SAR and pH Stability of Cyano-Substituted Epothilones

SAR and pH Stability of Cyano-Substituted Epothilones

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 sta...

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Veröffentlicht in:Organic letters 2002-10, Vol.4 (22), p.3815-3818
Hauptverfasser: Regueiro-Ren, Alicia, Leavitt, Kenneth, Kim, Soong-Hoon, Höfle, Gerhard, Kiffe, Michael, Gougoutas, Jack Z, DiMarco, John D, Lee, Francis Y. F, Fairchild, Craig R, Long, Byron H, Vite, Gregory D
Format: Artikel
Sprache:eng
Schlagworte:
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
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Zusammenfassung: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.
ISSN:1523-7060
1523-7052
DOI:10.1021/ol026589j