Fluorinated <i>N</i>-Heterocyclic Carbene Silver(I) Complexes with High Cancer Cell Selectivity

<p dir="ltr">This work presents the synthesis of five new functionalized (benz)imidazolium <i>N</i>-heterocyclic (NHC) ligands (<b>L</b>) and four new (benz)imidazole silver(I) NHC (Ag(I)-NHC) complexes of mononuclear <b>[Ag(L)</b>_{<strong>2</strong>}<b>](PF</b>_{<strong>6</strong>}<b>)</b> or binuclear <b>[Ag</b>_{<strong>2</strong>}<b>(L)</b>_{<strong>2</strong>}<b>](PF</b>_{<strong>6</strong>}<b>)</b>_{<strong>2</strong>} type. The complexes have been fully characterized, including single crystal X-ray diffraction of three new structures. The complexes and their corresponding free NHC ligands have been screened against breast cancer and noncancerous cell lines, showing the mononuclear benzimidazole complex has the highest activity, while the binuclear benzimidazole complex has the highest cancer cell selectivity. The silver uptake was measured by ICP-MS and highlights a strong link between cytotoxicity and cellular uptake. DNA interaction studies, molecular docking, and evaluation of reactive oxygen species (ROS) have been conducted for the most promising complexes to identify modes of action. Overall, the binuclear benzimidazole complex is the most selective and promising candidate against the MDA-MD-231 (breast cancer) cell line and has potential to be developed for treatment of late-stage breast cancers.