Design, Synthesis, and Biological Evaluation of 1-Methyl-1,4-dihydroindeno[1,2-c]pyrazole Analogues as Potential Anticancer Agents Targeting Tubulin Colchicine Binding Site,Journal of Medicinal Chemistry

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Design, Synthesis, and Biological Evaluation of 1-Methyl-1,4-dihydroindeno[1,2-c]pyrazole Analogues as Potential Anticancer Agents Targeting Tubulin Colchicine Binding Site
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2016-05-20 00:00:00 , DOI: 10.1021/acs.jmedchem.6b00071
Yan-Na Liu ₁ , Jing-Jing Wang ₁ , Ya-Ting Ji ₁ , Guo-Dong Zhao ₁ , Long-Qian Tang ₁ , Cheng-Mei Zhang ₁ , Xiu-Li Guo ₁ , Zhao-Peng Liu ₁

Affiliation

By targeting a new binding region at the interface between αβ-tubulin heterodimers at the colchicine binding site, we designed a series of 7-substituted 1-methyl-1,4-dihydroindeno[1,2-c]pyrazoles as potential tubulin polymerization inhibitors. Among the compounds synthesized, 2-(6-ethoxy-3-(3-ethoxyphenylamino)-1-methyl-1,4-dihydroindeno[1,2-c]pyrazol-7-yloxy)acetamide 6a and 2-(6-ethoxy-3-(3-ethoxyphenylamino)-1-methyl-1,4-dihydroindeno[1,2-c]pyrazol-7-yloxy)-N-hydroxyacetamide 6n showed noteworthy low nanomolar potency against HepG2, Hela, PC3, and MCF-7 cancer cell lines. In mechanism studies, 6a inhibited tubulin polymerization and disorganized microtubule in A549 cells by binding to tubulin colchicine binding site. 6a arrested A549 cells in G2/M phase that was related to the alterations in the expression of cyclin B1 and p-cdc2. 6a induced A549 cells apoptosis through the activation of caspase-3 and PARP. In addition, 6a inhibited capillary tube formation in a concentration-dependent manner. In nonsmall cell lung cancer xenografts mouse model, 6a suppressed tumor growth by 59.1% at a dose of 50 mg/kg (ip) without obvious toxicity, indicating its in vivo potential as anticancer agent.

中文翻译：

设计，合成和生物评价1-甲基-1,4-二氢茚并[1,2- c ]吡唑类似物作为潜在的靶向微管蛋白秋水仙碱结合位点的抗癌药。

通过在秋水仙碱结合位点的αβ-微管蛋白异二聚体之间的界面处靶向新的结合区域，我们设计了一系列7-取代的1-甲基-1,4-二氢茚并[1,2- c ]吡唑类作为潜在的微管蛋白聚合抑制剂。在合成的化合物中，2-（6-乙氧基-3-（3-乙氧基苯基氨基）-1-甲基-1,4-二氢茚并[1,2 - c ]吡唑-7-酰氧基）乙酰胺6a和2-（6-乙氧基-3-（3-乙氧基苯基氨基）-1-甲基-1,4-二氢茚并[1,2- c ]吡唑-7-酰氧基）-N-羟基乙酰胺6n对HepG2，Hela，PC3和MCF-7癌细胞系。在机理研究中，6a通过与微管蛋白秋水仙碱结合位点结合，抑制A549细胞中的微管蛋白聚合和微管紊乱。6a在G2 / M期阻滞了A549细胞，这与细胞周期蛋白B1和p-cdc2表达的改变有关。6a通过激活caspase-3和PARP诱导A549细胞凋亡。另外，6a以浓度依赖的方式抑制毛细管的形成。在非小细胞肺癌异种移植小鼠模型中，6a以50 mg / kg（ip）的剂量将肿瘤生长抑制了59.1％，而没有明显的毒性，表明其在体内具有作为抗癌剂的潜力。

更新日期：2016-05-20

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