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

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

  • Eur J Med Chem. 2021 Nov 15:224:113676. doi: 10.1016/j.ejmech.2021.113676.
Paolo Coghi 1,  Jerome P L Ng 2,  Onat Kadioglu 3,  Betty Yuen Kwan Law 2,  Alena Congling Qiu 2,  Mohamed E M Saeed 3,  Xi Chen 2,  Chi Kio Ip 2,  Thomas Efferth 4,  Liang Liu 5,  Vincent Kam Wai Wong 6
Affiliations

Affiliations

  • 1 School of Pharmacy, Macau University of Science and Technology, Macau, China.
  • 2 Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China.
  • 3 Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany.
  • 4 Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany. Electronic address: efferth@uni-mainz.de.
  • 5 Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China. Electronic address: lliu@must.edu.mo.
  • 6 Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China. Electronic address: kawwong@must.edu.mo.
PMID: 34256125 DOI: 10.1016/j.ejmech.2021.113676
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.

Keywords

Antitumor activity; Celastrol derivatives; Molecular docking; P-glycoprotein; SERCA; Traditional Chinese medicine.

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