Synthesis and Cytotoxicity Studies of Novel NHC*-Gold(I) Complexes Derived from Lepidiline A

Ten novel N-heterocyclic carbene gold(I) complexes derived from lepidiline A (1,3-dibenzyl-4,5-dimethylimidazolium chloride) are reported here with full characterisation and biological testing. (1,3-Dibenzyl-4,5-diphenylimidazol-2-ylidene)gold(I) chloride (NHC*-AuCl) (1) was modified by substituting the chloride for the following: cyanide (2), dithiocarbamates (3-5), p-mercaptobenzoate derivatives (12-14) and N-acetyl-l-cysteine derivatives (15-17). All complexes were synthesised in good yields of 57-78%. Complexes 2, 12, 13, and 14 were further characterised by X-ray crystallography. Initial evaluation of the biological activity was conducted on all ten complexes against the multidrug resistant MCF-7(topo) breast cancer, HCT-116(wt), and p53 knockout mutant HCT-116(-/-) colon carcinoma cell lines. Across the three cell lines tested, mainly single-digit micromolar IC50 values were observed. Nanomolar activity was exhibited on the MCF-7(topo) cell line with 3 displaying an IC50 of 0.28 mu M +/- 0.03 mu M. Complexes incorporating a Au-S bond resulted in higher cytotoxic activity when compared to complexes 1 and 2. Theoretical calculations, carried out at the MN15/6-311++G(2df,p) computational level, show that NHC* is the more favourable ligand for Au(I)-Cl when compared to PPh3.