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

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 =...

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Bibliographic Details
Published in:European journal of inorganic chemistry 2018-06, Vol.2018 (20-21), p.2461-2470
Main Authors: Gothe, Yvonne, Romero‐Canelón, Isolda, Marzo, Tiziano, Sadler, Peter J., Messori, Luigi, Metzler‐Nolte, Nils
Format: Article
Language:English
Subjects:
Biological activity
Biomolecules
Carbenes
Coordination compounds
Inorganic chemistry
Iridium
Lysozyme
Medicinal chemistry
Metal‐based drugs
Protein interactions
Proteins
Synthesis
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Summary: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. Synthesis, characterization, and biological activity of IrI complexes with N‐heterocyclic carbene ligands based on triazole (NNHC) and thiazole (NSHC) are reported, and compounds with a mixed NHC ligand set were found to have the highest antiproliferative activity.
ISSN:1434-1948
1099-0682
DOI:10.1002/ejic.201800225