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Design and synthesis of newer 1,3,4-oxadiazole and 1,2,4-triazole based Topsentin analogues as anti-proliferative agent targeting tubulin.
Bioorganic Chemistry ( IF 5.1 ) Pub Date : 2019-12-23 , DOI: 10.1016/j.bioorg.2019.103519
Fatima Naaz 1 , Faiz Ahmad 2 , Bilal Ahmad Lone 2 , Yuba Raj Pokharel 2 , Neeraj Kumar Fuloria 3 , Shivkanya Fuloria 3 , Manickam Ravichandran 4 , Lalitha Pattabhiraman 5 , Syed Shafi 6 , M Shahar Yar 1
Affiliation  

A set of two series of 1,3,4-oxadiazole (11a-n) and 1,2,4-Triazole (12a, c, e, g, h, j-n) based topsentin analogues were prepared by replacing imizadole moiety of topsentin through a multistep synthesis starting from indole. All the compounds synthesized were submitted for single dose (10 µM) screening against a NCI panel of 60-human cancer cell lines. Among all cancer cell lines, colon (HCC-2998) and Breast (MCF-7, T-47D) cancer cell lines were found to be more susceptible for this class of compounds. Among the compounds tested, compounds 11a, 11d, 11f, 12e and 12h, were exhibited good anti-proliferative activity against various cancer cell lines. Compounds 11d, 12e and 12h demonstrated better activity with IC50 2.42 µM, 3.06 µM, and 3.30 µM respectively against MCF-7 human cancer cell line than that of the standard drug doxorubicin IC50 6.31 µM. Furthermore, 11d induced cell cycle arrest at G0/G1 phase and also disrupted mitochondrial membrane potential with reducing cell migration potential of MCF-7 cells in dose dependent manner. In vitro microtubule polymerization assays found that compound 11d disrupt tubulin dynamics by inhibiting tubulin polymerization with IC50 3.89 μM compared with standard nocodazole (IC50 2.49 μM). In silico docking studies represented that 11d was binding at colchicine binding site of β-tubulin. Compound 11d emerged as lead molecule from the library of compounds tested and this may serve as a template for further drug discovery.

中文翻译:

设计和合成新型的1,3,4-恶二唑和1,2,4-三唑基Topsentin类似物作为靶向微管蛋白的抗增殖剂。

通过取代托普汀的咪唑并部分,制备了两个系列的基于1,3,4-恶二唑(11a-n)和1,2,4-三唑(12a,c,e,g,h,jn)的两个系列。从吲哚开始进行多步合成。提交的所有合成化合物均针对60个人类癌细胞系的NCI组进行单剂量(10 µM)筛选。在所有癌细胞系中,结肠(HCC-2998)和乳腺癌(MCF-7,T-47D)癌细胞系被发现对这类化合物更敏感。在测试的化合物中,化合物11a,11d,11f,12e和12h对各种癌细胞系表现出良好的抗增殖活性。与标准药物阿霉素IC50 6.31 µM相比,化合物11d,12e和12h分别以IC50 2.42 µM,3.06 µM和3.30 µM表现出更好的针对MCF-7人癌细胞系的活性。此外,11d诱导的细胞周期停滞在G0 / G1期,并且还以剂量依赖性方式降低了MCF-7细胞的细胞迁移潜能,从而破坏了线粒体膜电位。体外微管聚合测定法发现,与标准诺考达唑(IC50 2.49μM)相比,化合物11d通过抑制微管蛋白聚合(IC50为3.89μM)来破坏微管蛋白动力学。在计算机对接研究中,表明11d在β-微管蛋白的秋水仙碱结合位点结合。化合物11d作为先导分子从被测化合物的库中出现,这可作为进一步药物发现的模板。体外微管聚合测定法发现,与标准诺考达唑(IC50 2.49μM)相比,化合物11d通过抑制微管蛋白聚合(IC50为3.89μM)来破坏微管蛋白动力学。在计算机对接研究中,表明11d在β-微管蛋白的秋水仙碱结合位点结合。化合物11d作为先导分子从被测化合物的库中出现,这可作为进一步药物发现的模板。体外微管聚合测定法发现,与标准诺考达唑(IC50 2.49μM)相比,化合物11d通过抑制微管蛋白聚合(IC50为3.89μM)来破坏微管蛋白动力学。在计算机对接研究中,表明11d在β-微管蛋白的秋水仙碱结合位点结合。化合物11d作为先导分子从被测化合物的库中出现,这可作为进一步药物发现的模板。
更新日期:2019-12-23
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