The Epothilones: An Outstanding Family of Anti-Tumor Agents: From Soil to the Clinic (Fortschritte der Chemie organischer Naturstoffe Progress in the Chemistry of Organic Natural Products)

266 Pages·2009·6.8 MB·English

by  Johann H. Mulzer

W
Fortschritte der Chemie
organischer Naturstoffe
Progress in the Chemistry
of Organic Natural Products
Founded by L. Zechmeister
Editors:
A. D. Kinghorn, Columbus, OH
H. Falk, Linz
J. Kobayashi, Sapporo
Honorary Editor:
W. Herz, Tallahassee, FL
Editorial Board:
V. Dirsch, Vienna
S. Gibbons, London
N. H. Oberlies, Research Triangle Park, NC
Y. Ye, Shanghai
90
Fortschritte der Chemie
organischer Naturstoffe
Progress in the Chemistry
of Organic Natural Products
The Epothilones: An Outstanding
Family of Anti-Tumor Agents
From Soil to the Clinic
Authors:
K.-H. Altmann, G. Höfle, R. Müller,
J. Mulzer, and K. Prantz
SpringerWienNewYork
Prof.A.DouglasKinghorn,CollegeofPharmacy,
OhioStateUniversity,Columbus,OH,USA
em.Univ.-Prof.Dr.H.Falk,Institutfu¨rOrganischeChemie,
Johannes-Kepler-Universita¨t,Linz,Austria
Prof.Dr.J.Kobayashi,GraduateSchoolofPharmaceuticalSciences,
HokkaidoUniversity,Sapporo,Japan
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The Epothilones: An Outstanding
Family of Anti-Tumor Agents
From Soil to the Clinic
Contents
ListofContributors........................................... IX
1.Preface
J.Mulzer................................................ 1
2.GeneralAspects
G.Ho¨fle................................................. 5
2.1. HistoryofEpothiloneDiscoveryandDevelopment ................. 5
2.1.1. TheEarlyDays ..................................... 5
2.1.2. IndustryBecomesInterestedinEpothilones–andLoses
InterestAgain ...................................... 7
2.1.3. Re-DiscoveryofEpothiloneintheNineties.................. 8
2.1.4. DevelopmentofEpothilonesasAnticancerDrugs ............. 10
2.1.5. Epilogue .......................................... 13
Acknowledgements........................................... 13
References................................................. 14
2.2. NaturalEpothilones ....................................... 16
2.2.1. IsolationandLargeScaleProduction ...................... 16
2.2.2. StructureofEpothilonesandRelatedCompounds.............. 20
2.2.3. PhysicalandChemicalProperties......................... 23
Acknowledgements........................................... 27
References................................................. 27
3.BiosynthesisandHeterologousProductionofEpothilones
R.Mu¨ller................................................ 29
3.1. Introduction............................................. 29
3.2. FeedingStudiesandtheDiscoveryofNaturalEpothiloneVariants....... 32
VI Contents
3.3. IdentificationoftheEpothiloneBiosynthesisGeneCluster............ 36
3.4. StudiesinvitrointotheBiochemistryofEpothiloneAssembly......... 39
3.5. HeterologousExpressionandGeneticEngineering
oftheEpothiloneBiosynthesisGeneCluster...................... 43
3.6. NutrientRegulationinS.cellulosumandM.xanthus................ 47
3.7. Conclusions............................................. 49
Acknowledgements........................................... 50
References................................................. 50
4.TotalSynthesisofEpothilonesA–F
J.Mulzer,K.Prantz ........................................ 55
4.1. Introduction............................................. 56
4.2. SynthesisApproachestoboththeEpothiloneA/C-andB/D-Series ...... 58
4.2.1. DanishefskySyntheses................................. 58
4.2.2. NicolaouSyntheses................................... 67
4.2.3. SchinzerSynthesis ................................... 73
4.2.4. SinhaSyntheses..................................... 77
4.2.5. Carreira’sSynthesisof2aand2b ........................ 81
4.2.6. ShibasakiApproach .................................. 84
4.3. SynthesesofEpothiloneA/C(1a,2a)........................... 87
4.3.1. Fu¨rstner’sAlkyneRCM ............................... 87
4.3.2. LiuSynthesis....................................... 87
4.3.3. PanekApproach..................................... 93
4.3.4. Wong’sDERAApproach............................... 93
4.3.5. Ley’sApproach ..................................... 96
4.4. SynthesisofEpothilonesB/D(1b,2b).......................... 97
4.4.1. MulzerSyntheses.................................... 97
4.4.2. Grieco’sFormalSynthesisof2b ......................... 101
4.4.3. White’sSyntheses.................................... 101
4.4.4. ErmolenkoVariationoftheWhiteSynthesis.................. 105
4.4.5. SynthesisbyE.J.Thomas.............................. 107
4.4.6. Avery’sSynthesis .................................... 109
4.4.7. R.E.Taylor’sSynthesis................................ 111
4.5. SynthesesofFragments .................................... 112
4.5.1. Kalesse’sSynthesisofNicolaou’sIntermediates60and82 ....... 112
4.5.2. Chandrasekhar’sSynthesisofKetoAcid378andC7–C16
Fragment381....................................... 113
4.5.3. Ramachandran’sSynthesisoftheMEM-protected
Nicolaou-Aldehyde(390)............................... 115
4.5.4. DeBrabander’sSynthesisofAldehyde63andAcid59 ......... 115
4.5.5. Wessjohann’sSynthesisofFragments398and401............. 115
4.5.6. Kulinkovich’sSynthesisofAldehyde408 ................... 117
4.5.7. Georg’sSynthesisofAldehyde70 ........................ 117
4.5.8. Lipase-CatalyzedSynthesisoftheC1–C6Fragment414......... 118
4.6. SemisyntheticDegradation/Reconstructionof2b................... 118
Contents VII
4.7. SynthesesofEpothilonesEandF(1c,1d)andTheir
12,13-DeoxyDerivatives(2c,2d).............................. 119
4.7.1. Nicolaou’sSynthesisof1d ............................. 119
4.7.2. Sinha’sSynthesisof1c,1dand2c,2d..................... 119
4.8. Nicolaou’sSynthesisofEpothiloneAnalogues .................... 119
4.9. ConclusionandIndustrialApplication(ZK-Epo(Sagopilone)).......... 123
Abbreviations............................................... 125
References................................................. 126
5. SemisyntheticDerivativesofEpothilones
K.-H.Altmann ............................................ 135
5.1. Introduction............................................. 135
5.2. TheO16–C8Sector(‘‘PolyketideSector’’)....................... 137
5.2.1. ModificationoftheEsterMoiety ......................... 137
5.2.2. ModificationintheC2–C8Region........................ 139
5.3. ModificationoftheEpoxideMoiety............................ 141
5.4. SideChainModifications ................................... 146
5.4.1. ModificationsoftheC16/C17BondandtheThiazoleMoiety ..... 146
5.4.2.Cleavage/RestitutionoftheC16/C17Bond................... 148
5.5. Removal/IncorporationoftheC13–O16Segment................... 150
5.6. Conclusions............................................. 153
References................................................. 154
6. PreclinicalPharmacologyandStructure-ActivityStudiesofEpothilones
K.-H.Altmann ............................................ 157
6.1. Introduction............................................. 157
6.2. InvitroPharmacologyofEpoB .............................. 161
6.3. InvivoPharmacologyofEpoB............................... 170
6.4. EpothiloneAnalogsandSARStudies........................... 171
6.4.1. TheO16–C8Sector(‘‘PolyketideSector’’) .................. 171
6.4.1.1. Lactam-basedAnalogs .......................... 171
6.4.1.2. ModificationsintheC2–C8Region ................. 174
6.4.2. TheC9–C13Sector(‘‘EpoxideSector’’).................... 178
6.4.2.1. ModificationsoftheC9–C12Segment ............... 178
6.4.2.2. ModificationsintheEpoxideRegion(C12/C13)......... 182
6.4.3. TheC14–C21Sector.................................. 191
6.4.3.1. SideChainModifications......................... 191
6.4.3.2. C14Modifications ............................. 205
6.4.4. MiscellaneousModifications ............................ 206
6.5. StructuralStudiesandPharmacophoreModeling................... 206
6.6. Conclusions............................................. 209
References................................................. 210
VIII Contents
7. ClinicalStudieswithEpothilones
K.-H.Altmann ............................................ 221
7.1. Introduction............................................. 221
7.2. Patupilone(EPO906,EpoB)................................. 223
7.3. Ixabepilone............................................. 224
7.4. KOS-862............................................... 228
7.5. BMS-310705............................................ 229
7.6. KOS-1584.............................................. 230
7.7. Sagopilone(ZK-Epo)...................................... 232
7.8. ABJ879 ............................................... 232
7.9. Conclusions............................................. 233
References................................................. 234
AuthorIndex .............................................. 239
SubjectIndex .............................................. 251
List of Contributors
Altmann, Prof. Dr. K.-H., ETH Zu¨rich, Department of Chemistry and Applied
Biosciences, Institute of Pharmaceutical Sciences, ETH Ho¨nggerberg. HCI H 405,
Wolfgang-Pauli-Str.10,8093Zu¨rich,Switzerland
e-mail:[e-mail]
Ho¨fle, Prof. Dr. G., Helmholtz-Zentrum fu¨r Infektionsforschung, (formerly: GBF,
Gesellschaftfu¨rBiotechnologischeForschung),Inhoffenstr.7,38124Braunschweig,
Germany
e-mail:G.Hofl[e-mail]
Mu¨ller, Prof. Dr. R., Institut fu¨r Pharmazeutische Biotechnologie, Universita¨t des
Saarlandes,Postfach151150,66041Saarbru¨cken,Germany
e-mail:[e-mail]
Mulzer,Prof.Dr.J.,Institutfu¨rOrganischeChemie,Fakulta¨tfu¨rChemiederUniversita¨t
Wien,Wa¨hringerstr.38,1090Wien,Austria
e-mail:[e-mail]
Prantz, Mag. K., Institut fu¨r Organische Chemie, Fakulta¨t fu¨r Chemie der Universita¨t
Wien,Wa¨hringerstr.38,1090Wien,Austria
e-mail:[e-mail]