Synthesis and Mode of Action Studies on Iridium(I)–NHC Anticancer Drug Candidates

Yvonne Gothe, Isolda Romero-Canelón, Tiziano Marzo, Peter J. Sadler, Luigi Messori, Nils Metzler-Nolte

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)

Abstract

We report the synthesis, characterization, and biological activity of IrI complexes with triazole- (NNHC) and thiazole-based (NSHC) N-heterocyclic carbene ligands. Starting from the dimeric [Ir(COD)Cl]2, we obtained complexes of composition Ir(COD)(NNHC)Cl (4a), Ir(COD)(NNHC)X (4b: X = Cl; 4bBr: X = Br), [Ir(COD)(NNHC)(NHC)]I (5a), [Ir(COD)(NSHC)2]Cl (6a), and [Ir(COD)(NSHC)(NNHC)]Cl (6b) by adaptation of established synthetic methods for metal–NHC complexes. Their interactions with model proteins cytochrome c and lysozyme, as well as with the oligonucleotide hexamer (CG)3 (ODN1), were studied. Although most complexes did not show any strong interactions with these biomolecules, all complexes were active against HT-29 and MCF-7 cancerous cells, with IC50 values ranging between 1 and 60 µm. The most active compounds were the cationic bis(carbene) derivatives 5 and 6. All compounds generated high levels of reactive oxygen species (ROS) after incubation for 48 h in MCF-7 cells, possibly suggesting a redox-mediated mechanism of action. Interestingly, there were distinctive differences in the superoxide/(total ROS) ratios induced by the different groups of compounds.

Original languageEnglish
Pages (from-to)2461-2470
Number of pages10
JournalEuropean Journal of Inorganic Chemistry
Volume2018
Issue number20-21
Early online date24 May 2018
DOIs
Publication statusPublished - 7 Jun 2018

Keywords

  • Carbenes
  • Iridium
  • Medicinal chemistry
  • Metal-based drugs
  • Protein interactions

ASJC Scopus subject areas

  • Inorganic Chemistry

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