Design, synthesis and biological evaluation of new SIRT3 activators for the treatment of triple-negative breast cancer.

Triple-negative breast cancer (TNBC) represents a highly malignant subtype of breast cancer with limited therapeutic options. In this study, we designed and synthesized a series of 1,4-DHP derivatives by structure-based strategy, 43 was documented to be a potent SIRT3 activator and exhibited profound anti-proliferative activity in BT-549 and MDA-MB-231 cells with low toxicity over normal cells. Additionally, 43 displayed the ability of direct binding to SIRT3 with a K value of 51.51 μM in BLI assay, and the potential bonding mode was elucidated through molecular docking. 43 could inhibit the proliferation, migration, and glycolysis, induced mitochondrial membrane potential decreased and apoptosis in BT-549 and MDA-MB-231 cells. Collectively, these results demonstrate that 43 is a potent SIRT3 activator with the potential to anti-TNBC through signaling pathways regulated by SIRT3.