Guichan Huang, Hailing Wang, Xi Zhao, Chen Wang, Jin Zhang, Dahong Yao, Chenyang Li
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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 Kd 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.
期刊介绍：
Bioorganic & Medicinal Chemistry provides an international forum for the publication of full original research papers and critical reviews on molecular interactions in key biological targets such as receptors, channels, enzymes, nucleotides, lipids and saccharides.
The aim of the journal is to promote a better understanding at the molecular level of life processes, and living organisms, as well as the interaction of these with chemical agents. A special feature will be that colour illustrations will be reproduced at no charge to the author, provided that the Editor agrees that colour is essential to the information content of the illustration in question.
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