SAR and pH stability of cyano-substituted epothilones

Alicia Regueiro-Ren; Kenneth Leavitt; Soong-Hoon Kim; Gerhard Höfle; Michael Kiffe; Jack Z Gougoutas; John D DiMarco; Francis Y F Lee; Craig R Fairchild; Byron H Long; Gregory D Vite

doi:10.1021/ol026589j

SAR and pH stability of cyano-substituted epothilones

Org Lett. 2002 Oct 31;4(22):3815-8. doi: 10.1021/ol026589j.

Authors

Alicia Regueiro-Ren¹, Kenneth Leavitt, Soong-Hoon Kim, Gerhard Höfle, Michael Kiffe, Jack Z Gougoutas, John D DiMarco, Francis Y F Lee, Craig R Fairchild, Byron H Long, Gregory D Vite

Affiliation

¹ 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. [email protected]

PMID: 12599466
DOI: 10.1021/ol026589j

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.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology
Cell Division / drug effects
Drug Stability
Epothilones / chemical synthesis*
Epothilones / chemistry
Epothilones / pharmacology
Humans
Hydrogen-Ion Concentration
Molecular Structure
Structure-Activity Relationship
Tubulin / drug effects
Tubulin / metabolism
Tumor Cells, Cultured

Substances

Antineoplastic Agents
Epothilones
Tubulin