Chemistry of Gold Complexes Related to Anti-Arthritis Drugs

Abstract

The synthesis and characterization of complexes analogous to the novel anti-arthritis gold drug auranofin is presented. The general composition of these compounds is L-Au-X where L=triethyl-phosphine and X=tetraacetylthioglucose or chloride in the case of auranofin or its synthetic precursor. Incorporation of ligands (L) such as isocyanides and aromatic nitrogen donors fail to impart the same stability to gold(I) that phosphines or thiols are capable of. Complexes of aromatic nitrogen ligands are prone to decomposition and those of isocyanides, although thermodynamically stable, are labile and subject to relatively rapid isocyanide substitution as well as the expected substitution of the halide group. Complexes have been investigated with regard to their in vitro and in vivo DNA-binding capabilities in light of the reported anticancer properties of auranofin itself. Isocyanide and phosphine gold(I) complexes as well as a series of gold(lll) complexes have shown their ability to bind to DNA in vitro but lose their viability in vivo. This is likely a result of reduction of the gold by thiol groups present in a living system and is associated with the observed cytotoxicity at increasing concentrations. The tris-2-pyridylphosphine (TPP) ligand has also been utilized as a choice for L which has led to the synthesis of the auranofin analogue, (tris-2-pyridylphosphine)(tetraacetylthioglucose)gold(l). Metal ions such as Zn(ll), Co(lll), Cu(ll), Fe(II), Fe(III) and Cr(lll) have been incorporated at the pyridyl nitrogen sites and this series of complexes has been studied crystallographically. N-bound and mixed N-and P-bound complexes have been studied by other techniques as well, depending on the nature of the metal ion involved. Copper(ll) complexes have been investigated by E.S.R. and UV/Visible spectroscopies, Moessbauer data is presented for iron(ll) and iron(lll) complexes and infrared data has been collected and summarized for all complexes. In general, the TPP ligand is an accomodating chelate; N-bound complexes are octahedral and little ligand strain is observed upon coordination. The nitrogen and phosphorus sites are independent in that there appear to be no electronic effects exerted by one site on the other. An important effect of coordinating metal ions to the nitrogen sites is to alter the solubility of the hydrophobic ClAuTPP complex to one with hydrophilic properties.