Synthesis and biological activity of novel Au(I) complexes with a protective antioxidant 2,6-di-tert-butylphenol group

Abstract Novel gold(I) complexes, PPh3AuSR (1) and [(Ph3PAu)2SR]2(BF4)2 (2), with a protective antioxidant group R (R = 3,5-di-tert-butyl-4-hydroxyphenyl) were synthesized and characterized by 1H, 13C, 31P NMR, IR and elemental analyses. The crystal structures of compounds 1 and 2 were determined by X-ray diffraction. Compound 2 has a cluster structure with four Au–Au bonds in the crystal. The tetragold(I) dication is composed of four PPh3Au units with bridging sulfur atoms, where the Au4 moiety has a distorted tetrahedral geometry. The biological impact of gold complexes 1 and 2, and their precursors (RSH and AuPPh3Cl), on lipid peroxidation, mitochondrial functions, the tubulin polymerization, activity of glutathione reductase and cell viability were investigated. A comparative study of the structure–activity relationship was performed. We found that RSH and Au complexes 1 and 2 as opposed to AuPPh3Cl, prevented Fe3+ and tBHP-induced lipid peroxidation in isolated mitochondria. The number of 2,6-di-tert-butylphenol fragments influences the inhibitory effect. AuPPh3Cl induced swelling and depolarization of mitochondria, whereas RSH and the gold complexes 1 and 2, containing 2,6-di-tert-butylphenol groups, showed little to null effect. The thiol ligand RSH and AuPPh3Cl as well as gold complexes 1 and 2 have no impact on tubulin polymerization. The gold complexes were found to inhibit glutathione reductase. The compounds were tested for cytotoxicity against a primary culture of rat cerebellar granule cells. A high toxicity was determined for AuPPh3Cl, while introduction of antioxidant phenol groups decreased the cytotoxicity of the Au complexes. These results open up scope for the design of novel low toxic, gold based pharmacological agents.