Synthesis and biological evaluation of gold(III) Schiff base complexes for the treatment of hepatocellular carcinoma through attenuating TrxR activity

Mianli Bian; Xin Wang; Ying Sun; Wukun Liu

doi:10.1016/j.ejmech.2020.112234

Synthesis and biological evaluation of gold(III) Schiff base complexes for the treatment of hepatocellular carcinoma through attenuating TrxR activity

Eur J Med Chem. 2020 May 1:193:112234. doi: 10.1016/j.ejmech.2020.112234. Epub 2020 Mar 14.

Authors

Mianli Bian¹, Xin Wang¹, Ying Sun¹, Wukun Liu²

Affiliations

¹ School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, PR China.
² School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, PR China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, PR China; State Key Laboratory of Coordination Chemistry, Nanjing University, Nanjing, 210023, PR China. Electronic address: [email protected].

PMID: 32213395
DOI: 10.1016/j.ejmech.2020.112234

Abstract

Hepatocellular carcinoma (HCC) is one of the most common cancers and a leading cause of death worldwide. Increased thioredoxin reductase (TrxR) levels were recently identified as possible prognostic markers for HCC. Here, four gold(III) complexes 1b-4b bearing Schiff base ligands were synthesized, characterized, and screened for antitumor activity against HCC. All complexes triggered significant antiproliferative effects against HCC cells, especially the most active complex 1b induced HepG2 cells apoptosis by activating the endoplasmic reticulum stress (ERS). 1b could clearly inhibit the TrxR activity to elevate reactive oxygen species (ROS), mediate ERS and lead to mitochondrial dysfunction. Notably, treatment of 1b improved the CCl₄-induced liver damage in vivo by down-regulation of TrxR expression and inflammation level.

Keywords: Endoplasmic reticulum stress; Gold(III) Schiff base complexes; Hepatocellular carcinoma; Reactive oxygen species; Thioredoxin reductase.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Carcinoma, Hepatocellular / drug therapy*
Carcinoma, Hepatocellular / metabolism
Carcinoma, Hepatocellular / pathology
Cell Cycle Checkpoints / drug effects
Cell Proliferation / drug effects
Crystallography, X-Ray
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Endoplasmic Reticulum Stress / drug effects
Gold / chemistry
Gold / pharmacology*
Hep G2 Cells
Humans
Liver Neoplasms / drug therapy*
Liver Neoplasms / metabolism
Liver Neoplasms / pathology
Models, Molecular
Molecular Structure
Reactive Oxygen Species / metabolism
Schiff Bases / chemistry
Schiff Bases / pharmacology
Structure-Activity Relationship
Thioredoxin-Disulfide Reductase / antagonists & inhibitors*
Thioredoxin-Disulfide Reductase / genetics
Thioredoxin-Disulfide Reductase / metabolism

Substances

Antineoplastic Agents
Reactive Oxygen Species
Schiff Bases
Gold
Thioredoxin-Disulfide Reductase