Synthesis and Biological Evaluation of 3-Alkyl-1,5-Diaryl-1H-Pyrazoles as Rigid Analogues of Combretastatin A-4 with Potent Antiproliferative Activity.

PLoS One 2015 10;10(6):e0128710. Epub 2015 Jun 10.

Department Key Laboratory of Structure-Based Drug Design and Discovery Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China.

A series of novel 3-alkyl-1,5-diaryl-1H-pyrazoles were synthesized as combretastatin A-4 (CA-4) analogues and evaluated for antiproliferative activity against three human cancer cell lines (SGC-7901, A549 and HT-1080). Most of the target compounds displayed moderate to potent antiproliferative activity, and 7k was found to be the most potent compound. Structure-activity relationships indicated that compounds with a trimethoxyphenyl A-ring at the N-1 position of the pyrazole skeleton were more potent than those with the A-ring at the C-5 position. Tubulin polymerization and immunostaining experiments revealed that 7k potently inhibited tubulin polymerization and disrupted tubulin microtubule dynamics in a manner similar to CA-4. Computational modelling demonstrated that the binding of 7k to the colchicine binding site on microtubules may involve a similar mode as CA-4.

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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0128710PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4462585PMC
March 2016
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