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SAR and pH stability of cyano-substituted epothilones
Alicia Regueiro-Ren1, Kenneth Leavitt, Soong-Hoon Kim
1Divisions of Discovery Chemistry, Oncology Drug Discovery and Pharmaceutical Development, Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 4000, Princeton, New Jersey 08543-4000, USA. alicia.regueiroren@bms.com
Organic Letters
|February 26, 2003
Abstract:
[formula: see text] 3-Cyano epothilones 15-18 are the only examples of non-hydroxy C-3-substituted analogues. Their tubulin binding affinity and cytotoxicity provide meaningful structure-activity relationship information on the dependence of C-1/C-3 conformation upon activity. 12-Cyano epothilone 24 has improved pH stability over epothilone B, and its activity further supports the hypothesis that C-12 stereochemistry is not critical for tubulin affinity.