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

6533b830fe1ef96bd1297114

RESEARCH PRODUCT

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

Liang Liu Vincent Kam Wai Wong Xi Chen Paolo Coghi Jerome P.l. Ng Onat Kadioglu Alena Congling Qiu Chi Kio Ip Mohamed E.m. Saeed Betty Yuen Kwan Law Thomas A. Efferth

subject

SERCA Antineoplastic Agents Apoptosis Pharmacology Sarcoplasmic Reticulum Calcium-Transporting ATPases chemistry.chemical_compound Structure-Activity Relationship Cell Line Tumor Drug Discovery medicine Cytotoxic T cell Humans ATP Binding Cassette Transporter Subfamily B Member 1 P-glycoprotein Cell Proliferation Pharmacology Binding Sites biology Organic Chemistry Cancer General Medicine medicine.disease Molecular Docking Simulation chemistry Apoptosis Docking (molecular)Celastrol Cell culture Drug Resistance Neoplasm Drug Design biology.protein Drug Screening Assays Antitumor Pentacyclic Triterpenes

description

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.

year	journal	country	edition	language
2021-11-01	European journal of medicinal chemistry

10.1016/j.ejmech.2021.113676 https://pubmed.ncbi.nlm.nih.gov/34256125