Document Detail

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.
MedLine Citation:
PMID:  17373779     Owner:  NLM     Status:  MEDLINE    
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.
Mukund K Gurjar; 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
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2007-03-21
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  50     ISSN:  0022-2623     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2007 Apr 
Date Detail:
Created Date:  2007-04-12     Completed Date:  2007-06-18     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1744-53     Citation Subset:  IM    
Division of Organic Chemistry: Technology, National Chemical Laboratory, Pune 411008, India.
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MeSH Terms
Antineoplastic Agents / chemical synthesis*,  pharmacokinetics,  pharmacology
Cell Line, Tumor
Cyclopentanes / chemical synthesis*,  pharmacokinetics,  pharmacology
DNA Fragmentation
Drug Screening Assays, Antitumor
Endothelial Cells / drug effects
Mice, Inbred BALB C
Mice, Nude
Stilbenes / chemical synthesis*,  pharmacokinetics,  pharmacology
Structure-Activity Relationship
Transplantation, Heterologous
Tubulin Modulators / chemical synthesis,  pharmacokinetics,  pharmacology
Reg. No./Substance:
0/Antineoplastic Agents; 0/Cyclopentanes; 0/Stilbenes; 0/Tubulin Modulators; 117048-59-6/combretastatin A-4

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