Cytotoxicity of asymmetric mononuclear silver(I)-N-heterocyclic carbene complexes against human cervical cancer: Synthesis, crystal structure, DFT calculations and effect of substituents

Abstract

A new series of asymmetrical N,N’-disubstituted benzimidazolium derived N-heterocyclic carbene (NHC) ligands and their mononuclear silver(I)-NHC complexes are reported. The ligands were prepared from N-alkylation of 1-methylbenzimidazole with alkyl bromides (n = 10-18 in even parity), non-fluorinated or fluorinated benzyl bromides. In situ deprotonation of the ligands with silver oxide, followed by metathesis reaction with potassium hexafluorophosphate facilitated the formation of the mononuclear silver(I)-NHC complexes. Chemical structures of all the compounds were elucidated using Fourier transform infrared, 1H and 13C nuclear magnetic resonance (NMR) spectroscopy, and CHN elemental microanalysis. The coordination mode of the Ag(I)-NHC complexes was confirmed by single crystal XRD analysis. Single crystal analysis of ortho-fluorinated benzyl-containing complex showed that each complex consisted of one Ag(I) ion coordinated with two NHC ligands in a linear geometry in the presence of one PF6− anion in the lattice. Cytotoxic effects of the NHC ligands and their silver(I) complexes against human cervical cancer cells (HeLa) and normal human skin fibroblasts (Hs27) were investigated using the MTT assay. Cytotoxicity of these compounds was dependent on the N-substituents in the benzimidazolium moiety and the presence of silver ions. Benzylated ligands were non-active whilst their dialkylated analogues showed weak to excellent cytotoxic effects on HeLa cells. The incorporation of silver ions and elongation of alkyl chains significantly enhanced cytotoxicity. Density functional theory revealed that Ag–C bond strength was insensitive to the NHC ligand design, and about one-third of the overall complex binding enthalpy was contributed by the non-covalent interaction between the long alkyl chains. Long-chain ligands (n = 16-18) and all silver(I)-NHC complexes exhibited superior cytotoxicity against HeLa cells (IC50 ranged between 1.18 µM–9.38 µM) as compared to that of the anticancer drug, Etoposide (IC50 = 25.67 µM).