Fiche publication


Date publication

novembre 2018

Journal

Inorganic chemistry

Auteurs

Membres identifiés du Cancéropôle Est :
Dr GAIDDON Christian


Tous les auteurs :
Lam NYS, Truong D, Burmeister H, Babak MV, Holtkamp HU, Movassaghi S, Ayine-Tora DM, Zafar A, Kubanik M, Oehninger L, Söhnel T, Reynisson J, Jamieson SMF, Gaiddon C, Ott I, Hartinger CG

Résumé

The promise of the metal(arene) structure as an anticancer pharmacophore has prompted intensive exploration of this chemical space. While N-heterocyclic carbene (NHC) ligands are widely used in catalysis, they have only recently been considered in metal complexes for medicinal applications. Surprisingly, a comparatively small number of studies have been reported in which the NHC ligand was coordinated to the Ru(arene) pharmacophore and even less with an Os(arene) pharmacophore. Here, we present a systematic study in which we compared symmetrically substituted methyl and benzyl derivatives with the nonsymmetric methyl/benzyl analogues. Through variation of the metal center and the halido ligands, an in-depth study was conducted on ligand exchange properties of these complexes and their biomolecule binding, noting in particular the stability of the M-C bond. In addition, we demonstrated the ability of the complexes to inhibit the selenoenzyme thioredoxin reductase (TrxR), suggested as an important target for anticancer metal-NHC complexes, and their cytotoxicity in human tumor cells. It was found that the most potent TrxR inhibitor diiodido(1,3-dibenzylbenzimidazol-2-ylidene)(η-p-cymene)ruthenium(II) 1b was also the most cytotoxic compound of the series, with the antiproliferative effects in general in the low to middle micromolar range. However, since there was no clear correlation between TrxR inhibition and antiproliferative potency across the compounds, TrxR inhibition is unlikely to be the main mode of action for the compound type and other target interactions must be considered in future.

Mots clés

Animals, Antineoplastic Agents, chemical synthesis, Benzimidazoles, chemical synthesis, Cell Line, Tumor, Coordination Complexes, chemical synthesis, Cytochromes c, chemistry, DNA, chemistry, Drug Stability, Female, Humans, Mice, Inbred BALB C, Molecular Dynamics Simulation, Molecular Structure, Osmium, chemistry, Ruthenium, chemistry, Structure-Activity Relationship, Thioredoxin-Disulfide Reductase, antagonists & inhibitors, Ubiquitin, chemistry

Référence

Inorg Chem. 2018 Nov 8;: