Structural and solution chemistry of gold(I) and silver(I) complexes of bidentate pyridyl phosphines: selective antitumour agents

The 1:2 adducts of Ag(I) and Au(I) with 1,2-bis(di-n-pyridylphosphino)ethane (dnpype) for n = 2, 3 and 4 have been synthesised and solution properties characterised by multinuclear NMR, spectroscopy. The complexes are hydrophilic analogs of the lipophilic Au(I) antitumour complex [Au(dppe)(2)](+) and the degree of hydrophilicity depends critically on the position of the N atom in the pyridyl ring. The complexes of d3pype and d4pype are simple monomeric [M(d3pype)(2)](+) and [M(d4pype)(2)](+) species which have a much higher water solubility than the 2-pyridyl complexes which crystallise in the solid state as dimeric [{M(d2pype)(2)}(2)](2+). In Solution these 1:2 M:d2pype species exist as equilibrium mixtures of monomeric,:dimeric and trimeric (AE) or tetrameric (Au) clusters, The Au(I) and Ag(I)pyridyl phosphine complexes have been evaluated for antitumour activity against a panel of cultured human ovarian carcinoma cell lines. The results show both potent and selective activity for the compounds with IC50 values ranging from 0.18 to 1500 mu M. There is a correlation between the degree of antitumour selectivity and the octanol/water partition coefficients with the greatest selectivity (500-fold range) found for the most hydrophilic complex [Au(d4pype)(2)]Cl. Clinical development of the parent compound [Au(dppe)(2)](+) was halted by liver toxicity and the hydrophilic pyridylphosphine analogs are significantly less toxic than [Au(dppe)(2)](+) when exposed to isolated rat hepatocytes. Convenient synthetic routes to the bidentate pyridyl phosphines d2pype, d3pype and d4pype are also described. (C) 1999 Elsevier Science S.A. All rights reserved.