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Abstract
The reaction of gold reagents [HAuCl4•3H2O], [AuCl(tht)], or cyclometalated gold(III) precursor, [C^NAuCl2] 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 ~0.10–2.53 μΜ 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.
Highlights
The inherent electrochemical properties of the gold complexes were studied by cyclic voltammetry and theoretical insight of the complexes was gained by density functional theory and TD-Density functional theory (DFT) calculations
Strong σ-donating ligands such as phosphines and N-heterocyclic carbenes are used to improved stability of gold complexes against rapid reduction[59]
Work that studied the anticancer potential of gold-phosphino complexes offered impetus that the complexes synthesized in our laboratory will be active against cancer cells in vitro
Summary
These gold compounds were characterized by multinuclear NMR, microanalysis, mass spectrometry, and X-ray crystallography. Gold-based probe development and drug discovery remain a burgeoning area of biological research and treatment for disease indications such as cancer[1,2,3,4,5], arthritis[6,7,8,9], and microbial infection[10,11] following the FDA approval of tetra-O-acetylglucose-1-thiolgold(I) triethylphosphine complex (auranofin). Despite effective clinical and preclinical treatment of cancer and rheumatoid arthritis by gold complexes such as auranofin, the molecular basis of drug action remains unclear for gold(III) phosphine compounds present in this report. Years of research implicates a number of disease targets including: (i) proteasome-associated deubiquitinases[6,7,8,9]; (ii) thiol-rich enzymes such as thioredoxin and glutathione reductase[17,18,19,20]; (iii) thiol-dependent proteases[21]; iv) autophagy induction[22]; and superoxide/oxyradical ion generation[23]
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