title: Synthesis and Bioevaluation of 3,6-Diaryl-[1,2,4]triazolo[4,3-b] Pyridazines as Antitubulin Agents.
abstract: A series of 3,6-diaryl-[1,2,4]triazolo[4,3-b]pyridazines were designed as a class of vinylogous CA-4 analogues. The easily isomerized (Z,E)-butadiene linker of vinylogous CA-4 was replaced by a rigid [1,2,4]triazolo[4,3-b]pyridazine scaffold. Twenty-one target compounds were synthesized and exhibited moderate to potent antiproliferative activity. The compound4qwith a 3-amino-4-methoxyphenyl moiety as the B-ring, comparable to CA-4 (IC50= 0.009-0.012 μM), displayed the highly active antiproliferative activity against SGC-7901, A549, and HT-1080 cell lines with IC50values of 0.014, 0.008, and 0.012 μM, respectively. Tubulin polymerization experiments indicated that4qeffectively inhibited tubulin polymerization, and immunostaining assay revealed that4qsignificantly disrupted tubulin microtubule dynamics. Moreover, cell cycle studies revealed that compound4qdramatically arrested cell cycle progression at G2/M phase in A549 cells. Molecular modeling studies showed that4qcould bind to the colchicine binding site on microtubules.
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University , 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
authors.forename: Qile
authors.initials: Q
authors.lastname: Xu
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University , 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
authors.forename: Yueting
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University , 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
authors.forename: Jingwen
authors.initials: J
authors.lastname: Xu
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University , 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
authors.forename: Maolin
authors.initials: M
authors.lastname: Sun
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University , 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
authors.forename: Haiqiu
authors.initials: H
authors.lastname: Tian
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University , 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
authors.forename: Daiying
authors.initials: D
authors.lastname: Zuo
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University , 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Guan
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China; Gordon Center for Medical Imaging, Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02214, United States.
authors.forename: Kai
authors.initials: K
authors.lastname: Bao
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University , 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
authors.forename: Yingliang
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University , 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
authors.forename: Weige
authors.initials: W
authors.lastname: Zhang
keywords: [1,2,4]Triazolo[4,3-b]pyridazine; colchicine binding site; combretastatin A-4; molecular modeling; tubulin