 | The epothilones: an outstanding family of anti-tumour agents: from soil to the clinic / Altmann K.-N., Höfle G., Müller R., Mulzer J., Prantz K.; ed. by Kinghorn A.D., Falk H., Kobayaschi J. - Wien; New-York: Springer, 2008. - viii, 260 p.: ill. - (Fortschritte der chemie organischer naturstoffe = Progress in the chemistry of organic natural products; 90). - ISBN 978-3-211-78206-4; ISSN 0071-7886
|
List of Contributors ........................................... IX
1. Preface
J. Mulzer ................................................. 1
2. General Aspects
G. Höfle .................................................. 5
2.1. History of Epothilone Discovery and Development ......... 5
2.1.1. The Early Days ................................... 5
2.1.2. Industry Becomes Interested in Epothilones -
and Loses Interest Again ......................... 7
2.1.3. Re-Discovery of Epothilone in the Nineties ....... 8
2.1.4. Development of Epothilones as Anticancer
Drugs ........................................... 10
2.1.5. Epilogue ........................................ 13
Acknowledgements ............................................ 13
References .................................................. 14
2.2. Natural Epothilones .................................... 16
2.2.1. Isolation and Large Scale Production ............ 16
2.2.2. Structure of Epothilones and Related
Compounds ....................................... 20
2.2.3. Physical and Chemical Properties ................ 23
Acknowledgements ............................................ 27
References .................................................. 27
3. Biosynthesis and Heterologous Production of Epothilones
R. Muller ................................................ 29
3.1. Introduction ........................................... 29
3.2. Feeding Studies and the Discovery of Natural
Epothilone Variants .................................... 32
3.3. Identification of the Epothilone Biosynthesis Gene
Cluster ................................................ 36
3.4. Studies in vitro into the Biochemistry of Epothilone
Assembly ............................................... 39
3.5. Heterologous Expression and Genetic Engineering
of the Epothilone Biosynthesis Gene Cluster ............ 43
3.6. Nutrient Regulation in S. cellulosum and M. xanthus .... 47
3.7. Conclusions ............................................ 49
Acknowledgements ............................................ 50
References .................................................. 50
4. Total Synthesis of Epothilones A-F
J. Mulzer, K. Prantz ..................................... 55
4.1. Introduction ........................................... 56
4.2. Synthesis Approaches to both the Epothilone A/C- and
B/D-Series ............................................. 58
4.2.1. Danishefsky Syntheses ........................... 58
4.2.2. Nicolaou Syntheses .............................. 67
4.2.3. Schinzer Synthesis .............................. 73
4.2.4. Sinha Syntheses ................................. 77
4.2.5. Carreira's Synthesis of 2a and 2b ............... 81
4.2.6. Shibasaki Approach .............................. 84
4.3. Syntheses of Epothilone A/C (la, 2a) ................... 87
4.3.1. Fürstner's Alkyne RCM ........................... 87
4.3.2. Liu Synthesis ................................... 87
4.3.3. Panek Approach .................................. 93
4.3.4. Wong's DERA Approach ............................ 93
4.3.5. Ley's Approach .................................. 96
4.4. Synthesis of Epothilones B/D (lb, 2b) .................. 97
4.4.1. Mulzer Syntheses ................................ 97
4.4.2. Grieco's Formal Synthesis of 2b ................ 101
4.4.3. White's Syntheses .............................. 101
4.4.4. Ermolenko Variation of the White Synthesis ..... 105
4.4.5. Synthesis by E.J. Thomas ....................... 107
4.4.6. Avery's Synthesis .............................. 109
4.4.7. R.E. Taylor's Synthesis ........................ 1ll
4.5. Syntheses of Fragments ................................ 112
4.5.1. Kalesse's Synthesis of Nicolaou's
Intermediates 60 and 82 ........................ 112
4.5.2. Chandrasekhar's Synthesis of Keto Acid 378
and C7-C16 Fragment 381 ........................ 113
4.5.3. Ramachandran's Synthesis of the MEM-
protected Nicolaou-Aldehyde (390) .............. 115
4.5.4. De Brabander's Synthesis of Aldehyde 63 and
Acid 59 ........................................ 115
4.5.5. Wessjohann's Synthesis of Fragments 398
and 401 ........................................ 115
4.5.6. Kulinkovich's Synthesis of Aldehyde 408 ........ 117
4.5.7. Georg's Synthesis of Aldehyde 70 ............... 117
4.5.8. Lipase-Catalyzed Synthesis of the C1-C6
Fragment 414 ................................... 118
4.6. Semisynthetic Degradation/Reconstruction of 2b ........ 118
4.7. Syntheses of Epothilones E and F (lc, 1d) and Their
12,13-Deoxy Derivatives (2c, 2d) ...................... 119
4.7.1. Nicolaou's Synthesis of Id ..................... 119
4.7.2. Sinha's, Synthesis of lc, Id and 2c, 2d ........ 119
4.8. Nicolaou's Synthesis of Epothilone Analogues .......... 119
4.9. Conclusion and Industrial Application (ZK-Epo
(Sagopilone)) ......................................... 123
Abbreviations .............................................. 125
References ................................................. 126
5. Semisynthetic Derivatives of Epothilones
K.-H. Altmann ........................................... 135
5.1. Introduction .......................................... 135
5.2. The 016-C8 Sector ("Polyketide Sector") ............... 137
5.2.1. Modification of the Ester Moiety ............... 137
5.2.2. Modification in the C2-C8 Region ............... 139
5.3. Modification of the Epoxide Moiety .................... 141
5.4. Side Chain Modifications .............................. 146
5.4.1. Modifications of the C16/C17 Bond and the
Thiazole Moiety ................................ 146
5.4.2. Cleavage/Restitution of the C16/C17 Bond ....... 148
5.5. Removal/Incorporation of the C13-016 Segment .......... 150
5.6. Conclusions ........................................... 153
References ................................................. 154
6. Preclinical Pharmacology and Structure-Activity Studies
of Epothilones
K.-H. Altmann ........................................... 157
6.1. Introduction .......................................... 157
6.2. In vitro Pharmacology of Epo В ........................ 161
6.3. In vivo Pharmacology of Epo В ......................... 170
6.4. Epothilone Analogs and SAR Studies .................... 171
6.4.1. The 016-C8 Sector ("Polyketide Sector") ........ 171
6.4.1.1. Lactam-based Analogs .................. 171
6.4.1.2. Modifications in the C2-C8 Region ..... 174
6.4.2. The C9-C13 Sector ("Epoxide Sector") ........... 178
6.4.2.1. Modifications of the C9-C12 Segment ... 178
6.4.2.2. Modifications in the Epoxide Region
(C12/C13) ............................. 182
6.4.3. The C14-C21 Sector ............................. 191
6.4.3.1. Side Chain Modifications .............. 191
6.4.3.2. C14 Modifications ..................... 205
6.4.4. Miscellaneous Modifications .................... 206
6.5. Structural Studies and Pharmacophore Modeling ......... 206
6.6. Conclusions ........................................... 209
References ................................................. 210
7. Clinical Studies with Epothilones
K.-H. Altmann ........................................... 221
7.1. Introduction .......................................... 221
7.2. Patupilone (EPO906, Epo B) ............................ 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
Author Index .................................................. 239
Subject Index ................................................. 251
|
|
