Conformation-activity relationships in polyketide natural products: a new perspective on the rational design of epothilone analogues.
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.
Taylor
Richard E
RE
Department of Chemistry and Biochemistry, Walther Center for Excellence in Cancer Research, University of Notre Dame, 251 Nieuwland Science Hall, Notre Dame, IN 46556-5670, USA. taylor.61@nd.edu
Chen
Yue
Y
Beatty
Alicia
A
Myles
David C
DC
Zhou
Yiqing
Y
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D034261:Epothilones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D019906:Nuclear Magnetic Resonance, Biomolecular; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D034261:Epothilones