Gold(I/III)-Phosphine Complexes as Potent Antiproliferative Agents

The reaction of gold reagents [HAuCl4 center dot 3H(2)O], [AuCl(tht)], or cyclometalated gold(III) precursor, [(CNAuCl2)-N-boolean AND] with chiral ((R,R)-(-)-2,3-bis(t-butylmethylphosphino) quinoxaline) and non-chiral phosphine (1,2-Bis(diphenylphosphino)ethane, dppe) ligands lead to distorted Au(I), (1, 2, 4, 5) and novel cyclometalated Au(III) complexes (3, 6). These gold compounds were characterized by multinuclear NMR, microanalysis, mass spectrometry, and X-ray crystallography. The inherent electrochemical properties of the gold complexes were also studied by cyclic voltammetry and theoretical insight of the complexes was gained by density functional theory and TD-DFT calculations. The complexes effectively kill cancer cells with IC50 in the range of similar to 0.10-2.53 mu M across K562, H460, and OVCAR8 cell lines. In addition, the retinal pigment epithelial cell line, RPE-Neo was used as a healthy cell line for comparison. Differential cellular uptake in cancer cells was observed for the compounds by measuring the intracellular accumulation of gold using ICP-OES. Furthermore, the compounds trigger early- late stage apoptosis through potential disruption of redox homeostasis. Complexes 1 and 3 induce predominant G1 cell cycle arrest. Results presented in this report suggest that stable gold-phosphine complexes with variable oxidation states hold promise in anticancer drug discovery and need further development.