2. Academic Validation
  3. 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

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

  • J Med Chem. 2007 Apr 19;50(8):1744-53. doi: 10.1021/jm060938o.
Mukund K Gurjar 1,  Radhika D Wakharkar,  Anu T Singh,  Manu Jaggi,  Hanumant B Borate,  Popat D Shinde,  Ritu Verma,  Praveen Rajendran,  Sarjana Dutt,  Gurvinder Singh,  Vinod K Sanna,  Manoj K Singh,  Sanjay K Srivastava,  Vishal A Mahajan,  Vinod H Jadhav,  Kakali Dutta,  Karthik Krishnan,  Anika Chaudhary,  Shiv K Agarwal,  Rama Mukherjee,  Anand C Burman
Affiliations

Affiliation

  • 1 Division of Organic Chemistry: Technology, National Chemical Laboratory, Pune 411008, India.
PMID: 17373779 DOI: 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 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.

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