Division of Preventive Oncology, ICMR-National Institute of Cancer Prevention and Research and WHO-FCTC Smokeless Tobacco Global Knowledge Hub, Department of Health Research (Govt. of India), I-7, Sector-39, District Gautam Buddha Nagar, Noida, Uttar Pradesh, 201301, India.
Division of Molecular Genetics and Biochemistry, ICMR-National Institute of Cancer Prevention and Research and WHO-FCTC Smokeless Tobacco Global Knowledge Hub, Department of Health Research (Govt. of India), I-7, Sector-39, District Gautam Buddha Nagar, Noida, India.
Top Curr Chem (Cham). 2019 May 9;377(3):15. doi: 10.1007/s41061-019-0240-9.
As the emergence of resistance to clinical cancer treatments poses a significant problem in cancer management, there is a constant need to explore novel anticancer agents which have the ability to overcome multidrug resistance (MDR) mechanisms. The search for the development of novel isatin-based antitumor agents accelerated after the approval by the Food and Drug Administration (FDA) of sunitinib malate, a C-3 isatin derivative, as a multitargeted receptor tyrosine kinase inhibitor. However, it is interesting to note that, over the last decade, various N-substituted analogs of isatin with intact carbonyl functionalities have been found to show more promising anticancer potential than its C-3 derivatives. Microtubule-targeting agents are a class of anticancer drugs which affect mitosis by targeting microtubules and suppressing their dynamic behavior. This review presents a systematic compilation of the in vitro cytotoxic and anticancer properties of various N-substituted isatins and illustrates their mechanism of action to overcome MDR by acting as microtubule-destabilizing agents. Predictions of the biological activities and cytotoxic effects of potential N-substituted isatins against various cancer cell lines have also been performed using the PASS computer-aided drug discovery program. Findings from such in vitro and in silico studies will act as a guide for the development of structure-activity relationship and will facilitate the design and exploration of more potent analogs of isatin with high potency and lower side effects for treatment of drug-resistant cancer. Mechanism of action of N-substituted isatin as microtubule-destabilizing agent on tumor cells. N-Substituted isatins bind to colchicine binding site on β-tubulin, which inhibits microtubule polymerization and thereby destabilizes microtubule dynamics, resulting in mitotic arrest leading to tumor cell growth suppression.
随着临床癌症治疗耐药性的出现对癌症管理构成了重大问题，因此需要不断探索具有克服多药耐药（MDR）机制的新型抗癌药物。在食品和药物管理局（FDA）批准马来酸舒尼替尼（一种 C-3 靛红衍生物）作为多靶点受体酪氨酸激酶抑制剂之后，寻找新型靛红类抗肿瘤药物的研究加速了。然而，有趣的是，在过去的十年中，已发现各种具有完整羰基功能的 N-取代靛红类似物比其 C-3 衍生物具有更有前途的抗癌潜力。微管靶向药物是一类通过靶向微管并抑制其动态行为来影响有丝分裂的抗癌药物。本文系统综述了各种 N-取代靛红的体外细胞毒性和抗癌特性，并说明了它们作为微管不稳定剂克服多药耐药的作用机制。还使用 PASS 计算机辅助药物发现程序对潜在 N-取代靛红对各种癌细胞系的生物活性和细胞毒性作用进行了预测。此类体外和计算机研究的结果将作为构效关系研究的指南，并将有助于设计和探索具有高功效和低副作用的新型强效靛红类似物，以治疗耐药性癌症。N-取代靛红作为微管破坏剂对肿瘤细胞的作用机制。N-取代靛红与β-微管蛋白上的秋水仙碱结合位点结合，抑制微管聚合，从而破坏微管动力学，导致有丝分裂停滞，从而抑制肿瘤细胞生长。
