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 RelatedTitles MethodsandPrinciplesinMedicinalChemistry EditedbyR.Mannhold,H.Kubinyi,G.Folkers EditorialBoard H.Buschmann,H.Timmerman,H.vandeWaterbeemd,T.Wieland PreviousVolumesofthisSeries: Lackey,Karen/Roth,Bruce(Eds.) Brown,Nathan(Ed.) MedicinalChemistryApproaches BioisosteresinMedicinal toPersonalizedMedicine Chemistry 2014 2012 ISBN:978-3-527-33394-3 ISBN:978-3-527-33015-7 Vol.59 Vol.54 Brown,Nathan(Ed.) Gohlke,Holger(Ed.) ScaffoldHoppinginMedicinal Protein-LigandInteractions Chemistry 2012 2014 ISBN:978-3-527-32966-3 ISBN:978-3-527-33364-6 Vol.53 Vol.58 Kappe,C.Oliver/Stadler,Alexander/ Hoffmann,Rémy/Gohier,Arnaud/ Dallinger,Doris Pospisil,Pavel(Eds.) MicrowavesinOrganicand DataMininginDrugDiscovery MedicinalChemistry Second, CompletelyRevisedand 2014 ISBN:978-3-527-32984-7 EnlargedEdition Vol.57 2012 ISBN:978-3-527-33185-7 Dömling,Alexander(Ed.) Vol.52 Protein-ProteinInteractionsin Smith,DennisA./Allerton,Charlotte/ DrugDiscovery Kalgutkar,AmitS./vandeWaterbeemd, 2013 Han/Walker,DonK. ISBN:978-3-527-33107-9 Pharmacokineticsand Vol.56 MetabolisminDrugDesign Kalgutkar,AmitS./Dalvie,Deepak/ Third,RevisedandUpdatedEdition Obach,R.Scott/Smith,DennisA. 2012 ReactiveDrugMetabolites ISBN:978-3-527-32954-0 Vol.51 2012 ISBN:978-3-527-33085-0 DeClercq,Erik(Ed.) Vol.55 AntiviralDrugStrategies 2011 ISBN:978-3-527-32696-9 Vol.50 Edited by Stephen Hanessian Natural Products in Medicinal Chemistry Series Edi tors All books published by Wiley-VCH are carefully produced . Neverthel ess, authors, editors, and Prof. Dr. Raimun d Man nhold publisher do not warrant the information contained Rosenw eg 7 in these books, inclu ding this book, to be free of 40489 Düsseldorf errors. Rea ders are advised to keep in mind that Germany statemen ts, data, illust rations, procedural details or mannhold @uni-duesseld orf.de other items may inadver tently be inaccurate . Library of Congress Car d No.: applied for Prof. Dr. Hugo Kubinyi Donner sbergstrasse 9 British Library Catalogu ing-in-Publica tion Dat a 67256 Weisenheim am Sand A catalogu e record for this book is av ailable from the Germany British Library. kubinyi@t-o nline.de Bibliog raphic inform ation publ ished by the Deutsche Nation albibliothek Prof. Dr. Gerd Folkers TheDeutscheNationalbibliothekliststhis Collegium Helveticu m publicationintheDeutscheNationalbibliografie; STW/ETH Zurich detailedbibliographicdataareavailableonthe 8092 Zurich Internet at < http:// dnb.d-nb.d e> . Switzerland #2014Wiley-VCHVerlagGmbH&Co.KGaA, Boschstr.12,69469Weinheim,Germany Volume Editor Allrightsreserved(includingthoseoftranslationinto otherlanguages).Nopartofthisbookmaybe Prof. Dr. Stephen Haness ian reproducedinanyform–byphotoprinting, Universit y of Montreal microfilm,oranyothermeans–nortransmittedor Departme nt of Chemistry translatedintoamachinelanguagewithoutwritten H3C 3J7 NK permissionfromthepublishers.Registerednames, Canada trademarks,etc.usedinthisbook,evenwhennot specificallymarkedassuch,arenottobeconsidered unprotectedbylaw. PrintISBN: 978-3-527-33218-2 Cover Description ePDFISBN: 978-3-527-67655-2 ePubISBN: 978-3-527-67656-9 The cov er depicts the int erplay betwee n MobiISBN: 978-3-527-67657-6 structure, function, chirality, molecular oBookISBN: 978-3-527-67654-5 recognition, and the fascinating world of Nature ’ s macrobiomolecule s. CoverDesign Grafik-DesignSchulz,Fußgönheim Typesetting ThomsonDigital,Noida,India (Concepti on by Stephen Hanessian) PrintingandBinding MarkonoPrintMediaPteLtd, Singapore Printedonacid-freepaper j 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