Xu Qile, Wang Yueting, Xu Jingwen, Sun Maolin, Tian Haiqiu, Zuo Daiying, Guan Qi, Bao Kai, Wu Yingliang, Zhang Weige
Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University , 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
Department of Pharmacology, Shenyang Pharmaceutical University , 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
ACS Med Chem Lett. 2016 Oct 17;7(12):1202-1206. doi: 10.1021/acsmedchemlett.6b00252. eCollection 2016 Dec 8.
A series of 3,6-diaryl-[1,2,4]triazolo[4,3-]pyridazines were designed as a class of vinylogous CA-4 analogues. The easily isomerized (,)-butadiene linker of vinylogous CA-4 was replaced by a rigid [1,2,4]triazolo[4,3-]pyridazine scaffold. Twenty-one target compounds were synthesized and exhibited moderate to potent antiproliferative activity. The compound with a 3-amino-4-methoxyphenyl moiety as the B-ring, comparable to CA-4 (IC = 0.009-0.012 μM), displayed the highly active antiproliferative activity against SGC-7901, A549, and HT-1080 cell lines with IC values of 0.014, 0.008, and 0.012 μM, respectively. Tubulin polymerization experiments indicated that effectively inhibited tubulin polymerization, and immunostaining assay revealed that significantly disrupted tubulin microtubule dynamics. Moreover, cell cycle studies revealed that compound dramatically arrested cell cycle progression at G2/M phase in A549 cells. Molecular modeling studies showed that could bind to the colchicine binding site on microtubules.
设计了一系列3,6-二芳基-[1,2,4]三唑并[4,3 -]哒嗪作为一类乙烯基类似物CA-4类似物。乙烯基类似物CA-4中易于异构化的（,）-丁二烯连接基被刚性的[1,2,4]三唑并[4,3 -]哒嗪骨架取代。合成了21种目标化合物，它们表现出中度至强效的抗增殖活性。具有3-氨基-4-甲氧基苯基部分作为B环的化合物，与CA-4相当（IC = 0.009 - 0.012μM），对SGC-7901、A549和HT-1080细胞系表现出高活性抗增殖活性，IC值分别为0.014、0.008和0.012μM。微管蛋白聚合实验表明， 有效地抑制了微管蛋白聚合，免疫染色分析显示， 显著破坏了微管蛋白微管动力学。此外，细胞周期研究表明，化合物 在A549细胞中显著使细胞周期进程停滞在G2/M期。分子模拟研究表明， 可以结合到微管上的秋水仙碱结合位点。
