Synthesis of Thiazolidinedione- and Triazole-Linked Organoselenocyanates and Evaluation of Anticancer Activities Against Breast Cancer with Mechanistic Investigations.

Organoselenocyanates are important classes of organoselenium compounds having potential pharmaceutical applications in cancer biology. In the present study, two different series of organoselenocyanates (15 a-15 c and 16 a-16 c) incorporating crucial heterocyclic pharmacophores such as 2,4-thiazolidine-1,3-dione and 1,2,3-triazole were rationally designed. The organoselenocyanates were synthesized using multi-step organic synthesis and investigated for their anticancer activities against triple-negative breast cancer cells. Based on the preliminary anti-proliferative activities and the selectivity index towards cancer cells over the normal cells, 2,4-thiazolidine-1,3-dione-based selenocyanate 15 a was identified as the lead analogue for detailed investigations. In addition to the anti-migratory activity, compound 15 a induced G1-phase arrest of the cell cycle and led to early apoptosis. Further studies on the redox balance of MDA-MB-231 cells indicated the antioxidant nature of 15 a with the quenching of ROS level and upregulation of TrxR1 expression. Detailed mechanistic investigations with the expression levels of key-cancer marker proteins revealed that the selenocyanate 15 a induced the activation of ERK pathway by upregulating p-ERK expression with the subsequent downregulation of p-Akt and c-Myc levels leading to the inhibition of cellular proliferation. Therefore, the primary outcomes of the study would be valuable in the development of chemotherapeutic agents towards the treatment of triple-negative breast cancer.