New natural epothilones from Sorangium cellulosum, strains So ce90/B2 and So ce90/D13: isolation, structure elucidation, and SAR studies
- PMID: 11473410
- DOI: 10.1021/np000629f
New natural epothilones from Sorangium cellulosum, strains So ce90/B2 and So ce90/D13: isolation, structure elucidation, and SAR studies
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, only the 12,13-desoxyepothilones, epothilone C (14) and D (15), were produced in significant amounts (3-6 mg/L); the 21-hydroxy derivatives and epothilones 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 produced only in 1-100 microg/L amounts. The new compounds are very similar in structure to the parent compounds 1, 2 and 14, 15 and are presumably the result of the imperfect selectivity of the biosynthetic enzymes for acetate and propionate. Further, epothilones containing an oxazole moiety (10-13) in the side chain instead of a thiazole as well as ring-expanded 18-membered macrolides, epothilones I (30-35), and a ring contracted 14-membered macrolide, epothilone K (36), were found as very minor metabolites. The mutant strain, So ce90/D13, instead of macrolactones, produced short-chain carboxylic acids 40, 41, and 42 bearing the characteristic thiazole side chain. The structures of the new epothilones were elucidated on the basis of comprehensive NMR and MS data. The new epothilone variants were tested in a cytotoxicity assay with mouse fibroblasts (cell line L929), and structure-activity relationships were established. Several new natural epothilones showed activity comparable to 1 and 2, but in no case exceeded that of 2.
Similar articles
-
The biosynthetic gene cluster for the microtubule-stabilizing agents epothilones A and B from Sorangium cellulosum So ce90.Chem Biol. 2000 Feb;7(2):97-109. doi: 10.1016/s1074-5521(00)00075-2. Chem Biol. 2000. PMID: 10662695
-
Epothilons A and B: antifungal and cytotoxic compounds from Sorangium cellulosum (Myxobacteria). Production, physico-chemical and biological properties.J Antibiot (Tokyo). 1996 Jun;49(6):560-3. doi: 10.7164/antibiotics.49.560. J Antibiot (Tokyo). 1996. PMID: 8698639
-
New epothilone congeners from Sorangium cellulosum strain So0157-2.Nat Prod Res. 2011 Oct;25(18):1707-12. doi: 10.1080/14786419.2011.553719. Epub 2011 Sep 8. Nat Prod Res. 2011. PMID: 21899481
-
Discovery and development of the epothilones : a novel class of antineoplastic drugs.Drugs R D. 2008;9(1):1-10. doi: 10.2165/00126839-200809010-00001. Drugs R D. 2008. PMID: 18095749 Free PMC article. Review.
-
[The PKS/NRPS hetero-gene cluster of epothilones].Sheng Wu Gong Cheng Xue Bao. 2003 Sep;19(5):511-5. Sheng Wu Gong Cheng Xue Bao. 2003. PMID: 15969075 Review. Chinese.
Cited by
-
Characterization of the lnmKLM genes unveiling key intermediates for β-alkylation in leinamycin biosynthesis.Org Lett. 2011 Feb 4;13(3):498-501. doi: 10.1021/ol102838y. Epub 2010 Dec 30. Org Lett. 2011. PMID: 21192727 Free PMC article.
-
Antibiotic Skeletal Diversification via Differential Enoylreductase Recruitment and Module Iteration in trans-Acyltransferase Polyketide Synthases.J Am Chem Soc. 2024 Mar 6;146(9):6114-6124. doi: 10.1021/jacs.3c13667. Epub 2024 Feb 23. J Am Chem Soc. 2024. PMID: 38389455 Free PMC article.
-
Engineering the acyltransferase domain of epothilone polyketide synthase to alter the substrate specificity.Microb Cell Fact. 2021 Apr 21;20(1):86. doi: 10.1186/s12934-021-01578-3. Microb Cell Fact. 2021. PMID: 33882930 Free PMC article.
-
ClusterMine360: a database of microbial PKS/NRPS biosynthesis.Nucleic Acids Res. 2013 Jan;41(Database issue):D402-7. doi: 10.1093/nar/gks993. Epub 2012 Oct 26. Nucleic Acids Res. 2013. PMID: 23104377 Free PMC article.
-
Polyketide-nonribosomal peptide epothilone antitumor agents: the EpoA, B, C subunits.J Ind Microbiol Biotechnol. 2003 Aug;30(8):448-55. doi: 10.1007/s10295-003-0044-2. Epub 2003 Apr 18. J Ind Microbiol Biotechnol. 2003. PMID: 12707798 Review.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Miscellaneous
