Design, synthesis and biological evaluation of bridged epothilone D analogues.

Abstract

Six epothilone D analogues with a bridge between the C4-methyl and the C12-methyl carbons were prepared in an attempt to constrain epothilone D to its proposed tubulin-binding conformation. Ring-closing metathesis (RCM) was employed as the key step to build the C4-C26 bridge. In antiproliferative assays in the human ovarian cancer (A2780) and prostate cancer (PC3) cell lines, and also in tubulin assembly assay, all these compounds proved to be less active than epothilone D.

• Authors: Qiao-Hong Chen, Thota Ganesh, Peggy Brodie, Carla Slebodnick, Yi Jiang, Abhijit Banerjee, Susan Bane, James P Snyder, David G I Kingston
• Journal: Organic & biomolecular chemistry (Org Biomol Chem) Vol. 6 Issue 24 Pg. 4542-52 (Dec 21 2008) ISSN: 1477-0539 [Electronic] England
• PMID: 19039362 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antineoplastic Agents
• Epothilones
• Tubulin
• desoxyepothilone B

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Drug Design
• Epothilones (chemical synthesis, chemistry, pharmacology)
• Humans
• Models, Molecular
• Molecular Conformation
• Protein Binding (drug effects)
• Tubulin (metabolism)