Document Report Card

ID: ALA1143007

Journal: J Med Chem

Title: 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.

Authors: Gurjar MK, Wakharkar RD, Singh AT, Jaggi M, Borate HB, Shinde PD, Verma R, Rajendran P, Dutt S, Singh G, Sanna VK, Singh MK, Srivastava SK, Mahajan VA, Jadhav VH, Dutta K, Krishnan K, Chaudhary A, Agarwal SK, Mukherjee R, Burman AC.

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 microg/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.

CiteXplore: 17373779

DOI: 10.1021/jm060938o