SAR and pH stability of cyano-substituted epothilones.
[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.
Regueiro-Ren
Alicia
A
Divisions 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
Leavitt
Kenneth
K
Kim
Soong-Hoon
SH
Höfle
Gerhard
G
Kiffe
Michael
M
Gougoutas
Jack Z
JZ
DiMarco
John D
JD
Lee
Francis Y F
FY
Fairchild
Craig R
CR
Long
Byron H
BH
Vite
Gregory D
GD
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D004355:Drug Stability; D034261:Epothilones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000187:drug effects / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D034261:Epothilones; D014404:Tubulin