New natural epothilones from Sorangium cellulosum, strains So ce90/B2 and So ce90/D13: Isolation, structure elucidation, and SAR studies

Citation
Ih. Hardt et al., New natural epothilones from Sorangium cellulosum, strains So ce90/B2 and So ce90/D13: Isolation, structure elucidation, and SAR studies, J NAT PROD, 64(7), 2001, pp. 847-856
Citations number
44
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Agricultural Chemistry","Pharmacology & Toxicology
Journal title
JOURNAL OF NATURAL PRODUCTS
ISSN journal
0163-3864 → ACNP
Volume
64
Issue
7
Year of publication
2001
Pages
847 - 856
Database
ISI
SICI code
0163-3864(200107)64:7<847:NNEFSC>2.0.ZU;2-7
Abstract
In addition to epothilones A (1) and B (2), 37 natural epothilone variants and epothilone-related compounds were isolated from the culture broth of a 700 L fermentation of Sorangium cellulosum, strain So ce90/ B2. Of these, o nly the 12,13-desoxyepothilones, epothilone C 14) and D (15), were produced in significant amounts (3-6 mg/L); the 21-hydroxy derivatives and epothilo nes E (3) and F (4), in low and variable amounts due to further degradation by the producing organism. Most of the other epothilone variants were prod uced only in 1-100 mug/L amounts. The new compounds are very similar in str ucture to the parent compounds 1, 2 and 14, 15 and are presumably the resul t of the imperfect selectivity of the biosynthetic enzymes for acetate and propionate. Further, epothilones containing an oxazole moiety (10-13) in th e side chain instead of a thiazole as well as ring-expanded 18-membered mac rolides, epothilones I (30-35), and a ring contracted 14-membered macrolide , epothilone K (36), were found as very minor metabolites. The mutant strai n, So ce90/D13, instead of macrolactones, produced short-chain carboxylic a cids 40, 41, and 42 bearing the characteristic thiazole side chain. The str uctures of the new epothilones were elucidated on the basis of comprehensiv e NMR and MS data. The new epothilone variants were tested in a cytotoxicit y assay with mouse fibroblasts (cell line L929), and structure-activity rel ationships were established. Several new natural epothilones showed activit y comparable to 1 and 2, but in no case exceeded that of 2.