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 (original) (raw)

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 (IC 50 < 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. * To whom correspondence should be addressed. Phone: (91) 020-25902284 (R.D.W.); (91) 0120-4378505 (A.T.S.); (91) 0120-4378610 (M.J.). Fax: (91) 020-25902629 (R.D.W.); (91) 0120-4376902 (A.T.S. and M.J.).