A Cytotoxic Bis(1,2,3-triazol-5-ylidene)carbazolide Gold(III) Complex Targets DNA by Partial Intercalation

The syntheses of bis(triazolium)carbazole precursors and their corresponding coinage metal (Au, Ag) complexes are reported. For alkylated triazolium salts, di- or tetranuclear complexes with bridging ligands were isolated, while the bis(aryl) analogue afforded a bis(carbene) Au^I -CNC pincer complex suitable for oxidation to the redox-stable [Au^III (CNC)Cl]⁺ cation. Although the ligand salt and the [Au^III (CNC)Cl]⁺ complex were both notably cytotoxic toward the breast cancer cell line MDA-MB-231, the Au^III complex was somewhat more selective. Electrophoresis, viscometry, UV-vis, CD and LD spectroscopy suggest the cytotoxic [Au^III (CNC)Cl]⁺ complex behaves as a partial DNA intercalator. In silico screening indicated that the [Au^III (CNC)Cl]⁺ complex can target DNA three-way junctions with good specificity, several other regular B-DNA forms, and Z-DNA. Multiple hydrophobic π-type interactions involving T and A bases appear to be important for B-form DNA binding, while phosphate O⋅⋅⋅Au interactions evidently underpin Z-DNA binding. The CNC ligand effectively stabilizes the Au^III ion, preventing reduction in the presence of glutathione. Both the redox stability and DNA affinity of the hit compound might be key factors underpinning its cytotoxicity in vitro.