Novel nicotinoyl pyrazoline derivates bearing N-methyl indole moiety as antitumor agents: Design, synthesis and evaluation
Novel nicotinoyl pyrazoline derivates bearing N-methyl indole moiety as antitumor agents: Design, synthesis and evaluation
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DOI：
10.1016/j.ejmech.2018.07.044
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发表时间：
2018-08-05
影响因子：
6.7
通讯作者：
Zhu, Hai-Liang
中科院分区：
文献类型：
--
作者：
Chen, Kun;Zhang, Ya-Liang;Zhu, Hai-Liang
在目前的工作中，已经设计并合成了二十五种带有N-甲基吲哚部分的烟酰基吡唑啉衍生物。对这些化合物作为微管蛋白组装抑制剂的生物学评价表明，它们中的大多数是潜在的抗肿瘤药物。其中，化合物28对癌细胞系组表现出最强的效力（对于HeLa、HepG2和MCF-7细胞，GI(50)=29-90nM），对非肿瘤细胞无毒性（对于293T细胞，CC50>300μM），与微管蛋白的秋水仙碱位点结合，并在微管蛋白组装测定中显示出优异的抑制活性（IC50=1.6μM，优于CA-4）。通过分子动力学模拟验证了化合物28与微管蛋白晶体的对接姿势。对HepG2和HeLa细胞的进一步研究表明，化合物28可以导致有丝分裂阻滞至G2/M期，并随后诱导细胞凋亡。还在HeLa-Xenograft裸鼠上评估了化合物28的体内效率，相对肿瘤抑制率高达61.52%，没有明显的体重减轻和组织损伤（通过H&E染色检查），与CA-4（抑制59.92%）相当。简而言之，化合物 28 是作为微管蛋白组装抑制剂用于肿瘤治疗的有前途的候选者。 (C) 2018 Elsevier Masson SAS。版权所有。
In the present work, twenty-five nicotinoyl pyrazoline derivates bearing N-methyl indole moiety have been designed and synthesized. The biological evaluation of these compounds as tubulin assembly inhibitors revealed that most of them were potential antitumor agents. Among them, compound 28 exhibited most potency against cancer cell line panels (GI(50) = 29-90 nM for HeLa, HepG2 and MCF-7 cells) without toxicity to non-tumor cells (CC50 > 300 mu M for 293 T cell), bound to the colchicine site of tubulin and displayed excellent inhibitory activity in tubulin assembly assay (IC50 = 1.6 mu M, better than CA-4). Molecular dynamics simulation was carried out to validate the docking pose of compound 28 with tubulin crystalline. Further investigation on HepG2 and HeLa cells demonstrated that compound 28 could cause mitosis arrest to G2/M phase, and subsequently induced cell apoptosis. The efficiency in vivo of compound 28 was also evaluated on HeLa-Xenograft nude mice, and the relative tumor inhibition ration was up to 61.52% without noticeable weight loss and tissue damage (examined by H&E staining), which was comparable to CA-4 (inhibited 59.92%). In brief, compound 28 is a promising candidate for tumor therapy as tubulin assembly inhibitor. (C) 2018 Elsevier Masson SAS. All rights reserved.