Systematic Review on Cytotoxic and Anticancer Potential of N-Substituted Isatins as Novel Class of Compounds Useful in Multidrug-Resistant Cancer Therapy: In Silico and In Vitro Analysis.

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.