title: Synthesis and Biological Evaluation of 3-Alkyl-1,5-Diaryl-1H-Pyrazoles as Rigid Analogues of Combretastatin A-4 with Potent Antiproliferative Activity.
abstract: 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.
authors.affiliation: Department Key Laboratory of Structure-Based Drug Design and Discovery Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China.
authors.forename: Qile
authors.initials: Q
authors.lastname: Xu
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, China.
authors.forename: Huan
authors.initials: H
authors.lastname: Qi
authors.affiliation: Department Key Laboratory of Structure-Based Drug Design and Discovery Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China.
authors.forename: Maolin
authors.initials: M
authors.lastname: Sun
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, China.
authors.forename: Daiying
authors.initials: D
authors.lastname: Zuo
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, China.
authors.forename: Xuewei
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Department Key Laboratory of Structure-Based Drug Design and Discovery Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Wen
authors.affiliation: Department Key Laboratory of Structure-Based Drug Design and Discovery Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, China.
authors.forename: Yingliang
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department Key Laboratory of Structure-Based Drug Design and Discovery Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China.
authors.forename: Weige
authors.initials: W
authors.lastname: Zhang
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D006801:Humans; D008958:Models, Molecular; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D013267:Stilbenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D011720:Pyrazoles; D013267:Stilbenes; C058728:fosbretabulin