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

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.

Evaluation Of 5-hydroxy-2,3-diaryl (substituted)-cyclopent-2-en-1-ones as cis-restricted analogues of combretastatin A-4 as novel anti angiogenic and anticancer agents

“…The analogues also induced apoptosis in proliferating endothelial cells. When assessed for their ability to inhibit tubulin polymerization, compound 42 was found to be evidently more potent antitubulin than 11, but comparable with CA-4 which may indicate a similarity in the mechanism of action with CA-4 [18]. Further in-vitro anti-angiogenic evaluation of the compound 11 and 42 was carried out in the present study.…”

“…Based on previous published paper [18] two potent cisrestricted CA-4 analogues 11 and 42 were selected for further evaluation for anticancer and anti angiogenic activity both in vitro and in vivo. 13.35 µM respectively in a panel of cell lines representing colon, breast, lung, oral, ovary, prostate, skin fibroblast, pancreas, leukemia, and kidney.…”

“…PTC, MDA MB 453, PA1, SKOV3, DU145 and MiaPaCa2 whereas compound 11 showed its cytotoxic potential only against MiaPaCa2. Hence, based on the above in vitro cytotoxity data, and the results obtained from previous studies on antitubulin property, better aqueous solubility, metabolic stability, and pharmacokinetic profile of compound 42 as compared to CA-4 [18], compound 42 was selected for its evaluation of antitumor activity in prostate (DU145) and ovarian (SKOV3) xenografts in vivo. Both CA-4 and compound 42 showed tumor regression in prostate and ovarian tumors, but the results for compound 42 were not statistically significant unlike CA-4.…”

“…Antitubulin property of analogue 42 was superior to that of 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 [18].…”

Enantioselective Synthesis of Chiral Cyclopent‐2‐enones by Nickel‐Catalyzed Desymmetrization of Malonate Esters

“…However, reversible E / Z isomerization of ( Z )‐ 2 would give the alkenylnickel species ( E )‐ 2 , which could now attack an ester in an enantioselective desymmetrization to give 2,3‐diaryl cyclopent‐2‐enones ( 3 ) . The 2,3‐diaryl cyclopent‐2‐enone scaffold is present in the highly potent COX‐2 inhibitor 4 , as well as in the combretocyclopentenones 5 and related compounds, which exhibit antitumor activity. Moreover, there are few asymmetric methods for the de novo construction of cyclopent‐2‐enones with a quaternary stereocenter at the 5‐position (as in 3 ) .…”