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J Med Chem. 2010 May 27;53(10):4248-58. doi: 10.1021/jm100245q.

Synthesis and antitumor activity of 1,5-disubstituted 1,2,4-triazoles as cis-restricted combretastatin analogues.

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Dipartimento di Scienze Farmaceutiche, Università di Ferrara, Ferrara, Italy.


A series of 1-aryl-5-(3',4',5'-trimethoxyphenyl) derivatives and their related 1-(3',4',5'-trimethoxyphenyl)-5-aryl-1,2,4-triazoles, designed as cis-restricted combretastatin analogues, were synthesized and evaluated for antiproliferative activity, inhibitory effects on tubulin polymerization, cell cycle effects, and apoptosis induction. Their activity was greater than, or comparable with, that of the reference compound CA-4. Flow cytometry studies showed that HeLa and Jurkat cells treated with the most active compounds 4l and 4o were arrested in the G2/M phase of the cell cycle in a concentration dependent manner. This effect was accompanied by apoptosis of the cells, mitochondrial depolarization, generation of reactive oxygen species, activation of caspase-3, and PARP cleavage. Compound 4l was also shown to have potential antivascular activity, since it induced endothelial cell shape change in vitro and disrupted the sprouting of endothelial cells in the chick aortic ring assay.

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