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J Med Chem ; 50(8): 1744-53, 2007 Apr 19.
Article in English | MEDLINE | ID: mdl-17373779

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.


Subject(s)
Antineoplastic Agents/chemical synthesis , Apoptosis , Cyclopentanes/chemical synthesis , Stilbenes/chemical synthesis , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cyclopentanes/pharmacokinetics , Cyclopentanes/pharmacology , DNA Fragmentation , Drug Screening Assays, Antitumor , Endothelial Cells/drug effects , Humans , Mice , Mice, Inbred BALB C , Mice, Nude , Solubility , Stilbenes/pharmacokinetics , Stilbenes/pharmacology , Structure-Activity Relationship , Transplantation, Heterologous , Tubulin Modulators/chemical synthesis , Tubulin Modulators/pharmacokinetics , Tubulin Modulators/pharmacology
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