Lead identification of conformationally restricted benzoxepin type combretastatin analogs: synthesis, antiproliferative activity, and tubulin effects.

Irene Barrett, Miriam Carr, Niamh O'Boyle, Lisa M Greene, Andrew J S Knox, David G Lloyd, Daniela M Zisterer, Mary J Meegan

School of Pharmacy and Pharmaceutical Sciences, Centre for Synthesis and Chemical Biology, Trinity College Dublin, Dublin, Ireland.

Journal of enzyme inhibition and medicinal chemistry 2010 Apr

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We have synthesized a series of polymethoxylated rigid analogs of combretastatin A-4 which contain a benzoxepin ring in place of the usual ethylene bridge present in the natural combretastatin products. The compounds display antiproliferative activity when evaluated against the MCF-7 and MDA human breast carcinoma cell lines. 5-(3-Hydroxy-4-methoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-2,3-dihydro-benzoxepine (11g) was found to be the most potent product when evaluated against the MCF-7 breast cancer cell line. A brief computational study of the structure-activity relationship for the synthesized compounds is presented. These 4,5-diarylbenzoxepins are identified as potentially useful scaffolds for the further development of antitumor agents which target tubulin.

Citation

Irene Barrett, Miriam Carr, Niamh O'Boyle, Lisa M Greene, Andrew J S Knox, David G Lloyd, Daniela M Zisterer, Mary J Meegan. Lead identification of conformationally restricted benzoxepin type combretastatin analogs: synthesis, antiproliferative activity, and tubulin effects. Journal of enzyme inhibition and medicinal chemistry. 2010 Apr;25(2):180-94