Synthesis and anti-proliferative effect of novel 4-Aryl-1, 3-Thiazole-TPP conjugates via mitochondrial uncoupling process

With the advent of mitochondrial targeting moiety such as triphenlyphosphonium cation (TPP⁺), targeting mitochondria in Cancer cells has become a promising strategy for combating tumors. Herein, a series of novel 4-aryl-1,3-thiazole derivatives linked to TPP⁺ moiety were designed and synthesized. The cytotoxicity against a panel of four Cancer cell lines was evaluated by CCK-8 assay. Most of these compounds exhibited moderate to good inhibitory activity over HeLa, PC-3 and HCT-15 cells while MCF-7 cells were less sensitive to most compounds. Among them, compound 12a exhibited a significant anti-proliferative activity against HeLa cells, and prompted for further investigation. Specifically, 12a decreased mitochondrial membrane potential and enhanced levels of Reactive Oxygen Species (ROS). The flow cytometry analysis revealed that compound 12a could induce Apoptosis and cell cycle arrest at G0/G1 phase in HeLa cells. In addition, mitochondrial bioenergetics assay revealed that 12a displayed mild mitochondrial uncoupling effect. Taken together, these findings suggest the therapeutic potential of compound 12a as an antitumor agent targeting mitochondria.

Anticancer; Mitochondrial bioenergetics; Mitochondrial targeting; Mitochondrial uncoupler; Oxidative phosphorylation.