Synthesis and biological evaluation of 2-indolyloxazolines as a new class of tubulin polymerization inhibitors. Discovery of A-289099 as an orally active antitumor agent.

Abstract

A series of indole containing oxazolines has been discovered as a result of structural modifications of the lead compound A-105972. The compounds exert their anticancer activity through inhibition of tubulin polymerization by binding at the colchicine site. A-289099 was identified as an orally active antimitotic agent active against various cancer cell lines including those that express the MDR phenotype. The anticancer activity, pharmacokinetics, and an efficient and enantioselective synthesis of A-289099 are described.

• Authors: Qun Li, Keith W Woods, Akiyo Claiborne, Stephen L Gwaltney 2nd, Kenneth J Barr, Gang Liu, Laura Gehrke, R Bruce Credo, Yu Hua Hui, Jang Lee, Robert B Warner, Peter Kovar, Michael A Nukkala, Nicolette A Zielinski, Stephen K Tahir, Michael Fitzgerald, Ki H Kim, Kennan Marsh, David Frost, Shi-Chung Ng, Saul Rosenberg, Hing L Sham
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 12 Issue 3 Pg. 465-9 (Feb 11 2002) ISSN: 0960-894X [Print] England
• PMID: 11814821 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Indoles
• Oxazoles
• Polymers
• Tubulin
• A 289099

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, pharmacokinetics, pharmacology)
• Biological Availability
• Drug Screening Assays, Antitumor
• Humans
• Indoles (chemical synthesis, pharmacokinetics, pharmacology)
• Mice
• Microtubules (drug effects, metabolism)
• Models, Molecular
• Oxazoles (chemical synthesis, pharmacokinetics, pharmacology)
• Polymers (chemical synthesis)
• Rats
• Stereoisomerism
• Tubulin (metabolism)
• Tumor Cells, Cultured