Hura Neha, Naaz Afsana, Prassanawar Shweta S, Guchhait Sankar K, Panda Dulal
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab 160062, India.
Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India.
ACS Omega. 2018 Feb 28;3(2):1955-1969. doi: 10.1021/acsomega.7b01784. Epub 2018 Feb 19.
Twenty-three combretastatin A-4 (CA-4) analogues were synthesized by judiciously incorporating a functional -heterocyclic motif present in Celecoxib (a marketed drug) while retaining essential pharmacophoric features of CA-4. Combretastatin-(trifluoromethyl)pyrazole hybrid analogues, i.e., 5-trimethoxyphenyl-3-(trifluoromethyl)pyrazoles with a variety of relevantly substituted aryls and heteroaryls at 1-position were considered as potential tubulin polymerization inhibitors. The cytotoxicity of the compounds was evaluated using MCF-7 cells. Analog 23 () was found to be the most active among the tested compounds. It showed pronounced cytotoxicity against HeLa, B16F10, and multidrug-resistant mammary tumor cells EMT6/AR1. Interestingly, displayed significantly lower toxicity toward noncancerous cells, MCF10A and L929, than their cancerous counterparts, MCF-7 and B16F10, respectively. depolymerized interphase microtubules, disrupted mitotic spindle formation, and arrested MCF-7 cells at mitosis, leading to cell death. inhibited the assembly of tubulin . bound to tubulin at the colchicine binding site and altered the secondary structures of tubulin. The data revealed the importance of (trimethoxyphenyl)(trifluoromethyl)pyrazole as a cis-restricted double bond-alternative bridging motif, and carboxymethyl-substituted phenyl as ring B for activities and interaction with tubulin. The results indicated that the combretastatin-(trifluoromethyl)pyrazole hybrid class of analogues has the potential for further development as anticancer agents.
通过巧妙地引入塞来昔布（一种上市药物）中存在的功能性杂环基序，同时保留CA - 4的基本药效特征，合成了23种康普瑞他汀A - 4（CA - 4）类似物。康普瑞他汀 -（三氟甲基）吡唑杂合类似物，即1位带有各种相关取代芳基和杂芳基的5 - 三甲氧基苯基 - 3 -（三氟甲基）吡唑被视为潜在的微管蛋白聚合抑制剂。使用MCF - 7细胞评估了这些化合物的细胞毒性。发现类似物23（）在测试的化合物中活性最高。它对HeLa、B16F10和多药耐药性乳腺肿瘤细胞EMT6/AR1表现出显著的细胞毒性。有趣的是，与癌细胞MCF - 7和B16F10相比，对非癌细胞MCF10A和L929的毒性分别显著更低。使间期微管解聚，破坏有丝分裂纺锤体形成，并使MCF - 7细胞在有丝分裂期停滞，导致细胞死亡。抑制微管蛋白的组装。在秋水仙碱结合位点与微管蛋白结合并改变微管蛋白的二级结构。数据揭示了（三甲氧基苯基）（三氟甲基）吡唑作为顺式受限双键替代桥连基序以及羧甲基取代苯基作为环B对于活性和与微管蛋白相互作用的重要性。结果表明，康普瑞他汀 -（三氟甲基）吡唑杂合类类似物有作为抗癌剂进一步开发的潜力。
