Synthesis and biological evaluation of novel isatin-phenol hybrids as potential antitumor agents

Chemotherapy was one of indispensable methods for treating cancer, and the development of novel antitumor drugs was necessary due to the emergent drug resistance and undesirable side effects. In the current study, we successfully constructed a novel library of isatin-phenol hybrids by chemical coupling of isatin (1) with a series of active phenols including honokiol (2), magnolol (3), bis(4-hydroxy-3-methylphenyl) sulfide (4), bisphenol A (5), carvacrol (6), and hydroxyqunioline (7) respectively. The target molecules were screened for anticancer activity, and we further investigate the anti-cancer mechanism of the most potent compound IPH10 in vitro and in vivo. Animal experiments demonstrated that IPH10 possessed strong anti-tumor effects in vivo without hepatic and renal toxicity. Moreover, the effects of IPH10 on mitochondrial membrane potential (JC-1) and reactive oxygen species (ROS) in tumor cells were investigated, and the results showed that IPH10 could significantly increase the content of ROS and dramatically decrease the mitochondrial membrane potential in tumor cells. Furthermore, the effect of IPH10 on apoptotic proteins in tumor cells was also explored by Western blotting analysis, which revealed that IPH10 could significantly increase the protein content of cleaved caspase-9/cleaved caspase-3/cleaved caspase-7/cleaved PARP. Taken together, the current study reported a promising novel chemotherapeutic drug candidate IPH10 that could inhibit the growth and induce the apoptosis of tumor cells.