[M(HB(pz)3)(P)] complexes (P = monodentate phosphine): comparison of the antiproliferative activity of silver and copper “3+1” mixed-ligand compounds

In the last years we have reported a series of heteroleptic copper(I) compounds, comprising a monodentate phosphine and a tridentate tris(azolyl)borate ligand, which showed a remarkable in vitro cytotoxic activity also towards cisplatin sensitive and resistant cell lines suggesting a DNA-independent mechanism of action. Moreover, the lead compound [Cu(HB(pz)3)(PCN)] (HB(pz)3 = tris(pyrazolyl) borate, PCN = tris-cyanoethylphosphine) was successfully tested in vivo against murine Lewis Lung Carcinoma (LLC). Considering the known antiproliferative activity of several silver phosphine derivatives, as a development of our previous studies we synthesized and tested a series of neutral silver compounds, analogous to the copper ones, of general formulation [Ag(HB(pz)3)(P)] (P = PTA, DAPTA, PTASO2, PCN, PPh3). Syntheses were performed in acetonitrile solution starting from the labile precursor [Ag(CH3CN)4]BF4 by addition of a stoichiometric amount of the phosphine ligand followed by trispyrazolylborate salt. Air and light stability of the resulting silver derivatives depended on the nature of P-ligands, in particular their lipophilicity (Log P varied from 5.34 of PPh3 to -1.44 of DAPTA) and steric hindrance. The in vitro tests carried out with a panel of several human tumor cell lines showed that silver compounds have a valuable antiproliferative activity, similar or better of the activity exerted by cis-platinum, the reference metallo-drug. On the other hand copper(I) compounds are up to 8 times more active than silver analogues, a behavior already observed within the series of homoleptic coinage metal complexes [MP4]+ where copper derivatives were found to be the most efficient drugs. The most active complexes of copper and silver series are [Cu(HB(pz)3)(PCN)] (average IC50 0.74 μM) and [Ag(HB(pz)3)(PPh3)] (average IC50 2.72 μM) respectively; for both compounds mechanistic investigations were performed.