Cytotoxic Ag(I) and Au(I) NHC-carbenes bind DNA and show TrxR inhibition

J Inorg Biochem. 2020 Apr:205:110998. doi: 10.1016/j.jinorgbio.2020.110998. Epub 2020 Jan 15.

Abstract

A silver(I) and a gold(I) complex of the fluorescent N-heterocyclic carbenic (NHC) ligand 1-(9-anthracenylmethyl)-3-(3-trimethylsilyl-2-propynil)-benzimidazol-2-ylidene have been synthesized and characterized. These compounds show cytotoxicity in the micromolar range and higher antiproliferative properties than cisplatin (CDDP) against several tumour cell lines such as SW480 (colon), A549 (lung) and HepG2 (liver). Both metal complexes are successfully internalized by SW480 cells being the silver compound the most accumulated. Subsequently, they were evaluated as inhibitors of the selenoenzyme Thioredoxin reductase (TrxR) and as DNA binders. Fluorescence microscopy confirmed that both protein and DNA binding could be involved in the biological activity of the compounds. The silver carbene was the most effective enzyme inhibitor with an IC50 in the nanomolar range. Also, interaction studies with natural double stranded DNA highlight a strong stabilisation of the double helix after binding to the Ag(I) carbene, indicating its potential suitability as dual-targeting anticancer active molecule.

Keywords: Anthracenyl dyes; DNA interactions; Dual anticancer drug; Metal carbene complexes; Thioredoxin reductase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Animals
  • Cattle
  • Coordination Complexes* / chemistry
  • Coordination Complexes* / pharmacology
  • Cytotoxins* / chemistry
  • Cytotoxins* / pharmacology
  • DNA, Neoplasm* / chemistry
  • DNA, Neoplasm* / metabolism
  • Enzyme Inhibitors* / chemistry
  • Enzyme Inhibitors* / pharmacology
  • Gold* / chemistry
  • Gold* / pharmacology
  • Hep G2 Cells
  • Humans
  • Methane / analogs & derivatives
  • Methane / chemistry
  • Methane / pharmacology
  • Rats
  • Silver* / chemistry
  • Silver* / pharmacology
  • Thioredoxin-Disulfide Reductase* / antagonists & inhibitors
  • Thioredoxin-Disulfide Reductase* / chemistry
  • Thioredoxin-Disulfide Reductase* / metabolism

Substances

  • Coordination Complexes
  • Cytotoxins
  • DNA, Neoplasm
  • Enzyme Inhibitors
  • carbene
  • Silver
  • Gold
  • Thioredoxin-Disulfide Reductase
  • Methane