title: SAR and pH stability of cyano-substituted epothilones.
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.
authors.affiliation: 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
authors.forename: Alicia
authors.initials: A
authors.lastname: Regueiro-Ren
authors.forename: Kenneth
authors.initials: K
authors.lastname: Leavitt
authors.forename: Soong-Hoon
authors.initials: SH
authors.lastname: Kim
authors.forename: Gerhard
authors.initials: G
authors.lastname: Höfle
authors.forename: Michael
authors.initials: M
authors.lastname: Kiffe
authors.forename: Jack Z
authors.initials: JZ
authors.lastname: Gougoutas
authors.forename: John D
authors.initials: JD
authors.lastname: DiMarco
authors.forename: Francis Y F
authors.initials: FY
authors.lastname: Lee
authors.forename: Craig R
authors.initials: CR
authors.lastname: Fairchild
authors.forename: Byron H
authors.initials: BH
authors.lastname: Long
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Vite
mesh_terms: 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
chemical_list: D000970:Antineoplastic Agents; D034261:Epothilones; D014404:Tubulin