Conformation−Activity Relationships in Polyketide Natural Products: A New Perspective on the Rational Design of Epothilone Analogues
- 27 November 2002
- journal article
- Published by American Chemical Society (ACS) in Journal of the American Chemical Society
- Vol. 125 (1) , 26-27
- https://doi.org/10.1021/ja028196l
Abstract
The syntheses of C14-methyl analogues of epothilone B and D are described. Conformational analysis using computational methods, X-ray crystallography, and NMR studies showed that the stereochemistry at C14 has a pronounced effect on the conformation of the epoxide region. Biological assays indicated significant differences in their biological activity. Substitution which stabilized conformer I retained significant biological activity. In contrast, substitution which stabilized conformer II provided analogues with no measurable cytotoxicity. The conformation-activity relationships strongly support the importance of conformer I as the bioactive conformation of the epoxide region of epothilone. The approach presented here offers a new perspective on rational design of modified biologically active polyketides.Keywords
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