The Epothilones: An Outstanding Family of Anti-Tumor Agents From Soil to the Clinic
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Johann H. Mulzer
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The Epothilones: An Outstanding Family of Anti-Tumor Agents From Soil to the Clinic
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Springer-Verlag
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9783211782071
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1
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CHF 133.80
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Organische Chemie
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English
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260
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Wasserzeichen/DRM
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PC/MAC/eReader/Tablet
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PDF
Epothilones have received unusual attention over the past ten years. They are novel antitumor drugs which very much like their predecessor paclitaxel (Taxol) act via microtubule stabilization. In comparison to paclitaxel and a number of alternative drugs with a similar mode of bioaction (e.g. laulimalide, eleutherobin, peluroside, discodermolide) the epothilones have significant advantages, above all very high activity in the nanomolar range and low susceptibility towards multidrug resistance. Epothilone B and several derivatives thereof are in phase I-III clinical trials; one of them (ixabepilone, BMS) is already on the market, others are supposed to appear on the market in the near future. All naturally occurring epothilones have been isolated from Sorangium cellulosum; their antitumor action is traced back to the stabilization of microtubules. In consequence, the formation of the mitototic spindle is prohibited and the cell undergoes apoptosis.
2. General Aspects
(p. 5-6)
Gerhard Höfle
Helmholtz-Zentrum für Infektionsforschung (formerly: GBF, Gesellschaft für Biotechnologische Forschung), Braunschweig, Germany
2.1. History of Epothilone Discovery and Development
2.1.1. The Early Days
Epothilone is a microbial product, and thus its history may be traced back to the discovery of the respective microbe, Sorangium cellulosum, a bacterium belonging to the taxonomic group of myxobacteria, which originally has been described by Roland Thaxter in 1892 (1). Today this group of organisms comprises around 40 species, one of which is Sorangium cellulosum. For a long time, myxobacteria were only known for their gliding motility and sophisticated life cycle, although it had been occasionally speculated that they might produce secondarymetabolites like actinomycetes or bacilli (2).
In 1975 Hans Reichenbach and his group at the German Centre for Biotechnology (GBF, now called the Helmholtz Centre for Infection Research) set out to isolate strains of myxobacteria from soil samples collected all over the world, and to examine their secondary metabolism. In 1978, while work was already ongoing, I joined them and took over the chemistry part. In the same year the first structure of a myxobacterial metabolite, ambruticin, was published by a group from Warner-Lambert (3) making us very confident of being on the right track. Ambruticin had been isolated from a Sorangium cellulosum strain, and was identified as a unique cyclopropane polyketide structure exhibiting potentially useful antifungal properties. Ambruticin and its derivatives had been developed for medical application for some time, and recently gained new interest (4). Meanwhile we had been working at GBF quite successfully with the easily handled Myxococcus, Corallococcus, and Stigmatella strains, and only slowly shifted our focus to Sorangium. It took us considerable time to establish large-scale isolation and cultivation procedures of this slowly growing species. As soon as several hundred strains of Sorangium cellulosum had been accumulated by 1985, the screening for biological activity became productive, and a constant flow of unusual secondary metabolites came into our hands. Up to now, approximately 50 novel basic structures have been isolated from the various strains of this species, often with outstanding antifungal properties. The predominance of antifungal activity may be attributed to the fact that Sorangium cellulosum grows on cellulose as carbon source, and thus has to compete through chemical warfare (and other means) with fungi for its ecological niche.
In July 1985 Sorangium cellulosum, strain So ce90, the first producer of epothilone, was isolated by Hans Reichenbach from a soil sample collected at the banks of the river Zambesi in southern Africa in August 1980. Only two years after isolation, the strain was introduced in an antifungal screening of Sorangium strains by Klaus Gerth and identified as one of several hits in January 1987. Later, Florenz Sasse, responsible for cell culture tests, noticed high cytotoxicity of the culture extract. From these and other preliminary tests we were dealing with a new compound and Norbert Bedorf from the chemistry group immediately started to isolate the compound and elucidate its structure. Guided by biological activity, he isolated two closely related antifungal compounds later named epothilone A and B (5), and a structurally non-related family of polyene carboxylic acids, later named spirangiens inMay 1987 (5, 6).
Contents
6
List of Contributors
10
1. Preface
11
2. General Aspects
15
2.1. History of Epothilone Discovery and Development
15
2.2. Natural Epothilones
26
3. Biosynthesis and Heterologous Production of Epothilones
39
3.1. Introduction
39
3.2. Feeding Studies and the Discovery of Natural Epothilone Variants
42
3.3. Identification of the Epothilone Biosynthesis Gene Cluster
46
3.4. Studies in Vitro into the Biochemistry of Epothilone Assembly
49
3.5. Heterologous Expression and Genetic Engineering of the Epothilone Biosynthesis Gene Cluster
53
3.6. Nutrient Regulation in S. cellulosum and M. xanthus
57
3.7. Conclusions
59
References
60
4. Total Synthesis of Epothilones A–F
65
4.1. Introduction
66
4.2. Synthesis Approaches to both the Epothilone A/ C- and B/ D- Series
68
4.3. Syntheses of Epothilone A/C (1a, 2a)
97
4.4. Synthesis of Epothilones B/D (1b, 2b)
107
4.5. Syntheses of Fragments
122
4.6. Semisynthetic Degradation/Reconstruction of 2b ( 117, 118)
128
4.7. Syntheses of Epothilones E and F (1c, 1d) and Their 12,13- Deoxy Derivatives ( 2c, 2d) ( 126)
129
4.8. Nicolaou’s Synthesis of Epothilone Analogues ( 1, 129– 133)
129
4.9. Conclusion and Industrial Application ( ZK- Epo ( Sagopilone))
133
5. Semisynthetic Derivatives of Epothilones
145
5.1. Introduction
145
5.2. The O16–C8 Sector (‘‘Polyketide Sector’’)
147
5.3. Modification of the Epoxide Moiety
151
5.4. Side Chain Modifications
156
5.5. Removal/Incorporation of the C13–O16 Segment
160
5.6. Conclusions
163
References
164
6. Preclinical Pharmacology and Structure- Activity Studies of Epothilones
167
6.1. Introduction
167
6.2. In vitro Pharmacology of Epo B
171
6.3. In vivo Pharmacology of Epo B
180
6.4. Epothilone Analogs and SAR Studies
181
6.5. Structural Studies and Pharmacophore Modeling
216
6.6. Conclusions
219
7. Clinical Studies with Epothilones
231
7.1. Introduction
231
7.2. Patupilone (EPO906, Epo B)
233
7.3. Ixabepilone
234
7.4. KOS-862
238
7.5. BMS-310705
239
7.6. KOS-1584
240
7.7. Sagopilone (ZK-Epo)
242
7.8. ABJ879
242
7.9. Conclusions
243
Author Index
249
Subject Index
261
