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Synthesis and Evaluation of 1,5-Disubstituted Tetrazoles as Rigid Analogues of Combretastatin A-4 with Potent Antiproliferative and Antitumor Activity

Romagnoli, Romeo, Baraldi, Pier Giovanni, Salvador, Maria Kimatrai, Preti, Delia, Aghazadeh Tabrizi, Mojgan, Brancale, Andrea, Fu, Xian-Hua, Li, Jun, Zhang, Su-Zhan, Hamel, Ernest, Bortolozzi, Roberta, Basso, Giuseppe and Viola, Giampietro 2012. Synthesis and Evaluation of 1,5-Disubstituted Tetrazoles as Rigid Analogues of Combretastatin A-4 with Potent Antiproliferative and Antitumor Activity. Journal of Medicinal Chemistry 55 (1) , pp. 475-488. 10.1021/jm2013979

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Abstract

Tubulin, the major structural component of microtubules, is a target for the development of anticancer agents. Two series of 1,5-diaryl substituted 1,2,3,4-tetrazoles were concisely synthesized, using a palladium-catalyzed cross-coupling reaction, and identified as potent antiproliferative agents and novel tubulin polymerization inhibitors that act at the colchicine site. SAR analysis indicated that compounds with a 4-ethoxyphenyl group at the N-1 or C-5 position of the 1,2,3,4-tetrazole ring exhibited maximal activity. Several of these compounds also had potent activity in inhibiting the growth of multidrug resistant cells overexpressing P-glycoprotein. Active compounds induced apoptosis through the mitochondrial pathway with activation of caspase-9 and caspase-3. Furthermore, compound 4l significantly reduced in vivo the growth of the HT-29 xenograft in a nude mouse model, suggesting that 4l is a promising new antimitotic agent with clinical potential.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Subjects: R Medicine > RS Pharmacy and materia medica
Publisher: American Chemical Society
ISSN: 0022-2623
Last Modified: 04 Jun 2017 03:01
URI: http://orca.cf.ac.uk/id/eprint/15640

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