Chirality influence on the cytotoxic properties of anionic chiral bis(N-heterocyclic carbene)silver complexes

Complexes Na₃[Ag(NHC^R)₂], 2a-e and 2b'-c', where NHC^R is a N-heterocyclic carbene of the 2,2'-(1H-2λ³,3λ⁴-imidazole-1,3-diyl)dicarboxylate type, were prepared by treatment of compounds HL^R, 1a-e and 1b'-c' (2-(1-(carboxyalkyl)-1H-imidazol-3-ium-3-yl)carboxylate), with silver oxide in the presence of aqueous sodium hydroxide. They were characterized by analytical, spectroscopic (infrared, IR, ¹H and ¹³C nuclear magnetic resonance, NMR, and circular dichroism) and X-ray methods (2a). In the solid state, the anionic part of complex 2a, [Ag(NHC^H)₂]^3-, shows a linear disposition of C_carbene-Ag-C_carbene atoms and an eclipsed conformation of the two NHC ligands. The proposed bis(NHC) nature of the silver complexes was maintained in solution according to NMR and density functional theory (DFT) calculations. The cytotoxic activity of compounds 2 was evaluated against four cancer cell lines and one non-cancerous cell line and several structure-activity correlations were found for these complexes. For instance, the activity decreased when the bulkiness of the R alkyl group in Na₃[Ag(NHC^R)₂] increased. More interesting is the detected chirality-anticancer relationship, where complexes Na₃[Ag{(S,S)-NHC^R}₂] (R = Me, 2b; ⁱPr, 2c) showed better anticancer activity than those of their enantiomeric derivatives Na₃[Ag{(R,R)-NHC^R}₂] (R = Me, 2b'; ⁱPr, 2c').