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)ethan e (dnpype) for n = 2, 3 and 4 have been synthesised and solution properties characterised by multinuclear NMR, spectroscopy. The complexes are hydroph ilic analogs of the lipophilic Au(I) antitumour complex [Au(dppe)(2)](+) an d 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 mon omeric [M(d3pype)(2)](+) and [M(d4pype)(2)](+) species which have a much hi gher 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:d2 pype species exist as equilibrium mixtures of monomeric,:dimeric and trimer ic (AE) or tetrameric (Au) clusters, The Au(I) and Ag(I)pyridyl phosphine c omplexes have been evaluated for antitumour activity against a panel of cul tured 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 selectiv ity and the octanol/water partition coefficients with the greatest selectiv ity (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 signifi cantly less toxic than [Au(dppe)(2)](+) when exposed to isolated rat hepato cytes. Convenient synthetic routes to the bidentate pyridyl phosphines d2py pe, d3pype and d4pype are also described. (C) 1999 Elsevier Science S.A. Al l rights reserved.