Synthesis, computational docking and biological evaluation of celastrol derivatives as dual inhibitors of SERCA and P-glycoprotein in cancer therapy

A series of eleven celastrol derivatives was designed, synthesized, and evaluated for their in vitro cytotoxic activities against six human Cancer cell lines (A549, HepG2, HepAD38, PC3, DLD-1 Bax-Bak WT and DKO) and three human normal cells (LO₂, BEAS-2B, CCD19Lu). To our knowledge, six derivatives were the first example of dipeptide celastrol derivatives. Among them, compound 3 was the most promising derivative, as it exhibited a remarkable anti-proliferative activity and improved selectivity in liver Cancer HepAD38 versus human normal hepatocytes, LO₂. Compound 6 showed higher selectivity in liver Cancer cells against human normal lung fibroblasts, CCD19Lu cell line. The CA²⁺ mobilizations of 3 and 6 were also evaluated in the presence and absence of thapsigargin to demonstrate their inhibitory effects on SERCA. Derivatives 3 and 6 were found to induce Apoptosis on LO₂, HepG2 and HepAD38 cells. The potential docking poses of all synthesized celastrol dipeptides and Other known inhibitors were proposed by molecular docking. Finally, 3 inhibited P-gp-mediated drug efflux with greater efficiency than inhibitor verapamil in A549 lung Cancer cells. Therefore, celastrol-dipeptide derivatives are potent drug candidates for the treatment of drug-resistant Cancer.