Natural Products in Medicinal Chemistry

654 Pages·2014·11.24 MB·English

by  Stephen Hanessian

Edited by Stephen Hanessian
Natural Products in
Medicinal Chemistry
Volume 60
Series Editors:
R. Mannhold, H. Kubinyi,
G. Folkers
Methods and Principles in Medicinal Chemistry

Editedby
StephenHanessian
NaturalProductsin
MedicinalChemistry
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Natural Products in Medicinal Chemistry
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V
Contents
ListofContributors XV
Preface XIX
PersonalForeword XXI
PartOne NaturalProductsasSourcesofPotentialDrugsandSystematic
CompoundCollections 1
1 NaturalProductsasDrugsandLeadstoDrugs:AnIntroductionand
PerspectiveasoftheEndof2012 3
DavidJ.NewmanandGordonM.Cragg
1.1 Introduction 3
1.2 TheSponge-DerivedNucleosideLinktoDrugs 5
1.3 InitialRecognitionofMicrobialSecondaryMetabolites
asAntibacterialDrugs 8
1.4 b-LactamsofAllClasses 9
1.5 TetracyclineDerivatives 12
1.6 GlycopeptideAntibacterials 13
1.7 LipopeptideAntibacterials 16
1.8 MacrolideAntibiotics 18
1.9 PleuromutilinDerivatives 19
1.10 PrivilegedStructures 21
1.11 TheOriginoftheBenzodiazepines 21
1.12 Benzopyrans:ASourceofUnusualAntibacterialand
OtherAgents 22
1.13 MultipleEnzymaticInhibitorsfromRelativelySimpleNatural
ProductSecondaryMetabolites 23
1.14 AVariationonBIOS:The“Inside–Out”Approach 26
1.15 OtherPrivilegedStructures 26
1.16 PrivilegedStructuresasInhibitorsofProtein–Protein
Interactions 27
1.17 UnderprivilegedScaffolds 30
VIjContents
1.18 SoWhereShouldOneLookintheTwenty-FirstCenturyforNovel
StructuresfromNaturalSources? 31
1.19 Conclusions 33
References 33
2 NaturalProduct-DerivedandNaturalProduct-InspiredCompound
Collections 43
StefanoRizzo,VijayWakchaure,andHerbertWaldmann
2.1 Introduction 43
2.2 ModernApproachestoProduceNaturalProductLibraries 44
2.3 PrefractionatedNaturalProductLibraries 45
2.4 LibrariesofPureNaturalProducts 46
2.5 SemisyntheticLibrariesofNaturalProduct-DerivedCompounds 46
2.6 SyntheticLibrariesofNaturalProduct-InspiredCompounds 47
2.6.1 Solid-PhaseTechniques 48
2.6.2 Solution-PhaseTechniques 50
2.6.3 Solid-SupportedReagentsandScavengers 55
2.6.4 TaggingApproach 58
2.7 CompoundCollectionswithCarbocyclicCoreStructures 60
2.7.1 Illudin-InspiredCompoundCollection 60
2.7.2 Lapochol-InspiredNaphthoquinoneCollection 61
2.7.3 ACompoundCollectionwithDecalinCoreStructure 62
2.8 CompoundCollectionswithOxa-HeterocyclicScaffolds 63
2.8.1 Carpanone-InspiredCompoundCollection 63
2.8.2 Calanolide-InspiredCompoundCollection 64
2.8.3 Benzopyran-InspiredCompoundCollection 65
2.9 CompoundCollectionswithAza-HeterocyclicScaffolds 66
2.9.1 Solution-PhaseSynthesisof((cid:2))MarinopyrroleAanda
CorrespondingLibrary 66
2.9.2 Alkaloid/Terpenoid-InspiredCompoundCollection 67
2.10 MacrocyclicCompoundCollections 68
2.10.1 MacrosphelideA-InspiredCompoundCollection 68
2.10.2 Solid-PhaseSynthesisofAnalogsofErythromycinA 69
2.10.3 AnAldol-BasedBuild/Couple/PairStrategyfortheSynthesisof
MacrocyclesandMedium-SizedRings 71
2.11 Outlook 72
References 73
PartTwo FromMarketedDrugstoDesignedAnalogsandClinical
Candidates 81
3 ChemistryandBiologyofEpothilones 83
Karl-HeinzAltmannandDieterSchinzer
3.1 Introduction:DiscoveryandBiologicalActivity 83
3.2 SynthesisofNaturalEpothilones 86
ContentsjVII
3.3 SynthesisandBiologicalActivityofNon-naturalEpothilones 90
3.3.1 SemisyntheticDerivatives 90
3.3.2 FullySyntheticAnalogs 92
3.3.2.1 Polyketide-BasedMacrocycles 92
3.3.2.2 Aza-Epothilones(Azathilones) 109
3.3.2.3 HybridStructuresandAcyclicAnalogs 112
3.4 ConformationalStudiesandPharmacophoreModeling 114
3.5 Conclusions 115
References 115
4 Taxol,Taxoids,andRelatedTaxanes 127
IwaoOjima,AnushreeKamath,andJoshuaD.Seitz
4.1 IntroductionandHistoricalBackground 127
4.1.1 DiscoveryofTaxol(Paclitaxel):AnEpoch-MakingAnticancer
DrugfromNature 127
4.1.2 TaxaneFamily 128
4.1.3 SourcesandMethodsofProduction 129
4.1.3.1 ExtractionfromYewTrees 129
4.1.3.2 Semisynthesis 129
4.1.3.3 TotalSynthesis 130
4.1.3.4 BiotechnologyProcesses 131
4.1.4 ClinicalDevelopmentofTaxol(Taxol1) 131
4.2 MechanismofActionandDrugResistance 132
4.2.1 Taxol,CellCycleArrest,andApoptosis 132
4.2.2 DrugResistancetoTaxol 133
4.3 Structure–ActivityRelationships(SAR)ofTaxol 133
4.3.1 SARofTaxol 133
4.3.2 ChemicalModificationsofTaxol:TaxolDerivatives
andTaxoids 134
4.3.2.1 ModificationsintheC13SideChain 134
4.3.2.2 ModificationintheBaccatinComponent 135
4.3.2.3 ProdrugsofTaxol 140
4.4 StructuralandChemicalBiologyofTaxol 141
4.4.1 BioactiveConformationofTaxol 141
4.4.2 Microtubule-BindingKineticsofTaxol 145
4.5 New-GenerationTaxoidsfrom10-DAB 145
4.5.1 Taxoidsfrom10-DAB 145
4.5.2 Taxoidsfrom14b-HydroxybaccatinIII 148
4.5.3 Taxoidsfrom9-DihydrobaccatinIII 149
4.6 TaxoidsinClinicalDevelopment 150
4.6.1 Docetaxel(Taxotere1,RP56976) 150
4.6.2 Cabazitaxel(Jevtana1,RPR116258A,XRP6258) 153
4.6.3 Larotaxel(XRP9881,RPR109881) 153
4.6.4 Ortataxel(SB-T-101131,IDN5109,BAY59-8862,ISN5109) 154
VIIIjContents
4.6.5 Tesetaxel(DJ-927) 154
4.6.6 Milataxel(MAC-321,TL139) 155
4.7 NewApplicationsofTaxanes 155
4.7.1 Taxane-BasedMDRReversalAgents 155
4.7.2 TaxanesasAntiangiogenicAgents 156
4.7.3 TaxanesasAntitubercularAgents 157
4.8 ConclusionsandPerspective 158
References 159
5 CamptothecinandAnalogs 181
GiuseppeGiannini
5.1 Introduction 181
5.2 BiologyActivity 185
5.2.1 CamptothecinActsonEukaryoticTop1 187
5.2.2 DrugResistanceandTopoisomeraseMutation 189
5.2.3 Camptothecin:BeyondtheTopoisomeraseI 190
5.2.4 Off-LabelInvestigation 190
5.3 CamptothecininClinicalUseandUnderClinicalTrials 190
5.3.1 Homocamptothecin 203
5.4 Chemistry 204
5.4.1 TotalSyntheses 205
5.4.2 SynthesesofSomeRepresentativeCamptothecinDerivatives 207
5.5 Structure–ActivityRelationship 210
5.6 XenograftStudies 211
5.7 Prodrug/Targeting 212
5.8 DevelopmentsofModernChromatographicMethodsAppliedto
CPT 214
5.9 ConclusionsandPerspectives 214
References 215
6 AShortHistoryoftheDiscoveryandDevelopmentofNaltrexoneand
OtherMorphineDerivatives 225
VimalVargheseandTomasHudlicky
6.1 Introduction 225
6.2 HistoryandDevelopment 226
6.3 Pharmacology 238
6.4 Structure–ActivityRelationshipofMorphineanditsAnalogs 240
6.5 ConclusionsandOutlook 244
References 244
7 LincosamideAntibacterials 251
HardwinO’Dowd,AliceL.Erwin,andJasonG.Lewis
7.1 Introduction 251
7.2 MechanismofAction 253
7.3 AntibacterialSpectrum 254