Highly stable selenadiazole derivatives induce bladder cancer cell apoptosis and inhibit cell migration and invasion through the activation of ROS-mediated signaling pathways.

Bladder cancer is still a common malignancy of the urinary tract due to the high metastasis rate and unexpected side effects of drug treatments. The acidic environment of the urinary bladder also strongly limits the efficacy of the chemotherapeutic agents during the treatment of bladder cancer. In this study, a series of selenadiazole derivatives (SeDs) have been rationally designed and synthesized and could actively suppress the progression and metastasis of bladder cancer cells. SeDs demonstrated better antiproliferative activity and higher stability under different physiological conditions, especially in an acidic urocystic environment, than mitomycin, a clinically used anti-bladder cancer drug. In particular, compound 1b displayed better selectivity between cancer and normal cells in comparison with other compounds. Studies on the structure-activity relationship revealed that the introduction of strong electron donating substituents, such as the methoxy group, resulted in a dramatic enhancement in the anticancer efficacy. Furthermore, 1b induced anti-migration and anti-invasion activities against bladder cancer cells. Mechanistic investigation revealed that compound 1b was able to enter the cells through endocytosis and then trigger reactive oxygen species (ROS) overproduction, further causing DNA damage-mediated p53 phosphorylation and promoting cancer cell apoptosis by regulating the AKT and MAPKs signaling pathways. Altogether, the study provides a strategy for rational design of selenadiazole derivatives with improved stability to antagonize bladder cancer.