Young Son,4 Mi-Ock Lee,4 and Hyeung-geun Park2* 1College

of Pharmacy, Inje University, 607 Obang-dong, Gimhae, Gyeongnam 621-749, Korea, 2Research Institute of Pharmaceutical Sciences and College of Pharmacy, Seoul National University, Seoul 151-742, Korea, 3College of Pharmacy Chonnam National University Yongbong-dong Buk-gu, Kwangju 500-757, Korea,4Bio-MAX Institute and College of Pharmacy, Seoul National University, Seoul 151-742, South Korea

Retinoic acid related-receptor orphan receptor α (RORα) has been regarded as critical factors in the regulation of a number of physiological processes. This receptor plays an important role in the development of the cerebellum, lipid and steroid metabolism, hepatic lipid metabolism, homeostasis of cholesterol. Since those physiological functions of RORα can be possibly modulated by exogenous ligands, the discovery of new non-natural ligands may lead to the development of novel therapeutics for human diseases that involve RORα. In 1996, the thiazolidinone type compound CGP52608 were identified as efficient agonists of RORα and showed antiarthritic activity in vivo. As part of our program to develop novel drug-like RORα agonists for the treatment of metabolic disorders, we chose the first non-natural ligand, CGP52608 as a lead compound and attempted to replace the thiazolidin-4-one moiety with the phenyl rings, substituted with various functional groups. In this poster, we report the synthesis and RORα activity of thiourea derivatives. Thirty two N-methylthiourea derivatives were easily prepared in one step from the corresponding amines or aldehydes and their agonistic activities against ROR! were evaluated. Among them, 1methyl-3-(4-phenoxy-benzyl)-thiourea showed the best agonistic activity. We believe this pharmacophore information would be very useful in the design of

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Asymmetric Synthesis of Clemastine Amine Using Racemization-minimized and Regioselective Nallylation Hee-Doo Kim* and Seung Jin Kim College of Pharmacy, Sookmyung Women's University, Seoul 142-742, Korea

In connection with our recent report on the stereoselective synthesis of H1 receptor antagonist clemastine, we present here the stereoselective synthesis of (R)-2-(2-chloroethyl) pyrrolidine-1-carboxylic acid ethyl ester for clemastine amine using racemization-minimized and stereoselective N-allylation, and ring closing metathesis as key steps. The commercially available (S)-(-)-α-Amino-γbutyrolactone was treated with allyl bromide and LiI to give the corresponding N-diallylated butyrolactone in good yield. Selective removal of one allyl group with ethyl chloroformate gave the desired mono-N-allylated product in good yield. This two-step sequence permits us to minimize the racemization during the allylation process, and to get the product in high yield. Then, the mono-Nallylated butyrolactone was transformed to the requisite diene for ring closing metathesis in 2 steps via Dibal-H reduction and Horner-Wadsworth Emmons olefination. The diene was then subjected to RCM reaction using commercially available 2nd generation Grubbs’ catalyst in dichloromethane to produce the 5membered pyrrolidine in 90% yield. Subsequent hydrogenation, and followed by chlorination with Viehe salt produced (R)-2-(2-chloroethyl)pyrrolidine-1carboxylic acid ethyl ester. In summary, we will present that the optically active amine for clemastine can be be prepared efficiently from commercially available (S)-amino-gbutyrolactone. We will also demonstrate the potential of our methodology for the construction of the chiral 2-alkyl pyrrolidine ring starting from a-amino ester using Grubbs’ catalyst as the key step.

[P-68]

Design and synthesis of carbamate and thiocarbamate derivatives and their inhibitory activities of NO production in LPS activated macrophages Guo Hua Jin, Hwa Jin Lee, Hyo Jin Gim, Jae-Ha Ryu, Raok Jeon College of Pharmacy, Sookmyung Womenâ&#x20AC;&#x2122;s University, 52 Hyochangwon-Gil, Yongsan-Ku, Seoul 140-742, Republic of Korea

Nitric oxide (NO) plays critical roles in various physiological processes, including neurotransmission, smooth muscle contractility, platelet reactivity, and the cytotoxic activity of immune cells. The overproduction of NO caused by inducible NOS (iNOS) has been linked to the pathogenesis of a number of disease states, including septic shock, neurodegenerative disorders, and various inflammatory processes. Series of carbamate and thiocarbamate derivatives were designed and synthesized and their inhibitory activities of NO production in lipopolysaccharide-activated macrophages were evaluated. Several thoicarbamate derivatives revealed promising inhibitory activity. The structureâ&#x20AC;&#x201C;activity relationship study of these compounds is also reported. They suppressed the release of NO into culture media through the suppression of iNOS protein and mRNA expression and also inhibited the nuclear translocation of p65 subunit of NF-kB.

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ether and the facile removal of the naphthylethyl auxiliary and its application for the total synthesis of novel tripeptide containing a β-amino acid.

Expedient Synthesis of Chiral Homoallylamines via N, O-Acetal TMS Ethers and Its Application Jaebong Jang a, Jong-Wha Jung b, Hwayoung Yun a, Dongyun Shin c, Hongchan An a, Seungbeom Lee a, and Young-Ger Suha* aCollege

of Pharmacy, Seoul National University, Seoul 151-742, Korea of Pharmacy, Kyungpook National University, Daegu 702-701, Korea cCollege of Pharmacy, Gachon University of Medicine and Science, Incheon 406-799, Korea ygsuh@snu.ac.kr

bCollege

Homoallylamines and acylated homoallylamines are some of the important structural subunits of biologically active compounds such as β-amino acids and are useful intermediates in a wide range of syntheses of alkaloids and nitrogencontaining heterocycles. Thus, the enantio- and diastereoselective synthesis of homoallylamines has become one of the major goals in the fields of medicinal chemistry and organic synthesis. Consequently, the development of a new method for the synthesis of optically active homoallylamines has been continuously attempted by organic and synthetic chemists. We have recently reported a new approach to the synthesis of the Nacyliminium ion from N,O-acetal TMS ether, which was conveniently prepared from acylcarbamate. The N,O-acetal TMS ether proved to be an excellent acyliminium ion precursor in terms of convenience of preparation, chemical stability, and functional versatility in addition to the accessible structural diversity of cyclic and acyclic N-acyliminium ions. More recently, we have reported a novel asymmetric synthetic route for β-amino acids using this methodology. Herein, we describe a highly stereoselective and efficient method for the synthesis of optically active homoallylamines through chiral auxiliary assisted diastereoselective allylation of N-acyliminium ions prepared from N,O-acetal TMS

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activities and pharmacokinetic profiles, we designed and synthesized a series of phenylbenzyl amides with metabolically stable trifluoromethyl moiety and constrained heterocyclic linkers. As a result of the SAR study, we identified several promising heterocyclelinked TRPV1 antagonists with favorable PK profiles. In particular, one of the analogs that contain a furan linker exhibited excellent TRPV1 antagonistic activity and in vivo analgesic efficacy with improved PK profiles. In addition, we predicted the binding modes of dibenzyl thiourea, benzylphenethyl amide and furan-linked phenylbenzyl amide using the rTRPV1 homology model by the flexible docking study.

Heterocycle-linked Constrained Phenylbenzyl Amides as Novel TRPV1 Antagonists with Improved harmacological Properties and Insight into Their TRPV1 Binding Mode Kyeojin Kim,a Nam-Jung Kim,a Fu-Nan Li,b Jin Hee Lee,c Seul-gi Park,c Changjin Lim,a Young Taek Han,a Hwayoung Yun,a Hyun Su Kim,a Tae Woo Kim,a Hyeung-Geun Park,a Hee-Doo Kim,d Byoung Young Woo,e Song Seok Shin,e Sun-Young Kim,e Jin Kyu Choi,e Yeon-Su Jeong,e Yanghui, Park,e Young-Ho Park,e Sun Choi,c and Young-Ger Suh,a,* aCollege

of Pharmacy, Seoul National University, 599 Gwanak-ro, Gwanak-gu, Seoul 151-742, Korea, b School of Pharmaceutical Sciences, Xiamen University, Daxue Road, Xiamen 361005, P. R. China, cCollege of Pharmacy, Division of Life & Pharmaceutical Sciences, and National Core Research Center for Cell Signaling & Drug Discovery, Ewha Womans University, Korea, dCollege of Pharmacy, Sookmyung Womenâ&#x20AC;&#x2122;s University, 53-12, Chungpa-Dong, YongsanGu, Seoul, 140-742, Korea, eAmorepacific R&D Center 314-1, Bora-dong, Giheung-gu, Yongin-si, Gyeonggi-do 446-729, Korea, ygsuh@snu.ac.kr

The vanilloid receptor-1 (TRPV1) has evoked great interest since it was clearly demonstrated as a novel target for treatment of various pain states. In particular, recent intensive researches have implied that TRPV1 antagonists could be a promising candidate for novel analgesics. We have previously reported the structure-activity relationships (SARs) of dibenzyl thiourea TRPV1 antagonists, including SC-0030, which are highly potent competitive TRPV1 antagonists. Recently, we have extended our work on the structural optimization, and identified several analogs with highly potent in vitro activities. However, most of these analogs showed pharmacologically unsatisfactory in vivo activity, which might have resulted from unfavorable pharmacokinetic profiles. In this connection, to develop novel and potent TRPV1 antagonists with promising in vivo

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A Stereocontrolled Access to Functionalized Macrolactams via Aza-Claisen Rearrangement Hwayoung Yun a, Jong-Wha Jung b, Jaebong Jang a, Hyowon Seo a, Jung Min Ahn a and Young-Ger Suha* aCollege bCollege

of Pharmacy, Seoul National University, Seoul 151-742, Korea of Pharmacy, Kyungpook National University, Daegu 702-701, Korea ygsuh@snu.ac.kr

Macrolactams and related azacycles are often encountered in biologically active natural products, and especially in drug candidates such as bioisosteres of macrolides. However, direct cyclization approaches to the synthesis of macrocyclic rings are often limited because of entropic considerations, highly diluted conditions and the lack of functional diversity. A potential method to produce these heterocycles is to employ a lactam-ring-expansion strategy using the azaClaisen rearrangement (ACR). ACR-induced ring expansion, which offers an opportunity for the rapid assembly of complex alkaloids, such as macrolactams has been underemphasized, partly as a result of limited access to the requisite precursors. In this connection, we have reported synthesis of the bioactive natural products having β-alkoxy-α-substituted azacyclic moiety. Taking advantage of a highly stereospecific remote control of ACR-induced ring expansion, (E)-vinyl ether was successfully utilized to provide the anti-β-alkoxy-α-substituted azacycle. The successful applications of our strategy prompted us to undertake systematic investigation of ACR-induced ring expansions of the larger ring-sized lactams to the corresponding functionalized macrolactams as well as their stereochemical outcome, in view of both synthetic and bio-medicinal interests. Herein, we describe a stereocontrolled approach for the synthesis of functionalized macrolactams that relies on an efficient preparation of the medium-sized ACR precursors and a highly stereospecific ACR-induced ring expansion.

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Development of Novel Tyrosinase Regulators as Skin Lightening Agents Young Jin Kim, Jiho Song, Seul Lee, Doran Kim, Jong Min Kim, Saebeom Choi and Kyung Hoon Min* College of Pharmacy, Chung-Ang University, 221 Heukseok-Dong, DongjakGu, Seoul, 156-756, Republic of Korea

Tyrosinase is one of the key enzymes in mammalian melanin synthesis. Regulating this kinase is critical as skin lightening agents. For this reason we have synthesized some novel derivatives, which were evaluated for α-melanocytestimulating hormone (α-MSH) induced melanogenesis in a mouse melanoma B16 cell line. Compound 8 (IC50 =1.68 µM) and compound 10 (IC50 = 1.75 µM) exhibited a potent inhibitory activity approximately 50-fold greater than kojic acid, a well-known inhibitor. A biochemical study indicates that the activity of this series should be displayed via down-regulation of the expression of tyrosinase.

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Piceatannol, a Stilbene Natural Product, Stabilizes HIF-1a Protein by Inhibiting HIF Prolyl Hydroxylase Soo-Hwan Yum, Sung-Chae Hong, Woo-Seong Kim, Seong-Keun Jung, Yun-Jin Jung* Bio-medicinal Chemistry Laboratory, College of Pharmacy, Pusan National University, Busan, Korea

To explore a molecular mechanism underlying piceatannol (PCT)-mediated amelioration of experimental colitis, it was examined whether PCT could modulate HIF-1 activity whose activation is reported to have a beneficial effect on gut inflammation. PCT induced HIF-1a protein, leading to activation of HIF-1 resulting in induction of its target gene products, vascular endothelial growth factor (VEGF) and heme oxygenase (HO)-1, involved in amelioration of colitis. PCT induction of HIF-1a resulted from stabilization of HIF-1a protein, which occurred by inhibiting HIF-prolyl hydroxylase-2 (HPH-2). The PCT inhibition of HPH-2 was reversed by addition of a cofactor of HPH-2, ascorbate, but not the cosubstrate, 2-ketoglutarate, to the reaction mixture of an in vitro VHL capture assay and pretreatment with ascorbate attenuated PCT induction of cellular HIF-1a. Moreover, PCT prevented hydroxylation of cellular HIF-1a and PCT treated in HEK 293 cells transfected with Flag-VHL and HA HIF-1a attenuated coimmunoprecipitaion of Flag VHL with HA-HIF-1a. Structural analysis using derivatives of PCT revealed that the catechol moiety in PCT was required for the stabilization of HIF-1a protein. Taken together, PCT amelioration of colitis may be ascribed to HIF-1 activation resulting from inhibition of HPH by the natural product.

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Colon-specific Delivery of Celecoxib is a Potential Strategy to Improve Toxicological and Pharmacological Properties of the Selective COX-2 Inhibitor: Implication in Treatment of Familiar Adenomatous Polyposis Yong-Hyun Lee, Woo-Seong Kim, Seong-Keun Jung, Yun-Jin Jung* Bio-medicinal Chemistry Laboratory, College of Pharmacy, Pusan National University, Busan, Korea

In general, colon-specific delivery of a drug decreases systemic absorption and increases therapeutic concentration of the drug at the target site. Nsuccinylglutam-1 or 5-yl celecoxib (SG1C and SG5C) were prepared as a colon specific prodrug of celecoxib, a selective Cox-2 inhibitor, and investigated whether the celecoxib derivatives could deliver celecoxib to the target site and improve cardiovascular toxicity and therapeutic effectiveness for the treatment of familiar adenomatous polyposis. SG1C and SA5C were cleaved to release celecoxib in the cecal contents while stable in small intestinal contents. The cecal release of celecoxib was much greater for SG1C than SG5C. SG1C administered orally was barely detected in the blood and urine. SG1C delivered much greater amount of celecoxib to the large intestine while keeping the plasma concentration of celecoxib at much lower level compared with oral administration of free celecoxib. Consistent with these pharmacokinetic results, SG1C supplied a greater concentration of celecoxib for the entire colonic tissue and did not change the serum level of 6-keto-PGF1Îą whose decrease is associated with the cardiovascular toxicity of celecoxib. Taken together, colon specific delivery of celecoxib using a prodrug approach may be a useful strategy to improve toxicological and pharmacological properties of celecoxib.

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Colon Specific Delivery of Celecoxib Ameliorates TNBS-induced Rat Colitis without Lowering Serum Level of 6-keto-PGF1α, an Inverse Indicator of Cardiovascular Toxicity of Celecoxib Sung-Chae Hong, Yong-Hyun Lee, Soo-Hwan Yum, Woo-Seong Kim, YunJin Jung* Bio-medicinal Chemistry Laboratory, College of Pharmacy, Pusan National University, Busan, Korea

For treatment of colonic diseases such as inflammatory bowel disease, colontargeted drug delivery has advantages over conventional drug delivery. Colonic delivery of a drug tends to decrease the systemic absorption and increase the therapeutic concentration of the drug at the target site, thereby not only reducing side effects but also enhancing therapeutic effects. It was examined whether colon specific delivery of celecoxib elicited such benefit. N-succinylaspart-1-yl celecoxib (SA1C), a colon specific prodrug of celecoxib, was administered orally to rats with colitis induced by TNBS once a day for 6 days and the antiinflammatory effect was evaluated and compared with free celecoxib. While free celecoxib did not ameliorated the rat colitis at all, the prodrug significantly alleviated the injury and lowered myeloperoxidase activity along with improving inflammatory indices such as COX-2, iNOS and CINC-3 in the inflamed colon. After oral administration of the drugs for 6 days, much greater amount of celecoxib was detected in the inflamed colonic tissue for SA1C than free celecoxib. Moreover, while the serum level of 6-keto-PGF1α was substantially lowered by oral administration of celecoxib, SA1C did not change the serum level of 6-keto-PGF1α.. Take together, our data suggest that colon specific delivery of celecoxib would not only enhance the therapeutic effect but also reduce the side effect of celecoxib.

100

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together, introduction of cell permeability and colon targetability to NIP may be a feasible strategy for an orally active peptide therapy for treatment of IBD.

A Novel Strategy for Orally Active Peptide Therapy: a Colon-Targeted Cell-Permeable NFκB Inhibitory Peptide Ameliorates Experimental Colitis Sung-Chae Hong, Soo-Hwan Yum, Woo-Seong Kim, Seong-Kwun Jung, Yun-Jin Jung* Bio-medicinal Chemistry Laboratory, College of Pharmacy, Pusan National University, Busan, Korea

For the purpose of development of orally active peptide therapeutics targeting NFκB for treatment of inflammatory bowel disease (IBD), two major barriers in oral delivery of therapeutic peptides, metabolic lability and tissue impermeability, were circumvented by introduction of a colon-targeted delivery system and cell permeable peptides (CPP) to NFκB inhibitory peptides (NIP). Suppression of NFκB activation was compared following treatment with various CPP conjugated NIPs (CPP-NIP). The most potent CPP-NIP was loaded in a capsule coated with a colon specific polymer, which was administered orally to colitic rats. The anti-inflammatory activity of the colon-targeted CPP-NIP was evaluated by measuring inflammatory indices in the inflamed colonic tissue. For confirmation of the local action of the CPP-NIP, the same experiment was done after rectal administration. Tissue permeability of the CPP-NIP was examined microscopically and spectrophotometrically using FITC-labeled CPP-NIP (CPPNIP-FITC). NEMO binding domain peptide (NBD, TALDWSWLQTE) fused with a cell permeable peptide CTP (YGRRARRRARR), CTP-NBD, was most potent in inhibiting NFκB activity in cells. Colon-targeted CTP-NBD, but not colon-targeted NBD and CTP-NBD in an enteric capsule, ameliorated the colonic injury, which was in parallel with decrease in MPO activity and the levels of inflammatory mediators. Intracolonic treatment with CTP-NBD alleviated rat colitis and improved all the inflammatory indicators. CTP-NBD-FITC was detected at much greater level in the inflamed tissue than was NBD-FITC. Taken

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Using the sequence information along with the native enzyme structures of the open (homology model) and closed (X-ray crystal structure) forms, the statistical and computational simulation studies were performed to investigate the domain motion and allosteric dynamics of the enzyme. In order to identify the allosteric signaling network, we statistically extracted the information of coevolving residues from whole sequence space of the SAHH family. The functional dynamics encoded in their native topology of the enzyme structures were investigated using the normal mode analysis, and the hot spot residues important in their dynamics were also analyzed. Finally, the Brownian dynamics simulations were carried out with a coarse-grained model to study the link between the allosteric communication and functional dynamics of SAHH. Through this comprehensive study, it was found that the allosteric coupling from the residues distal to the active site is also important to the enzymatic function, as well as the formation of enzyme-ligand contacts at the active site.

Elucidation of the Domain Motion and Allosteric Dynamics of S-Adenosylhomocysteine Hydrolase through the Computational Simulation and Statistical Analysis of the Structure and Sequence Space Yoonji Lee1, Lak Shin Jeong1, Changbong Hyeon2, Sun Choi1,* 1

National Leading Research Lab (NLRL) of Molecular Modeling & Drug Design, College of Pharmacy, Division of Life & Pharmaceutical Sciences, and National Core Research Center for Cell Signaling & Drug Discovery Research, Ewha Womans University, Seoul, Korea 2 School of Computational Sciences, Korea Institute for Advanced Study, Seoul, Korea

S-adenosylhomocysteine hydrolase (SAHH) catalyzes the hydrolysis of Sadenosylhomocysteine to adenosine and L-homocysteine, and plays a key role in methylation reactions including those required for the maturation of viral mRNA. Thus, it is a promising therapeutic target for the antiviral drug discovery. Its monomer structure consists of the catalytic, cofactor (NAD+)-binding, and C-terminal domains, and the four monomers assemble the homotetrameric structure. Upon the ligand binding, this enzyme undergoes the conformational change from open to closed forms. Recently, we obtained the X-ray crystal structure of the human SAHH complexed with Fluoro-neplanocin A, which is an irreversible mechanism-based inhibitor of SAHH with the IC50 value of 480 nM. The crystallized complex shows the closed conformation, and it turned out to be the intermediate of the mechanism-based inhibition, confirming that the cofactor depletion caused by 3â&#x20AC;˛-oxidation of fluoro-neplanocin A also contributes to the inhibition of SAHH along with the mechanism-based covalent modification of the enzyme. In addition, we constructed the homology model of the open form structure of human SAHH to compare the open and closed structures depending on the ligand binding.

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The binding modes of a series of the C2-substituted derivatives were also compared. In this series of nucleosides, adenine and sugar moieties maintained almost exactly the same binding interactions, but the C2-substituents demonstrated the different binding modes. The molecules with relatively rigid substituent, i.e., hexynyl, at C2-position maintained the important interactions occupying the binding site very well. However, when the flexibility of the C2substituents increased, the binding modes were not consistent losing some of the key interactions. The docking results also showed a good correlation (r2 = 0.86) between the binding affinities and docking scores. Taken together, the appropriate size of the substituents at the N6 position and rigidity of the C2substitutents appear to contribute to the ligand binding.

Binding Modes and Structure-Activity Relationship Analysis of the A2A Adenosine Receptor Modulators Yoonji Lee, Jin Hee Lee, Seul-gi Park, Lak Shin Jeong, and Sun Choi* National Leading Research Lab (NLRL) of Molecular Modeling & Drug Design, College of Pharmacy, Division of Life & Pharmaceutical Sciences, and National Core Research Center for Cell Signaling & Drug Discovery Research, Ewha Womans University, Seoul, Korea

Adenosine receptors (ARs), which belong to the GPCR family, consist of four subtypes: A1, A2A, A2B and A3 ARs. Among them, A2A AR is a promising therapeutic target for inflammation and Parkinsonâ&#x20AC;&#x2122;s disease and the only subtype whose X-ray crystal structures are available. The truncated N6-aryl or N6-amino adenosine derivatives with C2 or C8 substitution were newly designed and synthesized as potential A2A AR ligands. The biological study demonstrated that the bulky groups at N6-position were detrimental to ligand binding at human A2A AR. In addition, while the C8-substituted derivatives displayed reduced A2A AR activities, the C2-substituted ones showed good binding affinities in order of C2-hexynyl > hexenyl > hexanyl derivatives. To investigate the structure-activity relationships of the molecules, the flexible docking studies were performed using the X-ray crystal structure of human A2A AR (3EML.pdb). The C2-substituted derivatives with good A2A AR binding affinities occupied the binding site very well and made tight interactions via pi-pi stacking with Phe168 and hydrogen bonding with Glu169, Asn253 andthe Ser277. In contrast, the C8-substituted or N6-aryl adenosine derivatives showed various binding modes and did not maintain some important interactions due to the spatial restriction of the hydrophobic pocket at the binding site. These results might explain why the binding affinities of the N6-unsubstituted-C2substituted derivatives were much better than other compounds.

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ent states of Rac1 and flexible docking studies support these ideas by predicting the binding modes of 8-OHdG in the nucleotide binding site of Rac1. Taken all these results together, we could propose the molecular mechanism of 8-OHdG which uniquely binds to the Rac1-GEF complex and causes the suppression of Rac1 activity.

Flexible Docking Studies of 8-OHdG to Elucidate its Molecular Mechanism which Suppresses ROS Production by Rac1 Inhibition Yoonji Lee, Junghyun Lee, Boyeon Kim, Joo Young Huh, Hunjoo Ha, and Sun Choi* National Leading Research Lab (NLRL) of Molecular Modeling & Drug Design, College of Pharmacy, Division of Life & Pharmaceutical Sciences, and National Core Research Center for Cell Signaling & Drug Discovery Research, Ewha Womans University, Seoul, Korea

As a well-known oxidative stress biomarker, 8-Hydroxy-2â&#x20AC;˛-deoxyguanosine (8-OHdG) or 8-oxo-7,8-dihydro-2â&#x20AC;˛-deoxyguanosine (8-oxodG) is generated from the DNA guanosine base attacked by reactive oxygen species (ROS). Recently, it was found that exogenous 8-OHdG inhibits inflammation and suppresses ROS production in macrophages through the reduction of Rac1 activity in dose-dependent manner. Rac1, which is a small signaling G protein, cycles between the GDP-bound inactive state and the GTP-bound active state and regulated by three classes of regulatory proteins: guanosine exchange factors (GEFs), GTPase-activating proteins (GAPs), and guanine nucleotide dissociation inhibitors (GDIs). Among them, GEFs stimulate the exchange of GDP for GTP and directly control the activation of Rac1. The GTP-bound active form of Rac1 binds with NADPH oxidase complexes and plays a significant role in the production of ROS. In order to investigate the molecular mechanism of 8-OHdG, molecular modeling studies were performed. Since the biological data demonstrates that 8OHdG suppresses Rac1 activity by reducing the Rac1-GTP level but has no influence on Rac1-guanosine exchange factor (Rac1-GEF) activity, 8OHdG is considered to bind to the Rac1-GEF complex. Structural comparison of differ-

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Discovery of Novel, Potent and Highly Selective Tyrosine Kinase Inhibitors Targeting EGFRT790M Jiho Song, Young Jin Kim, Seul Lee, Do Ran Kim, Jong Min Kim, Sae Beom Choi, Kyung Hoon Min* College of Pharmacy, Chung-Ang University, Seoul 156-756, Korea

Epidermal growth factor receptors (EGFR) had been validated as a suitable pharmacological target for non-small cell lung cancers (NSCLCs), which respond to EGFR tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib. However, most tumors develop acquired resistance to EGFR TKIs within a year after initiation of therapy. A secondary mutation of EGFR (T790M) is responsible for half of patients with the acquired resistance to gefitinib or erlotinib. Therefore, development of TKIs targeting EGFR-T790M has been a key subject for overcoming the resistance. In order to identify novel TKIs for EGFR T790M, we have screened in-house chemical library and confirmed several hits. The hit-tolead optimization was carried out to increase potency and selectivity for EGFRT790M. A series of MK compounds exhibited a 35.9 ~ 200 fold difference in potency against EGFR T790M compared to EGFR wild type.

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Design and Synthesis of 4-pyridone and 2Pyridone Analogs as Serine Protease Inhibitors Daesung Lim, Xiang Fei, Seonbong Choi, Sanglae Lim, Bit Lee, SeungYong Seo* College of Pharmacy, Woosuk University, Korea

Natural products SPF-32629A and SPF-32629B containing 4-Hydroxy-2pyridone were isolated from the cultured broth of a fungal strain Penicillium sp. SPF-32629 and showed the inhibitory effect on serine proteases. Our research goal is to develop the synthetic route of SPF-32629A and B as well as new type serine protease inhibitors based on a 4-hydroxy-2-pyridone.

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by the treatment of the resulting mesylate with selenium metal and sodium borohydride afforded the key intermediate, 4-selenosugar 5 [3]. Oxidation of 5 with mCPBA followed by treating with acetic anhydride gave the acetate, which was condensed with the purine bases in the presence of Lewis acid to give the protected nucleosides 6. Manipulation of N6-position of the purine base and/or 4’hydroxymethyl group afforded the final nucleosides 7. All AR binding experiments were performed using adherent mammalian CHO (Chinese hamster ovary) cells stably transfected with cDNA encoding the appropriate human ARs (A1 and A3 ARs in CHO cells and A2AAR in HEK-293 cells). Among compounds tested, compound 2a (R = 3-iodobenzyl, X = H, Y = CONHMe) exhibited the similar binding affinity at the A3AR to 1.

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Synthesis and Binding Affinity at the A3 Adenosine Receptor of Novel 4’-Selenoribofuranosyl purines Na Ra Lee1, Jin Ha Yu, Hyuk Woo Lee, Hankil Lee1, Kenneth A. Jacobson2, and Lak Shin Jeong1*

CONCLUSION

1College

of Pharmacy and Department of Bioinspired Science, Ewha Womans University, Seoul 120-750, Korea and 2Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 20892, USA. *Correspondence to: lakjeong@ewha.ac.kr

We have accomplished the syntheses of new 4’-selenopurine nucleosides on the basis of bioisosteric rationale and their binding affinity at the human A3AR. Although we could not discover new A3AR ligands, these new templates are expected to be utilized in understanding the binding mode in the A3AR.

ABSTRACT

REFERENCES 1. Jeong, L. S., Lee, H. W., Jacobson, K. A., Kim, H. O., Shin, D. H., Lee, J. A., Gao, Z.-G., Lu, C., Duong, H. T., Gunaga, P., Lee, S. K., Jin, D. Z., Chun, M. W., Moon, H. R. J. Med. Chem., 2006, 49, 273-281; 2. Kim, S.-J., Min,H.-Y., Chung, H.-J., Park, E.-J., Hong, J.-Y., Kang, Y.-J., Shin, D.-H., Jeong, L. S., Lee, S. K., Cancer Lett., 2008, 264, 309-315. 3. (a) Jeong, L. S., Tosh, D. K., Kim, H. O., Wang, T., Hou, X., Yun. H. S., Kwon, Y., Lee, S. K., Choi, J., Zhao, L. X. Org. Lett., 2008, 10, 209-212. (b) Jayakanthan, K., Johnston, B. D., Pinto, B. M. Carbohydr. Res., 2008, 343, 1790-1800.

On the basis of bioisosteric rationale, new 4’-selenopurine nucleosides were synthesized from D-ribose as new human A3 adenosine receptor ligands. All synthesized compounds exhibited weak binding affinity at the human A3 adenosine receptor. INTRODUCTION 4-Thionucloesides were recently discovered to be good templates for the design of A3 adenosine receptor (AR) ligands. Compound 1 (4’-thio-Cl-IBMECA) [1] was found to be very potent A3 AR agonist (Ki = 0.38 nM) and showed cell-cycle arrest by lowering levels of c-myc and cyclin D1 in concentration- and time-dependent manners at lower concentrations and apoptosis through PRRP cleavage at higher concentrations [2]. Compound 1 also inhibited Wnt signaling pathway at 10 nM of concentration [2]. As our ongoing efforts to develop new A3AR ligands, we designed and synthesized the new template, 4’-selenonucleosides 2, based on the bioisosteric rationale. Herein, we report the synthesis of novel 4’-selenopurine nucleosides and their binding affinity at the human ARs. RESULTS AND DISCUSSION D-Ribose was converted to known L-lyxonolactone (3). TBDPS protection of 3 followed by reduction with NaBH4 yielded diol 4. Mesylation of 4 followed

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verted to the glycosyl donor 12 after vinylic fluorination and desilylation reactions. Condensation with N3-benzoyluracil under Mitsunobu conditions yielded the uracil derivative 13 which was finally converted to the cytosine analogue 5a. Compound 14 on treatment with TIPDSCl2, deoxygenation and silyl deprotection gave the 2’-deoxyuridine derivative, which was finally converted to the cytidine derivative 5b. All synthesized final nucleosides were tested for their in vitro antigrowth effects in a variety of human tumor cell lines. Only compound 5a exhibited highly potent antitumor activity against a broad range of tumor cell lines at a concentration of 1 µM. In a nude mouse tumor xenograft model implanted with A549 human lung cancer cells, 5a significantly inhibited the tumor growth, the tumor volume, and tumor weight.

Synthesis and Broad Spectrum and Potent Antitumor Activity of Fluorocyclopentenyl-cytosine Varughese Alexander, Won Jun Choi, Girish Chandra, Sang Ah Kim, and Lak Shin Jeong* College of Pharmacy and Department of Bioinspired Science, Ewha Womans University, Seoul 120-750, Korea. *Correspondence to: lakjeong@ewha.ac.kr

CONCLUSION

ABSTRACT

The cytosine derivative 5a demonstrated broad spectrum and potent antitumor activity in a broad range of human tumor cell lines as well as in a xenograft nude mouse model. The biological activity suggests that compound 5a is a promising, clinically useful anticancer agent that should be further investigated.

Fluorocyclopentenyl-cytosine derivatives 5a and 5b were designed and synthesized from D-ribose. Among these, 5a showed highly potent antigrowth effects in a broad range of human tumor cell lines and very potent antitumor activity in a nude mouse tumor xenograft model with A549 human lung cancer cells. INTRODUCTION

REFERENCES

Neplanocin A (1, Figure 1), is a naturally occurring nucleoside which exhibits potent antiviral and antitumor activities by inhibition of Sadenosylhomocysteine (SAH) hydrolase. Its 6-fluoro analogue 2, the cytidine analogue 3, and the fluorocytosine analogue 4 exhibited potent antiviral and/or antitumor activity. Inspired by these pioneering works, we synthesized the fluorocyclopentenyl-cytosine derivative 5a (R = OH) in order to evaluate its biological potential. To explore if the ribosyl template was critical for the biological activity, the 2’-deoxy analogue 5b (R = H) was also synthesized. Herein, we report the synthesis of cytosine derivatives 5a and 5b and the potent antitumor activity of 5a, both in in vitro and in vivo studies.

1. Choi, W. J.; Moon, H. R.; Kim, H. O.; Yoo, B. N.; Lee, J. A.; Shin, D. H.; Jeong, L. S. J. Org. Chem. 2004, 69, 2634–2636..

RESULTS AND DISCUSSION For the synthesis of the desired nucleosides, the key intermediate 10 was first synthesized with a benzyl protecting group, as shown in Scheme 1. This was due to the fact that other protecting groups such as trityl, TBS, and TBDPS were not successful in the electrophilic vinyl fluorination. D-Ribose was converted to known diol 8,1 which on selective benzylation produced the benzylate 9. A ring-closing metathesis of 9 followed by oxidative rearrangement with PDC gave the key intermediate 10. Conventional iodination of 10 followed by reduction and TBDPS protection gave TBDPS ether 11. This was then con-

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The key intermediate, 4-selenosugar and 2-deoxy-4-selenosugar were efficiently synthesized from D-ribose and D-2-deoxyribose, respectively via the cyclization of dimesylate with selenium metal and sodium borohydride as a key step. 4’-Selenouridine (1) and cytidine (2) and 4’-selenothymidine (3) were synthesized by condensing and 4-selenoxide and 2-deoxy-4-selenoxide with uracil and cytosine and thymine, respectively, while 4’-selenoadenosine (4) and 4’selenoguanosine (5) were synthesized by the condensation of 4-selenosugar acetate with 6-chloropurine and 2-amino-6-chloropurine in the presence of Lewis acid, respectively. During the condensation, it was discovered that initially formed N-7 isomer was rearranged to the N-9 isomer, which was confirmed by X-ray crystallography. The X-ray crystallographic analyses indicated that 4’selenouridine (1) adopted the 2’-endo/3’-exo (South) conformation, different from that of uridine taking the 2’-exo/3’-endo (North) conformation, maybe due to the steric effect of bulky selenium atom. However, 4’-selenothymidine (3) took the same South conformation as the thymidine. Interestingly, the X-ray crystal structure of 4’-selenoadenosine (4) showed the unusual dynamic equilibrium of North and South conformations, indicating that the steric effect of bulky selenium atom may not play a key role in deciding the conformation.

Synthesis of New DNA and RNA Building Blocks, 4’-Selenonucleosides and Their Unusual Conformations Jin Ha Yu, Jin-Hee Kim, Ji Yoon Ahn, Varughese Alexander, Dilip K. Tosh, and Lak Shin Jeong* College of Pharmacy and Department of Bioinspired Science, Ewha Womans University, Seoul 120-750, Korea. *Correspondence to: lakjeong@ewha.ac.kr ABSTRACT New DNA and RNA building blocks, 4’-selenonucleosides were synthesized from D-ribose via the Pummerer type condensation as a key step. The DNA building block, 4’-selenothymidine adopted the same South conformation as the thymidine, while the RNA building block, 4’-selenoadenosine showed the unusual dynamic equilibrium of North and South conformations.

CONCLUSION We have accomplished the first syntheses of new RNA and DNA building blocks, 4’-selenonucleosides via the Pummerer type condensation as a key step. In the synthesis of purine derivatives 4 and 5, the rearrangement of the N-7 isomer to the N-9 isomer was confirmed and the structure of formerly known 4’selenoadenosine was revised. Unlike 4’-selenouridine (1) and 4’selenothymidine (3) showing one favoured conformation, 4’-selenoadenosine (4) was discovered to exist in N/S dynamic mixture from the X-ray crystal structures.

INTRODUCTION DNA or RNA building blocks have been utilized as excellent templates for the development of modified nucleosides. Modifications have been largely done on the furanose ring of DNA or RNA. However, appearances of side effects, drug resistances, and chemical and metabolic instability in these 4’oxonucleosides made these compounds ineffective clinically, requiring the discovery of new templates highly desirable. Thus, 4’-thionucleosides and carbocyclic nucleosides called the second generation nucleosides have come out to overcome these adverse effects. However, the 4’-thionucleosides were generally more cytotoxic than the 4’-oxonucleosides although they adopted the same sugar conformation, while the carbocylic nucleosides were in general inactive, maybe due to different sugar conformation from that of 4’-oxo- or 4’thionucleosides. As our ongoing efforts to develop new biologically active nucleosides, we created the new template, 4’-selenonucleosides1-3 as the third generation nucleosides. Herein, we report the synthesis of new RNA and DNA building blocks, 4’-selenouridine (1), 4’-selenocytidine (2), 4’-selenothymidine (3), 4’selenoadenosine (4), and 4’-selenoguanosine (5) and their unusual sugar puckerings.

REFERENCES 1. Jeong, L. S., Tosh, D. K. Org. Lett., 2008, 10, 209-212. 2. Alexander, V., Jeong, L. S. Org. Lett., 2010, 12, 2242-2245. 3. Jeong, L. S., Tosh, D. K. J. Med. Chem., 2009, 52, 5303-5306.

RESULTS AND DISCUSSION

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First, truncated 2-hexynyl-N6-substituted-carbaadenosine derivatives 4a-i were synthesized from glycosyl donor 5, which were easily synthesized from commercially available D-ribose (Scheme 1). The glycosyl donor 5 was condensed with 6-chloropurine under the Mitsunobu conditions to give 6. Treatment of 6 with LiTMP followed by trapping with n-Bu3SnCl produced 7, which underwent Pd-catalyzed Sonogashira coupling to give 2-hexynyl derivative 8. Treatment of 8 with various alkyl and arylalkyl amines afforded the C2-hexynyl derivatives 4a-i. Among compounds tested, N6cyclopropylamino derivative exhibited the highest binding affinity (Ki = 5.0 nM) at the human A3 adenosine receptor.

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Synthesis and Binding Affinity of Truncated 2Hexynyl-N6-substituted-(N)methanocarbanucleosides as A3 Adenosine Receptor Ligands Akshata Nayak1, Girish Chandra2, Khai Phan2, Kenneth A. Jacobson2, and Lak Shin Jeong1*

CONCLUSION

1College

The truncated 2-hexynyl-N6-substituted carbaadenosine derivatives were synthesized from D-ribose using the Sonogashira coupling as a key step. The N6methyamino derivative was discovered as a preferred ligand at the human A3AR, indicating that a hydrophobic C2 substituent can be tolerated for high binding affinity at the hA3AR.

ABSTRACT

REFERENCES 1. Jacobson, K. A., Gao, Z.-G. Nature Rev. Drug Disc. 2006, 5, 247â&#x20AC;&#x201C;264. 2. Jeong, L. S., Pal, S. J. Med. Chem. 2008, 51, 6609â&#x20AC;&#x201C;6613. 3. Hou, X., Jeong, L. S. J. Med. Chem. 2012, 55, 342-356. 4. Melman, A., Jacobson, K. A. Bioorg. Med. Chem. 2008, 16, 8546-8556.

Truncated 2-hexynyl-N6-substituted-(N)-methanocarba nucleosides were synthesized as A3 adenosine receptor ligands, among which N6-methylamino derivative exhibited high binding affinity (Ki = 2.46 nM) at the human A3 adenosine receptor. INTRODUCTION Extracellular adenosine acts as a signaling molecule with a generally cytoprotective function in the body. Adenosine mediates cell signalling through binding to adenosine receptors (ARs), consisting of four subtypes (A1, A2A, A2B, and A3).1 On the basis of the structure of adenosine, the extensive structure-activity relationship studies were carried out on N6 and/or 4'-hydroxymethyl moieties of adenosine, among which compound 12 was discovered as a potent and speciesindependent A3AR antagonist (Figure 1). Recently, truncated 2-hexynyl-4'-thioadenosine 33 was reported to be a dual acting A2AAR agonist and A3AR antagonist. On the other hand, the truncated (N)-metanocarbanucleoside 34 was also found to be a potent and selective A3AR antagonist. Thus, it is interesting to design and synthesize the 2-hexynylcarbanucleosides 4 which hybridize the properties of 2 and 3 and to measure their binding affinity at the ARs. RESULTS AND DISCUSION

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tions as key steps. The C8-substituted adenosine derivatives 4n-p was synthesized as in Scheme 2.3 The radioligand binding assays of all synthesized adenosine derivatives were performed. This study revealed that, an unsubstituted 6-amino group and a hydrophobic C2 substituent were required for high affinity at the hA2AAR, but hydrophobic C8 substitution abolished the binding affinity at the hA2AAR. However, most of synthesized compounds maintained the binding affinity at the hA3AR.

Synthesis and Potent In Vivo Anti-inflammatory Activity of Truncated C2- or C8-Substituted Adenosine Derivative Acting Dually as A2a and A3 Adenosine Receptor Ligands

CONCLUSION Xiyan Hou1, Varughese Alexande1,*, Shuhao Qu1, Seung Yeon Ryu1, Sun Choi1, Khai Phan2, Kenneth A. Jacobson2, and Lak Shin Jeong1,*

The structure-activity relationships of truncated N6-substituted 4’-oxo- and 4’-thioadenosine derivatives as dual acting A2A and A3 AR ligands were established. Compounds 4g and 4m were discovered as a preferred ligand to act dually with high affinity. Compound 4g exhibited potent anti-inflammatory activity on the carrageenan-induced paw edema. It was also discovered that the geometry of the C2 substituent is crucial for the binding affinity.

1College

REFERENCES

ABSTRACT

1. Jacobson, K. A., Gao, Z.-G. Nature Rev. Drug Disc. 2006, 5, 247–264. 2. Hou, X., Jeong, L. S. ACS Med. Chem. Lett. 2010, 1, 516–520 and references cited therein. 3. Hou, X., Jeong, L. S. J. Med. Chem. 2012, 55, 342-356 and references cited therein.

Truncated N6-substituted-4’-oxo and 4’-thioadenosine derivatives with C2 or C8 substitution were studied as dual acting A2A and A3 adenosine receptor ligands with potent anti-inflammatory activity. INTRODUCTION Adenosine, an endogenous material regulates many physiological functions in the cell through binding to four subtypes (A1, A2A, A2B, and A3) of adenosine receptors (ARs).1 Modifications on N6 and/or 4'-hydroxymethyl moieties of adenosine led to the discovery of 1 and 2 as A3AR agonists and antagonists, respectively (Figure 1). Recently, truncated C2-substituted 4'-thioadenosine derivatives 3 containing an appended hydrophobic hexenyl or hexynyl chain at the C2 position were reported as dual A2AAR agonists and A3AR antagonists.2 Thus, the truncated 4’-thio and 4’-oxo series 4 with various substituents at N6, C2, or C8 positions were synthesized. RESULTS AND DISCUSION First, 2-hexynyl-N6-substituted-adenosine derivatives 4a-e and 4g-k were synthesized from glycosyl donors 5 or 6, which were easily synthesized from commercially available 2,3-O-isopropylidene-D-erythronic-γ-lactone and D-mannose respectively (Scheme 1). The C2-hexynyl (4a-e, 4g-k) and C2-hexenyl derivatives (4l-m) were introduced using Sonogashira and Suzuki coupling reac-

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