NaturalProductsinMedicinalChemistry
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Prof. Dr. Stephen Hanessian University of Montreal Department of Chemistry H3C 3J7 NK Canada Cover Description
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Contents
ListofContributors XV
Preface XIX
PersonalForeword XXI
PartOneNaturalProductsasSourcesofPotentialDrugsandSystematic CompoundCollections 1
1NaturalProductsasDrugsandLeadstoDrugs:AnIntroductionand PerspectiveasoftheEndof2012 3 DavidJ.NewmanandGordonM.Cragg
1.1Introduction 3
1.2TheSponge-DerivedNucleosideLinktoDrugs 5
1.3InitialRecognitionofMicrobialSecondaryMetabolites asAntibacterialDrugs 8
1.4 b-LactamsofAllClasses 9
1.5TetracyclineDerivatives 12
1.6GlycopeptideAntibacterials 13
1.7LipopeptideAntibacterials 16
1.8MacrolideAntibiotics 18
1.9PleuromutilinDerivatives 19
1.10PrivilegedStructures 21
1.11TheOriginoftheBenzodiazepines 21
1.12Benzopyrans:ASourceofUnusualAntibacterialand OtherAgents 22
1.13MultipleEnzymaticInhibitorsfromRelativelySimpleNatural ProductSecondaryMetabolites 23
1.14AVariationonBIOS:The “Inside–Out” Approach 26
1.15OtherPrivilegedStructures 26
1.16PrivilegedStructuresasInhibitorsofProtein–Protein Interactions 27
1.17UnderprivilegedScaffolds 30
1.18SoWhereShouldOneLookintheTwenty-FirstCenturyforNovel StructuresfromNaturalSources? 31
1.19Conclusions 33 References 33
2NaturalProduct-DerivedandNaturalProduct-InspiredCompound Collections 43
StefanoRizzo,VijayWakchaure,andHerbertWaldmann 2.1Introduction 43
2.2ModernApproachestoProduceNaturalProductLibraries 44
2.3PrefractionatedNaturalProductLibraries 45
2.4LibrariesofPureNaturalProducts 46
2.5SemisyntheticLibrariesofNaturalProduct-DerivedCompounds 46
2.6SyntheticLibrariesofNaturalProduct-InspiredCompounds 47
2.6.1Solid-PhaseTechniques 48
2.6.2Solution-PhaseTechniques 50
2.6.3Solid-SupportedReagentsandScavengers 55
2.6.4TaggingApproach 58
2.7CompoundCollectionswithCarbocyclicCoreStructures 60
2.7.1Illudin-InspiredCompoundCollection 60
2.7.2Lapochol-InspiredNaphthoquinoneCollection 61
2.7.3ACompoundCollectionwithDecalinCoreStructure 62
2.8CompoundCollectionswithOxa-HeterocyclicScaffolds 63
2.8.1Carpanone-InspiredCompoundCollection 63
2.8.2Calanolide-InspiredCompoundCollection 64
2.8.3Benzopyran-InspiredCompoundCollection 65
2.9CompoundCollectionswithAza-HeterocyclicScaffolds 66
2.9.1Solution-PhaseSynthesisof( )MarinopyrroleAanda CorrespondingLibrary 66
2.9.2Alkaloid/Terpenoid-InspiredCompoundCollection 67
2.10MacrocyclicCompoundCollections 68
2.10.1MacrosphelideA-InspiredCompoundCollection 68
2.10.2Solid-PhaseSynthesisofAnalogsofErythromycinA 69
2.10.3AnAldol-BasedBuild/Couple/PairStrategyfortheSynthesisof MacrocyclesandMedium-SizedRings 71
2.11Outlook 72 References 73
PartTwoFromMarketedDrugstoDesignedAnalogsandClinical Candidates 81
3ChemistryandBiologyofEpothilones 83 Karl-HeinzAltmannandDieterSchinzer
3.1Introduction:DiscoveryandBiologicalActivity 83
3.2SynthesisofNaturalEpothilones 86
3.3SynthesisandBiologicalActivityofNon-naturalEpothilones 90
3.3.1SemisyntheticDerivatives 90
3.3.2FullySyntheticAnalogs 92
3.3.2.1Polyketide-BasedMacrocycles 92
3.3.2.2Aza-Epothilones(Azathilones) 109
3.3.2.3HybridStructuresandAcyclicAnalogs 112
3.4ConformationalStudiesandPharmacophoreModeling 114
3.5Conclusions 115 References 115
4Taxol,Taxoids,andRelatedTaxanes 127
IwaoOjima,AnushreeKamath,andJoshuaD.Seitz
4.1IntroductionandHistoricalBackground 127
4.1.1DiscoveryofTaxol(Paclitaxel):AnEpoch-MakingAnticancer DrugfromNature 127
4.1.2TaxaneFamily 128
4.1.3SourcesandMethodsofProduction 129
4.1.3.1ExtractionfromYewTrees 129
4.1.3.2Semisynthesis 129
4.1.3.3TotalSynthesis 130
4.1.3.4BiotechnologyProcesses 131
4.1.4ClinicalDevelopmentofTaxol(Taxol1) 131
4.2MechanismofActionandDrugResistance 132
4.2.1Taxol,CellCycleArrest,andApoptosis 132
4.2.2DrugResistancetoTaxol 133
4.3Structure–ActivityRelationships(SAR)ofTaxol 133
4.3.1SARofTaxol 133
4.3.2ChemicalModifi cationsofTaxol:TaxolDerivatives andTaxoids 134
4.3.2.1ModificationsintheC13SideChain 134
4.3.2.2ModificationintheBaccatinComponent 135
4.3.2.3ProdrugsofTaxol 140
4.4StructuralandChemicalBiologyofTaxol 141
4.4.1BioactiveConformationofTaxol 141
4.4.2Microtubule-BindingKineticsofTaxol 145
4.5New-GenerationTaxoidsfrom10-DAB 145
4.5.1Taxoidsfrom10-DAB 145
4.5.2Taxoidsfrom14b-HydroxybaccatinIII 148
4.5.3Taxoidsfrom9-DihydrobaccatinIII 149
4.6TaxoidsinClinicalDevelopment 150
4.6.1Docetaxel(Taxotere1,RP56976) 150
4.6.2Cabazitaxel(Jevtana1,RPR116258A,XRP6258) 153
4.6.3Larotaxel(XRP9881,RPR109881) 153
4.6.4Ortataxel(SB-T-101131,IDN5109,BAY59-8862,ISN5109) 154
4.6.5Tesetaxel(DJ-927) 154
4.6.6Milataxel(MAC-321,TL139) 155
4.7NewApplicationsofTaxanes 155
4.7.1Taxane-BasedMDRReversalAgents 155
4.7.2TaxanesasAntiangiogenicAgents 156
4.7.3TaxanesasAntitubercularAgents 157
4.8ConclusionsandPerspective 158 References 159
5CamptothecinandAnalogs 181 GiuseppeGiannini
5.1Introduction 181
5.2BiologyActivity 185
5.2.1CamptothecinActsonEukaryoticTop1 187
5.2.2DrugResistanceandTopoisomeraseMutation 189
5.2.3Camptothecin:BeyondtheTopoisomeraseI 190
5.2.4Off-LabelInvestigation 190
5.3CamptothecininClinicalUseandUnderClinicalTrials 190
5.3.1Homocamptothecin 203
5.4Chemistry 204
5.4.1TotalSyntheses 205
5.4.2SynthesesofSomeRepresentativeCamptothecinDerivatives 207
5.5Structure–ActivityRelationship 210
5.6XenograftStudies 211
5.7Prodrug/Targeting 212
5.8DevelopmentsofModernChromatographicMethodsAppliedto CPT 214
5.9ConclusionsandPerspectives 214 References 215
6AShortHistoryoftheDiscoveryandDevelopmentofNaltrexoneand OtherMorphineDerivatives 225 VimalVargheseandTomasHudlicky
6.1Introduction 225
6.2HistoryandDevelopment 226
6.3Pharmacology 238
6.4Structure–ActivityRelationshipofMorphineanditsAnalogs 240
6.5ConclusionsandOutlook 244 References 244
7LincosamideAntibacterials 251 HardwinO’Dowd,AliceL.Erwin,andJasonG.Lewis
7.1Introduction 251
7.2MechanismofAction 253
7.3AntibacterialSpectrum 254
7.4Resistance 257
7.5PseudomembranousColitis 258
7.6Next-GenerationLincosamides 259
7.7Conclusions 264 References 264
8PlatensimycinandPlatencin 271
ArunK.GhoshandKaiXi
8.1IntroductionandHistoricalBackground 271
8.2DiscoveryandBioactivitiesofPlatensimycinandPlatencin 272
8.3TotalandFormalSynthesesofPlatensimycin 278
8.4TotalandFormalSynthesesofPlatencin 283
8.5AnalogsofPlatensimycinandPlatencin 287
8.6ConclusionsandPerspective 295 References 296
9FromNaturalProducttoNewDiabetesTherapy:Phlorizinandthe DiscoveryofSGLT2InhibitorClinicalCandidates 301 VincentMascittiandRalphP.Robinson
9.1Introduction 301
9.2Phlorizin:ADrugLeadfromAppleTrees 302
9.3Phlorizin:MechanismofAction 304
9.4Phlorizin,SGLTs,andDiabetes 306
9.5PhlorizinAnalogs: O-Glucosides 306
9.6PhlorizinAnalogs: C-Glucosides 309
9.7 C-Glucosides:AglyconeModifications 314
9.8 C-Glucosides:SugarModifications 316
9.9Conclusions 325 References 325
10AeruginosinsasThrombinInhibitors 333
JuanR.DelValle,EricTherrien,andStephenHanessian
10.1Introduction 333
10.2TargetingtheBloodCoagulationCascade 333
10.3StructureofThrombin 335
10.4TheAeruginosinFamily 336
10.4.1Aeruginosin298AandRelatedMicrocystissp.Peptides 336
10.4.2OscillarinandRelatedOscillatoriasp.Peptides 339
10.4.3DysinosinAandRelatedPeptidesfromDysidaedaeSponges 340
10.4.4StructurallyRelatedAntithrombinPeptideNaturalProducts 342
10.4.5CloseAnalogsofAntithromboticAeruginosins 344
10.5MimickingNature 346
10.5.1The50-YearChallenge 348
10.5.2PeptideAnalogs 350
10.5.3Peptidomimetics 352
10.6Conclusions 355
References 356
PartThreeNaturalProductsasanIncentiveforEnablingTechnologies 365
11MacrolidesandAntifungalsviaBiotransformation 367
AaronE.MayandChaitanKhosla
11.1IntroductiontoPolyketidesandTheirActivity 367
11.2MechanismofPolyketideBiosynthesis 367
11.2.1Erythromycin 371
11.2.2Avermectin/Doramectin 377
11.2.3Tetracyclines 381
11.2.4Salinosporamides 385
11.3Conclusions 391
References 392
12UnnaturalNucleosideAnalogsforAntisenseTherapy 403 PunitP.SethandEricE.Swayze
12.1NatureUsesNucleicAcidPolymersforStorage,Transfer,Synthesis, andRegulationofGeneticInformation 403
12.2TheAntisenseApproachtoDrugDiscovery 404
12.3TheMedicinalChemistryApproachtoOligonucleotide Drugs 406
12.4StructuralFeaturesofDNAandRNADuplexes 407
12.5ImprovingBindingAffinityofOligonucleotidesbyStructuralMimicry ofRNA 410
12.5.120 -ModifiedRNA 411
12.5.1.120 -O-MeRNA 411
12.5.1.220 -O-MethoxyethylRNA 412
12.5.1.320 -FluoroRNA 413
12.5.220 ,40 -BridgedNucleicAcids 414
12.5.2.120 ,40 -ConstrainedMOEand20 ,40 -ConstrainedEthylBNA 415
12.5.2.250 -Me-LNA 416
12.5.2.3CarbocyclicLNAAnalogs 417
12.5.2.4Ring-ExpandedBNAAnalogs 417
12.5.2.5 a-L-BridgedNucleicAcids 418
12.5.3HexitolNucleicAcids 420
12.6ImprovingBindingAffinityofOligonucleotidesbyConformational RestraintofDNA – theBicyclo-andTricyclo-DNAClassofNucleicAcid Analogs 421
12.7ImprovingBindingAffinityofOligonucleotidesbyConformational RestraintofthePhosphodiesterBackbone – a,b-ConstrainedNucleic Acids 423
12.8NaturallyOccurringBackboneModifications 424
12.8.1ThePhosphorothioateModification 425
12.9NaturallyOccurringHeterocycleModifications 426
12.9.15-SubstitutedPyrimidineAnalogs 427
12.10Outlook 428 References 429
13HybridNaturalProducts 441
KeisukeSuzukiandYoshizumiYasui
13.1Introduction 441
13.2Staurosporines(AminoAcid–SugarHybrids) 444
13.2.1Occurrence 444
13.2.2Bioactivity 445
13.2.3Biosynthesis 446
13.2.4Synthesis 446
13.2.5MedicinalChemistry 447
13.3Lincomycins(AminoAcid–SugarHybrids) 448
13.3.1Occurrence 448
13.3.2Bioactivity 448
13.3.3Biosynthesis 448
13.3.4MedicinalChemistry 449
13.4Madindolines(AminoAcid–PolyketideHybrids) 449
13.4.1Occurrence 449
13.4.2Bioactivity 450
13.4.3Synthesis 451
13.5Kainoids(AminoAcid–TerpeneHybrids) 451
13.5.1Occurrence 451
13.5.2Bioactivity 451
13.5.3Biosynthesis 453
13.5.4Synthesis 453
13.5.5MedicinalChemistry 453
13.6Benanomicin–PradimicinAntibiotics(Sugar–PolyketideHybrids) 455
13.6.1Occurrence 455
13.6.2Bioactivity 455
13.6.3MedicinalChemistry 456
13.6.4Synthesis 457
13.7Angucyclines(Sugar–PolyketideHybrids) 457
13.7.1OccurrenceandBiosynthesis 457
13.7.2Bioactivity 459
13.7.3Synthesis 460
13.8Furaquinocins(Polyketide–TerpeneHybrids) 462
13.8.1Occurrence 462
13.8.2Biosynthesis 464
13.8.3Synthesis 464
13.9 Conclusions 467 References 467
14RethinkingtheRoleofNaturalProducts:Function-OrientedSynthesis, Bryostatin,andBryologs 475
PaulA.Wender,AlisonC.Donnelly,BrianA.Loy,KatherineE.Near,and DarylStaveness
14.1Introduction 475
14.2IntroductiontoFunction-OrientedSynthesis 476
14.2.1RepresentativeExamplesofFunction-OrientedSynthesis 478
14.3IntroductiontoBryostatin 489
14.4BryostatinTotalSyntheses 493
14.4.1TotalSynthesesofBryostatins2,3,and7(1990–2000) 493
14.4.2TotalSynthesisofBryostatin16(2008) 494
14.4.3TotalSynthesisofBryostatin1(2011) 495
14.4.4TotalSynthesisofBryostatin9(2011) 495
14.4.5TotalSynthesisofBryostatin7(2011) 495
14.5ApplicationofFOStotheBryostatinScaffold 496
14.5.1InitialPharmacophoricInvestigationsontheBryostatinScaffold 498
14.5.2DesignoftheFirstSyntheticallyAccessibleFunctionalBryostatin Analogs 500
14.5.3InitialPreclinicalInvestigationsofFunctionalBryostatinAnalogs 508
14.5.4Des-A-RingAnalogs 510
14.5.5C13-FunctionalizedAnalogs 514
14.5.6B-RingDioxolaneAnalog 516
14.5.7C20Analogs 518
14.5.8C7Analogs 520
14.5.9A-RingFunctionalizedBryostatinAnalogs 522
14.5.10NewMethodology:Prins-DrivenMacrocyclizationTowardB-RingPyran Analogs 527
14.5.11A-RingFunctionalizedAnalogsandInductionofLatentHIV Expression 529
14.6Conclusions 533 References 533
15CyclopamineandCongeners 545
PhilippHeretschandAthanassiosGiannis
15.1Introduction 545
15.2TheDiscoveryofCyclopamine 545
15.3AccessibilityofCyclopamine 547
15.4TheHedgehogSignalingPathway 549
15.5MedicalRelevanceofCyclopamineandtheHedgehogSignaling Pathway 551
15.5.1ModelsofCancerInvolvingtheHedgehogSignalingPathway 551
15.5.2HedgehogSignalingPathwayInhibitorsfortheTreatmentofPancreatic Cancer,Myelofibrosis,andChondrosarcoma 552
15.5.3ProdrugsofCyclopamine 555
15.6FurtherModulatorsoftheHedgehogSignalingPathway 556
15.7SummaryandOutlook 558
References 558
PartFiveNature:TheProvider,theEnticer,andtheHealer 565
16Hybrids,Congeners,Mimics,andConstrainedVariantsSpanning30 YearsofNaturalProductsChemistry:APersonalRetrospective 567 StephenHanessian
16.1Introduction 567
16.2Structure-BasedOrganicSynthesis 570
16.3Nucleosides 572
16.3.1Quantamycin 572
16.3.2MalayamycinA 573
16.3.3Hydantocidin 573
16.4 b-Lactams 576
16.4.1AnalogDesign 576
16.4.2Unnatural b-Lactams 577
16.5Morphinomimetics 579
16.6HistoneDeacetylaseInhibitors 580
16.6.1AcyclicInhibitors 581
16.6.2MacrocyclicInhibitors 582
16.7PactamycinAnalogs 583
16.8Aeruginosins:FromNaturalProductstoAchiralAnalogs 586
16.8.1Structure-BasedHybridsandTruncatedAnalogs 586
16.8.2ConstrainedPeptidomimetics 589
16.8.3AchiralInhibitors 589
16.9AvermectinB1a andBafilomycinA1 591
16.10BafilomycinA1 592
16.113-N,N-DimethylaminoLincomycin 594
16.12OxazolidinoneKetolideMimetics 595
16.13Epilogue 596
References 598
Index 611
ListofContributors
Karl-HeinzAltmann ETHZurich InstituteofPharmaceuticalSciences DepartmentofChemistryand AppliedBiosciences Wolfgang-Pauli-Str.10 HCIH405 8093Z € urich Switzerland
GordonM.Cragg DCTDandFNLCR NaturalProductsBranch DevelopmentalTherapeutics Program Frederick,MD21702 USA
JuanR.DelValle MoffittCancerCenter DrugDiscoveryDepartment 12902MagnoliaDr. Tampa,FL33612 USA
AlisonC.Donnelly StanfordUniversity DepartmentsofChemistryand ChemicalandSystemsBiology 337CampusDr Stanford,CA94305 USA
AliceL.Erwin ErwinConsulting 110CollegeAvenue#2 Somerville,MA02144 USA
ArunK.Ghosh PurdueUniversity DepartmentofChemistryand DepartmentofMedicinalChemistry 560OvalDrive WestLafayette,IN47907-2084 USA
GiuseppeGiannini RDCorporateSigma-TauIndustrie FarmaceuticheRiuniteS.p.A. 00040Pomezia,Rome Italy
AthanassiosGiannis UniversityofLeipzig InstituteforOrganicChemistry Johannisallee29 04103Leipzig Germany
StephenHanessian UniversitedeMontreal DepartmentofChemistry C.P.6128,SuccursaleCentre-Ville Montreal,QuebecH3C3J7 Canada
PhilippHeretsch RiceUniversity BioScienceResearchCollaborative 6500MainStreet Houston,TX77030
USA
TomasHudlicky BrockUniversity DepartmentofChemistryandCentre forBiotechnology
500GlenridgeAvenue St.Catharines,OntarioL2S3A1 Canada
AnushreeKamath StateUniversityofNewYork DepartmentofChemistryand InstituteofChemicalBiology& DrugDiscovery StonyBrook,NY11794-3400
USA
ChaitanKhosla StanfordUniversity DepartmentsofChemistry,Chemical Engineering,andBiochemistry 380RothWay Stanford,CA94305
USA
JasonG.Lewis Ardelyx 34175ArdenwoodBlvd.,Suite100 Fremont,CA94555
USA
BrianA.Loy StanfordUniversity DepartmentsofChemistryand ChemicalandSystemsBiology Stanford,CA94305
USA
VincentMascitti PfizerGlobalR&D GrotonLaboratories EasterPointRoad Groton,CT06340
USA
AaronE.May StanfordUniversity DepartmentsofChemistry,Chemical Engineering,andBiochemistry 380RothWay Stanford,CA94305
USA
KatherineE.Near StanfordUniversity DepartmentsofChemistryand ChemicalandSystemsBiology 337CampusDr Stanford,CA94305
USA
DavidJ.Newman DCTDandFNLCR NaturalProductsBranch DevelopmentalTherapeutics Program Frederick,MD21702
USA
HardwinO’Dowd VertexPharmaceuticals 130WaverlyStreet Cambridge,MA02139
USA
IwaoOjima StateUniversityofNewYork DepartmentofChemistryand InstituteofChemicalBiology& DrugDiscovery StonyBrook,NY11794-3400
USA
StefanoRizzo
MaxPlanckInstituteof MolecularPhysiology DepartmentofChemicalBiology Otto-Hahn-Str.11 44227Dortmund
Germany
RalphP.Robinson PfizerGlobalR&D GrotonLaboratories EasterPointRoad Groton,CT06340 USA
DieterSchinzer
Otto-von-GuerickeUniversit€ at Magdeburg ChemischesInstitut Lehrstuhlf € urOrganischeChemie Universitatsplatz2 39106Magdeburg Germany
JoshuaD.Seitz StateUniversityofNewYork DepartmentofChemistryand InstituteofChemicalBiology& DrugDiscovery StonyBrook,NY11794-3400 USA
PunitP.Seth IsisPharmaceuticals DepartmentofMedicinalChemistry 2855GazelleCourt Carlsbad,CA92010 USA
DarylStaveness StanfordUniversity DepartmentsofChemistryand ChemicalandSystemsBiology 337CampusDr Stanford,CA94305 USA
ListofContributors j XVII
KeisukeSuzuki TokyoInstituteofTechnology DepartmentofChemistry 2-12-1,O-okayama Meguro-ku,Tokyo152-8551 Japan
EricE.Swayze IsisPharmaceuticals 2855GazelleCourt Carlsbad,CA92010 USA
EricTherrien MolecularForecasterInc. 969Marc‐AureleFortin Laval,QuebecH7L6H9 Canada
VimalVarghese BrockUniversity DepartmentofChemistryand CentreforBiotechnology 500GlenridgeAvenue St.Catharines,OntarioL2S3A1 Canada
VijayWakchaure
MaxPlanckInstituteof MolecularPhysiology DepartmentofChemicalBiology Otto-Hahn-Str.11 44227Dortmund Germany
HerbertWaldmann MaxPlanckInstituteof MolecularPhysiology DepartmentofChemicalBiology Otto-Hahn-Str.11 44227Dortmund Germany
PaulA.Wender StanfordUniversity DepartmentsofChemistryand ChemicalandSystemsBiology
337CampusDr Stanford,CA94305
USA
KaiXi PurdueUniversity DepartmentofChemistryand DepartmentofMedicinalChemistry
560OvalDrive WestLafayette,IN47907-2084
USA
YoshizumiYasui KanagawaUniversityofHuman Services FacultyofHealthandSocialWork 1-10-1,Heiseicho Yokosuka,Kanagawa238-8522
Japan
Preface
TheEbersPapyrus,originatingfromabout1500BC,isoneoftheoldestdocuments thatdescribetheuseofnaturalproductsforhealingdiseases.Severalherbsare describedinitsabout700remediesandmagicalformulas,forexample,thesquill (Urgineamaritima)againstdropsy(edemacausedbycardiacinsuffi ciency).Indeed, thisplantcontainscardiacglycosidesthatarebeneficialinsuchacondition.Another importantdocument,fromthe firstcenturyAD,isthebookDeMateriaMedicaof theGreekphysicianDioscurides.Itlistsabout600medicinalplants,35animal products,and90minerals.Obviously,thesecollectionsofremediesresultedfrom theaccumulatedexperienceofearliermillennia.Notallcontainedinformationis reliable;inlatercenturies,thewheathadtobeseparatedfromthechaff,ataskthat stilltodayisnotcompletelyaccomplishedifweconsidersomanymarketedherbal preparationswithoutproventherapeuticvalue.Ontheotherhand,opium,thefeverloweringbarkoftheCinchonatree,thefoxglove(Digitalispurpurea),andmanyother herbaldrugsremainedintherapy,laterbeingreplacedbytheisolatedactive principlesmorphine,quinine,digitoxin,andothers.
Themainsourcesofdrugsfromnatureorleadstructuresforsuchdrugsare plants,microorganisms,animals,andhumans.Plantsprovidedrugsandlead structuresforthetreatmentofalargevarietyofdifferentdiseases.Microorganisms yieldmainlyantibioticsbutalsoothertherapeuticprinciples,forexample,the importantstatins.Animaltoxinsalmostexclusivelyserveaspharmacologicaltools, buthumanneurotransmittersandhormoneswere,andstillare,valuableleadsfor morepotentandselectiveanalogs,sometimesevenwithinversepharmacological activities.Themainadvantageofmanynaturalproductsistheirthree-dimensional structure,avoidingthe “flatness” ofsomanysyntheticcompounds,andtheirhigh degreeofchemicaldiversity,goingfarbeyondthecreativityoforganicchemists. However,thisisalsotheirmaindisadvantage,besidestheproblemsofaccessibility (considertheearlyproblemsintaxolsupply);duetothecomplexityoftheir structures,chemicalvariationisoftensodifficultandcostlythatpharmacompanies hesitatetoinvestintheiroptimization.Ontheotherhand,naturalproducts, whetherresultingfromplantsorfrommicroorganisms,areexcellentleadstructures,fromtheviewpointofligand–targetinteractions.Intheirbiosynthesis,all plantsecondarymetaboliteshavealready “seen” thebindingsiteofaprotein;thus, theirstructuralfeaturesandpropertiesmediatetheinteractionwithproteins.In
addition,manyofthesecompoundsserveacertainpurpose;theyprotectaplantthat cannotrunawayinsightofapredator,becausetheyarebitter,sharp,orslightlytoxic (onlybadexperiencetrainsthepredatortoavoidacertainplant – adeadanimal cannotlearnanymore!).Correspondingly,inevolution,theplantsproducingsuch compoundshadabetterchancetosurviveandtoreproduce.Microorganismsneed antibioticstocompetewithothermicroorganisms.Lastbutnotleast,animaland humanactiveprinciplesareperfectleadstructuresbecausetheyactatendogenous receptorsandothertherapeuticallyrelevanttargets.
Therearealreadynumerousbooksontheroleofnaturalproductsindrug research – therefore,whypresentanotherone?Thesimplereasonisthatnatural productswerenotonlyimportantinthepast.Taxol,thestatins,artemisinin,and epothilonearejustafewexamplesofnaturalproductsthatrecentlyyielded importantandsuccessfulnewdrugsandmanymoreareunderactiveinvestigation. Arecentpublicationanalyzedtheoriginof1073newchemicalentities(small molecules,excludingbiologicals)oftheyears1981–2010[1]:6%ofthesedrugswere naturalproductsthemselves,28%werederivativesofnaturalproducts,14%were characterizedasmimicsofnaturalproducts,and16%assyntheticswhosepharmacophorewasderivedfromanaturalproduct.Intotal,almost2/3ofthenewly introduceddrugsoriginatedinsomemannerfromanaturalproduct!Thispredominanceofnaturalproductsisevenmorepronouncedintheareaofanticancerdrugs andinthe fieldofantibiotics.
WeareverygratefultoStephenHanessian,aworld-leadingexpertinthe fieldof naturalproductchemistry,forundertakingthetasktoeditthisbookwithsomany chaptersonrecentdevelopmentsandsuccessstories.Inaddition,wearegratefulto allchapterauthorsfortheirexcellentwork,whichprovidesacomprehensive overviewofcurrentresearchonnewdrugsfromnaturalproducts.Finally,we wouldliketothankFrankWeinreichandHeikeNotheofWiley-VCHVerlagGmbH fortheirongoingcommitmenttoourbookseriesMethodsandPrinciplesin MedicinalChemistry.
October2013
Dusseldorf,Germany
RaimundMannhold WeisenheimamSand,Germany HugoKubinyi Zurich,Switzerland GerdFolkers
Reference
1 Newman,D.J.andCragg,G.M.(2012) Naturalproductsassourcesofnewdrugs overthe30yearsfrom1981to2010. JournalofNaturalProducts, 75,311–335.
PersonalForeword
Naturehasbeenanabundantsourceofbioactivecompoundsformillennia.Modern sciencehasunraveledthecomplexmoleculararchitecturesofnaturalproductsoften possessinganunusualassortmentoffunctionalgroupsthatwouldhavedefiedall oddsonlyafewdecadesago.
Naturehasalsobeentheprovider,theenticer,andthehealer.Indeed,someofthe mostimpressivecontributionstothe fieldoforganicchemistryhavebeenassociated withthedesignandtotalsynthesisofnaturalproducts.Thesamecouldbesaidoftheir biologicalactivities,modeofaction,andtherapeuticvalue.Thesemajoradvancesat theinterfacebetweenthechemistryandbiologyofnaturalproductshaveshowcased thecourage,resolve,and,aboveall,thepassionofdedicatedscientists.
Asthetitleitselfreflects,thisbookisdedicatedtotheimportanceofnatural productsinmedicinalchemistry.Structuredinto fivethematicparts,thebook consistsof16chapters,eachcontributedbyexpertsinthe field,whohaveadmirably writtenabouttheirseminalcontributionsovertheyearstoaddressdiverseaspectsof naturalproductsinchemistryandbiology.The fivethemescoverprincipallythe importanceofnaturalproductsasdrugs,platformsforbothchemicalandgenetic modificationstocreatenewerentities,uniquecollectionsofbiogeneticallydiverse compounds,andinspirationpointsforthedesignandsynthesisofsurrogates, mimics,hybrids,andchimeras.
Ithankallthecontributorsfortheireffortsandcollegialityinmakingthisavery specialvolumethatwillbepedagogicallyandpracticallyinformativetostudentsand professionalsalike.
October16,2013
StephenHanessian
NaturalProductsinMedicinalChemistry,FirstEdition.EditedbyStephenHanessian. 2014Wiley-VCHVerlagGmbH&Co.KGaA.Published2014byWiley-VCHVerlagGmbH&Co.KGaA.
NaturalProductsasDrugsandLeadstoDrugs:AnIntroduction andPerspectiveasoftheEndof20121)
DavidJ.NewmanandGordonM.Cragg
1.1 Introduction
Twoveryfrequentcomments(togetherorseparately)thathavebeenmade,in writingandverbally,overthelast15–20yearscanbesummarizedasfollows:
Theuse(orpursuit)ofnaturalproductsaseitherdrugsorasleadstonew chemistrythatwillleadtodrugsisnowpasse,andthatwhatisneededisthe useofveryhigh-throughputscreens,coupledtolargenumbersofnovel moleculesproducedbycombinatorialchemistry.
Thecleveruseofcomputationalmethodsto fi tcompoundsintotheactive sitesoftheenzyme(orreceptor)ofinterestwillpermitthederivationoflarge numbersofdrugstobediscoveredandthencommercializedrapidlyasaresult.
Wethinkthatperhapsthebestanswertocommentssuchasthesecanbeseenin twosimplegraphicalmodelsshowninFigures1.1and1.2.InFigure1.1,wehave plottedthenumberofsmall ie meaninguptoroughly45aminoacidresidues,with Byetta1 beingtheupperlimit,againstthenumberof “N” and “S ” classificationsas definedinRef.[1]fromJanuary1,1981throughDecember31,2012.InFigure1.2,we havetakenthetotalnumberof “N-related” approveddrugsoverthesametimeframe asapercentageoftheapproveddrugsforthatyear.Themeanpercentageperyearof “N-deriveddrugs” thestandarddeviationoverthistimeframeis33.4 8.9%,andin 2010,50%ofthe18approvedsmall-moleculedrugswereinthiscategory. Whatmustbeborneinmindisthatthesearethemostconservative figuresaswe onlycountadrugonce,intheUnitedStatesifitwas firstapprovedbytheFDA (FoodandDrugAdministration)ortheapprovingcountry’sequivalentoftheFDA. Thus,compoundsthataresubsequentlyapprovedforanotherdiseaseeitherinthe sameorinadifferentcountry,orwhosepharmaceuticalpropertiesareextendedby slowreleaseorbycombinationwithotheragents,arenotcountedagain.Thereare afewexceptionstothisgeneralrulesuchastheuseofnanoparticle-associated
1) Theopinionsexpressedinthischapterarethoseofauthors,andnotoftheUSGovernment.
NaturalProductsinMedicinalChemistry,FirstEdition.EditedbyStephenHanessian. 2014Wiley-VCHVerlagGmbH&Co.KGaA.Published2014byWiley-VCHVerlagGmbH&Co.KGaA.
Figure1.1 Numbersofnaturalproduct-related(NplusS )smallmoleculesperyear(1981—2012).
albuminsinthecaseofsomeversionsofTaxol1 andcombinationsofdifferent modifi edinsulins,butthese,however,accountforlessthan0.3%ofabout1500 compounds(smallandlarge)approvedinthelast32years.
InFigure1.3,wehaveshownthebreakdownbycategory,againusingthe classificationsusedpreviously[1]ofalldrugsandsmalldrugsapprovedover thelast32yearsfromJanuary1,1981throughDecember31,2012,whichshould bestudiedbytheinterestedreader.Again,ifonelooksatthesediagrams,therole ofnaturalproductstructuresasleads(N-andS -linkedmaterials)isstillvery signifi cantandevenin2011–2012,41ofthe62small-moleculedrugsfellintothese categories(datanotshownbutavailablefromtheauthorsonrequest).
Inaddition,inFigure1.4,asbefitsauthorsfromtheUSNationalCancerInstitute (NCI),wehaveshownthebreakdownforallantitumordrugsfromthebeginningof chemotherapytreatmentsinthemid-1930s,usingvariationsonthemustardgasused inwarfareinWorldWarI,throughtothelargenumberoftyrosineproteinkinase inhibitorsapprovedinthelastfewyears, withalmostallbeingisosteresofATPand bindingattheATPsite.Asalreadymentioned,inthe2011–2012NtoS breakdown, 16ofthe18small-moleculeantitumordrugsfellintotheseclassifications.The isosterelinkwasreconfirmedbyanexcellentpresentationgivenbyFabbro[2]of NovartisattherecentNAD2012Meeting inOlomouc,theCzechRepublicinJuly
Figure1.2 Percentageofnaturalproductrelated(N)smallmoleculesperyear(1981—2012).
1.2TheSponge-DerivedNucleosideLinktoDrugs 5
2012.Finallyinthissection,theinfluenceofnaturalproductstructuresonantitumor agentsissuchthatifonesumsthe “N-related” thentheansweris89or47%,withthe “S -related” equaling38or20%overall.Thus,onecanseethatnaturalproductrelatedcompoundsinthisdiseasecategoryequal67%ofallapprovedsmall-molecule drugentitiesinthistimeframe.Althoughnotshown,comparable figuresarealso seenforanti-infectiveagentsoverthe 32-yeartimeframecoveredbyFigure1.3 (wehavenotgonebacktothelate1930sforthesedata,butmaywelldosointime).
1.2
TheSponge-DerivedNucleosideLinktoDrugs
Untilaboutthe1960s,itwasaxiomaticthatifyouwishedtomakeabiologicallyactive nucleoside-derivedmolecule,youcouldmodifythebaseincludingsubstitutionsthat
Figure1.3 Sourcesofallapproveddrugs1981—2012.
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Henry Beauclerc removed his dwelling from the river margin to the crest of hill, building the First King’s House. This pile extended from the Devil’s tower to the Watch tower, now renamed Victoria tower. A part of Beauclerc’s edifice remains in massive walls of the Devil’s tower, and a cutting through the chalk, sustained by Norman masonry, leading from a shaft under the Queen’s apartment to the southern ditch.
Henry of Winchester, a man of higher genius as an architect, built the Second King’s House, sweeping into his lines the lower ground, which he covered by walls and towers, including Winchester tower, and the whole curtain by Curfew tower and Salisbury tower, round to the Lieutenant’s lodgings, now called Henry the Third’s tower. The Second King’s House, long since ruined and removed, stood on the site of the present cloisters. Much of Henry of Winchester’s work remains; in fact, the circuit of the lower ward is mainly his, both walls and towers, from the Devil’s tower, touching the upper ward, round to Curfew tower in the north-west angle of the lower ward.
Edward of Windsor built the Third King’s House, fronting towards the north, and gave the upper ward its final shape. On introducing a new patron saint to Windsor, Edward removed his own lodging, and renounced the lower ward entirely to the service of St. George. First came the chapel of St. George; next came the College of St. George; then came the Canons of St. George; lastly, came the Poor Knights of St. George. The central ground was given up to the chapel, and the adjoining quarter to the college. From Curfew tower to the Lieutenant’s lodgings, all the ground was consecrated to the saint. The first tower, reckoning from the south, became Garter House, the second Chancellor’s tower, the third Garter tower, while the land within the walls was covered by residences for the military knights. An area equal to the upper baily was surrendered to his patron saint.
Edward of York rebuilt St. George’s Chapel on a larger scale; for Edward of York had heavy sins to weigh him down, and pressing need for saintly help.
Henry of Richmond roofed that chapel, built a “new tower” in the King’s House, and made a fair causeway from Windsor to London— the first road ever made between the castle and the capital.
Queen Elizabeth built the gallery which bears her name, and raised the great terraces above the Thames. Before her time the scarp was rough and steep: she built this solid wall, and laid this level road.
George the Fourth raised the Norman keep in height, flanked the park entrance with another tower, opened St. George’s gate, buttressed the North-east tower, and called his new edifice Brunswick tower.
Like Queen Elizabeth, Queen Victoria has devoted her attention rather to the slopes and gardens than the structure; but the few additions of her reign have been effected with a proper reverence for the ancient pile. Her Majesty has cleared off slum and tenement from the slopes, and opened the southern terrace, just as Elizabeth opened the northern terrace. Work has been done in cloister and chapel. As Henry of Richmond made a road from Windsor to London, Queen Victoria has brought two railways to her castle gates.
Since the days of Edward of Windsor the Castle hill has kept the triple character—upper ward, middle ward, and lower ward—baily of the King, baily of the keep, and baily of St. George—the residence of our sovereign, the symbol of our power, the altar of our saint.
Royal Windsor (London, 1879).
THE CATHEDRAL OF COLOGNE.
ERNEST BRETON.
WE are now in the middle of the Tenth Century and in the city of Cologne; for several hours a man has been sitting upon the banks of a river, flowing majestically at the base of those ramparts which sixty years ago were erected by Philip von Heinsberg, and for several hours his thoughtful brow has not been lifted. This man was the first master-workman of his time; three centuries later he was called the prince of architects. The Archbishop of Cologne had said to him: “Master, we must build a cathedral here which will surpass all the buildings of the world in grandeur and magnificence.” The artist replied: “I will do it;” and now he was pondering over ways of accomplishing his promise about which he was frightened. At this moment he was trying to think out a marvellous plan which would give lustre to his country and immortalize his name; but nothing came into his mind worthy of the prodigy he was trying to conceive and could not create.
An unknown old man now approached and sat beside him, regarding him with a mocking air, as if he rejoiced in his perplexity and despair; every now and then he gave a little, dry cough, and when he had attracted the attention of the artist, he rapidly traced on the sand with a ring some lines which he immediately effaced. These lines formed exactly that plan which always escaped the artist and whose fugitive image he could not seize.
“You would like to have this plan?” asked the old man.
“I would give all I possess for it.”
“I exact nothing. The building that you construct will be the envy and the eternal despair of all your successors, the admiration of
centuries to come, and your brilliant and celebrated name will be known to the most remote generations. Your life will be long; you will pass it in glory, wealth, and pleasure. For all that I only ask for your soul when your life draws to its close.”
“Vade retro Satanas!” cried the agitated artist. “Better the nothingness of oblivion than eternal damnation.”
“Patience,” said Satan, “reflect: we shall see,” and he vanished. The master-workman returned to his humble dwelling, sadder and more dreamful than when he left it; he could not close his eyes all night. Glory, wealth, and pleasure for many long years, and all that for one word! In vain he tried to shake himself free from the fatal temptation; at every moment, at every step he again saw the tempter showing him his transitory plan; he succumbed.
“To-morrow, at midnight,” said Satan, “go to that spot and I will bring you the plan and the pact that you must sign.”
The artist returned to the city, divided between remorse and dreams of pride and ambition. Remorse conquered, and before the appointed hour he had told everything to his confessor. “It will be a master-stroke,” said the latter, “to deceive Satan himself and snatch the famous plan from him without paying the price of your soul,” and he sketched out the line of conduct that he should follow.
At the appointed hour the two parties stood face to face. “Here,” said Satan, “are the plan and pact; take it and sign it.” Quick as lightning the master-workman snatched the plan with one hand and with the other he brandished a piece of the True Cross, which the wily confessor had given to him. “I am vanquished,” cried Satan, “but you will reap little benefit through your treachery. Your name will be unknown and your work will never be completed.”
Such is the legend of the Cathedral of Cologne. I have told it here so that the admiration of the Middle Ages for this plan, which could not be considered the work of any human genius, may be measured, and for six centuries the sinister prediction of Satan has held good.4
At the north-east end of the elevation occupied by the ancient Colonia Agrippina, in the spot where the choir of the Cathedral raises its magnificent pinnacles, there existed in very remote ages a Roman Castellum. At a later period this was replaced by a palace of the French kings, which Charlemagne gave to his chancellor and confessor Hildebold....
The Cathedral of Cologne was one of the most ancient seats of Christianity in Germany; it contained in its jurisdiction the capital of Charlemagne’s Empire, the city where the Emperors were crowned. In the Twelfth Century, Frederick Barbarossa enriched it with one of those sacred treasures which in a time of faith attracted entire populations and gave birth to the gigantic enterprises which seem so incredible in our positive and sceptical age. All eyes were turned to the Holy Land, and the pilgrims of Germany, as well as of other countries, before undertaking this perilous voyage came by the thousands to the tomb of the Magi, to pray to God that the same star which guided the Three Wise Men to Christ’s cradle might lead them to his tomb. The celebrity and wealth of the Cologne Cathedral was greatly due to the custom of the Emperors visiting it after their coronation. Thus, from the moment it was in possession of the sacred relics, everything combined to augment its splendour; princes, emperors, and people of all classes were eager to add to its treasures. Therefore, it was only a natural consequence to erect on the site of the old Cathedral of St. Peter a building more vast and magnificent, and which would accord better with its important destiny The Archbishop Angebert, Count of Altena and Berg, upon whom Frederick II. conferred the dignity of vicar of the empire, conceived the first idea; but at about the age of forty he was assassinated by his cousin, the Count of Ysembourg, in 1225, and the enterprise was abandoned. Finally, a great fire devoured the Cathedral in 1248 and its immediate reconstruction was indispensable....
THE CATHEDRAL OF COLOGNE
Everyone knows that almost all churches of the pointed arch which occupied several centuries in building show the special mark of the periods in which their various additions were constructed; this is not the case with the Cathedral of Cologne, which is peculiar in the fact that its foundations and its additions were all constructed on one and the same plan, which preserves the original design, and therefore it presents a rare and admirable unity.
On the side of the Rhine, or rather on the Margreten, between the Trankgass and the Domhof, the choir of the basilica offers the most imposing effect. It is only from this side that the edifice seems to have an end. The end of the roof, edged in all its length by an open-worked ridge, is surmounted by an enormous cross, nine
metres high, finished with a fleur-de-lis at each extremity This cross, weighing 694 kil., was only placed there on August 3, 1825, but it was long in existence, having been, it is said, presented to the church by Marie de’ Medici. In the centre of the transept there rose a bell-tower, 65 metres high, which was demolished in 1812. The plan carries a superb flèche of stone, open-worked like the spires of the façade, and about 100 metres high.
Fifteen flying-buttresses on each side proceed from the central window and sustain the choir, leaning against the buttresses and surmounted by elegant pyramids. Each of these pyramids carries twelve niches destined to hold angels two metres high, many of which have been restored lately by Wilhelm Imhoff. The upper part of the flying-buttresses, at the point where they meet the balustrade of the roof, is crowned by another and more simple pyramid. Finally, between these flying-buttresses in the upper part of the wall of the choir, magnificent mullioned windows are disclosed. The entire edifice is covered with gargoyles, each more bizarre than the other....
Entering the cathedral by the door at the foot of the northern tower, you find yourself in the double-lower northern nave. The first bays do not contain altars, but their windows reveal magnificent panes, of the beginning of the Sixteenth Century. The Archbishop Herman von Hesse, the Chapter, the City, and many noble families united to have them painted by the most distinguished artists of the period, which was the apogee of Art in Germany; and therefore here are many of the most admirable chefs d’œuvre of glass-painting....
The Chapel of the Kings is almost entirely occupied by the building erected in 1688 and ornamented by Ionic pilasters of marble, and which, shut in by grilles and many locks, contains the marvellous reliquary in which are preserved the relics of the Three Magi. According to Buttler, these relics were found by Saint Helena, mother of Constantine, during her pilgrimage to the Holy Land; she carried them carefully to Constantinople. Soon afterwards the Archbishop Eustorge, to whom the Emperor had presented them, brought them to Milan, where they were deposited in the church subsequently consecrated to the same Eustorge, who was canonized. When Frederick Barbarossa invaded the town in 1163,
Reinald von Dassile, Archbishop of Cologne, received them as a reward for the services which he had rendered to the Emperor during the siege. At the same time Reinald obtained several relics of the Maccabees, of the Saints Apollinaris, Felix, Nabor, Gregory di Spoletto, etc. He, himself, accompanied this treasure, which crossed Switzerland in triumph, descended the Rhine to Remagen, where he gave it to Philip of Heinsberg, then provost of the Chapter.
On July 23, 1164, the relics were deposited in the ancient cathedral, from which they were transferred to the new one; they were guarded there simply by an iron grille until the Archbishop Maximilian Heinrich constructed the building which encloses them today, upon whose pediment you see sculptured in marble, by Michael Van der Voorst of Antwerp, the Adoration of the Magi, Saint Felix, Saint Nabor, and two female figures guarding the arms of the Metropolitan Chapter, in the midst of which figure those of the Archbishop Maximilian Heinrich. On the frieze you read the inscription: “Tribus ab oriente regibus devicto in agnitione veri numinis capitulum metropol erexit.” Above the grilled window, which is opened during grand ceremonies to permit the people to see the reliquary, is written:
“Corpora sanctorum recubant hic terna magorum; Ex his sublatum nihil est alibive locatum.”
Finally, above the reliquary placed to the right and left between the columns one reads: “Et apertis thesauris suis obtulerunt munera.”
In 1794 the relics were carried to the treasury of Arnsberg, then to Prague, where the three crowns of diamonds were sold, and finally to Frankfort-on-the-Main. When they were brought back in 1804, the reliquary was repaired and put in its old place. This reliquary, a chef d’œuvre of Twelfth Century orfèvrerie, is of gilded copper with the exception of the front, which is of pure gold; its form is that of a tomb; its length 1 m. 85, its breadth 1 m. at the base, its height 1 m. 50; on the side turned to the west you see represented
the Adoration of the Magi and the baptism of Jesus Christ. Above the sculpture is a kind of lid which may be raised, permitting you to see the skulls of the Three Kings ornamented with golden crowns garnished with Bohemian stones,—a kind of garnet; in the pediment is the image of the Divine Judge sitting between two angels who hold the attributes of the Passion; the two busts above represent Gabriel and Raphael; and, finally, an enormous topaz occupies the summit of the pediment. The right side of the reliquary is ornamented with images of the prophets, Moses, Jonah, David, Daniel, Amos, and Obadiah. The apostles Paul, Philip, Simon, Thomas, and Judas Thaddeus are placed in six niches above. In the left side you see the prophets Ezekiel, Jeremiah, Nahum, Solomon, Joel, and Aaron, and the apostles Bartholomew, Matthew, John the Lesser, Andrew, Peter, and John the Great. The back of the monument presents the flagellation of Jesus Christ, the Virgin Mary, Saint John, the Saviour on the Cross, Saint Felix, Saint Nabor, the Archbishop Reinald and eight busts of angels. The monument is surmounted by an openwork ridge of copper lace. This magnificent reliquary is covered with more than 1,500 precious stones and antique cameos representing subjects which are not exactly Christian such as the apotheosis of an Emperor, two heads of Medusa, a head of Hercules, one of Alexander, etc. Behind the reliquary is a bas-relief in marble 1 m. 33 in height and 1 m. 40 in length, representing the solemn removal of the relics. The bas-reliefs of richly-gilt bronze, placed below the windows which occupy the back of the chapel, represent the Adoration of the Magi: these were the gift of Jacques de Croy, Duke of Cambrai in 1516. This window is ornamented with beautiful panes of the Thirteenth Century, representing various subjects of sacred history.
Jules Gaillhabaud, Monuments anciens et modernes (Paris, 1865).
