Synthesis and evaluation of 4/5-hydroxy-2,3-diaryl(substituted)-cyclopent-2-en-1-ones as cis-restricted analogues of combretastatin A-4 as novel anticancer agents

Gurjar, Mukund K. ; Wakharkar, Radhika D. ; Singh, Anu T. ; Jaggi, Manu ; Borate, Hanumant B. ; Shinde, Popat D. ; Verma, Ritu ; Rajendran, Praveen ; Dutt, Sarjana ; Singh, Gurvinder ; Sanna, Vinod K. ; Singh, Manoj K. ; Srivastava, Sanjay K. ; Mahajan, Vishal A. ; Jadhav, Vinod H. ; Dutta, Kakali ; Krishnan, Karthik ; Chaudhary, Anika ; Agarwal, Shiv K. ; Mukherjee, Rama ; Burman, Anand C. (2007) Synthesis and evaluation of 4/5-hydroxy-2,3-diaryl(substituted)-cyclopent-2-en-1-ones as cis-restricted analogues of combretastatin A-4 as novel anticancer agents Journal of Medicinal Chemistry, 50 (8). pp. 1744-1753. ISSN 0022-2623

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Official URL: http://pubs.acs.org/doi/abs/10.1021/jm060938o

Related URL: http://dx.doi.org/10.1021/jm060938o

Abstract

A new series of 2,3-diaryl-4/5-hydroxy-cyclopent-2-en-1-one analogues replacing the cis double bond of combretastatin A-4 (CA-4) by 4/5-hydroxy cyclopentenone moieties was designed and synthesized. The analogues displayed potent cytotoxic activity (IC50 < 1 μg/mL) against a panel of human cancer cell lines and endothelial cells. The most potent analogues 11 and 42 belonging to the 5-hydroxy cyclopentenone class were further evaluated for their mechanism of action. Both of the analogues led to cell cycle arrest at G2/M phase and induced apoptosis in endothelial cells. Antitubulin property of 42 was superior to 11 and comparable to CA-4. The compound 42 had better aqueous solubility, metabolic stability, and pharmacokinetic profile than CA-4 and also demonstrated significant tumor regression in the human colon xenograft model. Our data suggests that cis-restricted analogues of CA-4 are a new class of molecules that have the potential to be developed as novel agents for the treatment of cancer.

Item Type:Article
Source:Copyright of this article belongs to American Chemical Society.
ID Code:11370
Deposited On:09 Nov 2010 05:09
Last Modified:02 Jun 2011 09:39

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