Synthesis, computational docking and biological evaluation of celastrol derivatives as dual inhibitors of SERCA and P-glycoprotein in cancer therapy
Paolo Coghi, Jerome P. L. Ng, Onat Kadioglu, Betty Yuen Kwan Law, Alena Congling Qiu, Mohamed E.M. Saeed, Xi Chen, Chi Kio Ip, Thomas Efferth, Liang Liu, Vincent Kam Wai Wong
Abstract
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.