Cytotoxicity, Cell Line Selectivity and Proapoptotic Activity of New Anticancer Agents Derived From...

A new series of N-decyl-N'-benzylbenzimidazolium N-heterocyclic carbene (NHC) precursors and their mononuclear silver(I)-NHC complexes were synthesised and characterised. The benzyl group was functionalised with various para substituents (H, CH₃, F, Cl, Br, CN, NO₂). The effect of these substituents on cytotoxicity and cell line selectivity against human cervical cancer (HeLa), oestrogen-positive human breast cancer (MCF-7), and normal skin fibroblasts (Hs-27) was investigated. All compounds exhibited significant growth inhibition against the tested cell lines. The activity and selectivity of the compounds were influenced by the para substituents and the type of cell line. The electron-donating methylated NHC precursor and its silver complex generally demonstrated higher growth inhibition potentials than the analogues with electron-withdrawing groups, except in two cases where the fluorinated compounds were more potent against Hs-27 and HeLa, while the chlorinated NHC precursor was more active against MCF-7. Notably, all compounds, particularly the silver(I)-NHC complexes, were more active towards MCF-7 but less toxic towards Hs-27. The methyl-, bromo-, and cyano-containing silver(I)-NHC complexes broadened the safety windows against MCF-7 (selectivity indices ≥ 3). The most selective (against MCF-7) chlorinated NHC precursor and its silver(I)-NHC exhibited ROS-mediated proapoptotic activity, which indicated that these compounds promoted cell death by inducing intracellular ROS formation and accumulation. Our findings highlight the potential use of silver(I)-NHC complexes in the design and development of safe and selective anticancer agents.