Abstract
Three 1-deoxynojirimycin (DNJ) derivatives (named C4-C6) including DNJ and tegafur (TGF) were designed and synthesized, and their antiproliferative effects were investigated. C4-C6, especially C6, exerted good lipophilicity, α-glucosidase inhibitory activity, and antitumor effects. Mechanism studies indicated that C6 significantly induced cell apoptosis and S-phase block and inhibited migration of HCT-116 cells. Besides, C6 induced mitochondrial damage by decreasing the mitochondrial membrane potential, improving the accumulation of ROS, upregulating the expression of Bax, and downregulating Bcl-2. Moreover, C6 induced excessive production of ROS to trigger oxidative stress, resulting in an increase in the level of MDA and NO, a decrease in the content of GSH and SOD, and an overexpression of Nrf2. Furthermore, C6 induced DNA damage by down-regulating the expression of thymidylate synthase. These results indicated that C6 is a potential antitumor agent and kills HCT-116 cells through DNA damage, mitochondrial dysfunction, and oxidative stress.