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

• Published in: PloS one Vol. 10; no. 6; p. e0128710
• Main Authors: Xu, Qile, Qi, Huan, Sun, Maolin, Zuo, Daiying, Jiang, Xuewei, Wen, Zhiyong, Wang, Zhiwei, Wu, Yingliang, Zhang, Weige
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 10.06.2015; Public Library of Science (PLoS)
• Subjects: Activated carbon; Alkyl groups; Analysis; Antineoplastic agents; Antiproliferatives; Binding sites; Cancer; Cell division; Cell Line, Tumor; Cell Proliferation - drug effects; Colchicine; Computer applications; Cytotoxicity; Education; Humans; Kinases; Laboratories; Microtubules; Models, Molecular; Pharmaceuticals; Pharmacology; Polymerization; Pyrazole; Pyrazoles; Pyrazoles - chemical synthesis; Pyrazoles - pharmacology; Signal transduction; Sodium; Stilbenes - chemical synthesis; Stilbenes - chemistry; Stilbenes - pharmacology; Structure-activity relationships; Tubulin; Tumor cell lines; China
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0128710

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.