Hydridotris(azolyl)borate Phosphino-Cu(I) Complexes: Ligand Effect on their in vitro Cytotoxicity

In the last three decades the research of new antitumor agents has spread over complexes of metals other than platinum. Among the considered metals, copper has gained a growing interest and many classes of copper(I/II) complexes have demonstrated anticancer activity and the ability of overcoming inherited or acquired resistance to cisplatin. In the last years we have focused our attention on copper(I) derivatives and due to the “soft” nature of Cu(I) the choice of ligands having soft donor atoms such phosphorous in tertiary phosphines or aromatic sp2 hybridized nitrogen of pyrazolyl derivatives, allowed us to obtain stable active derivatives. In particular, we have reported the synthesis of homoleptic phosphine copper(I) complexes and of heteroleptic copper(I) compounds comprising both phosphine and scorpionate ligands.[2,3] Trying to find a structure-activity relationship for copper(I) compounds containing a tridentate scorpionate or tris(azolyl)borate ligand (L) and an auxiliary monodentate phosphine (P), we have prepared and screened a series of ‘3+1’ [CuLP]0/+ compounds. All reported complexes showed in vitro antitumor activity comparable to that of cisplatin, the reference metallodrug. Among them, the complex [Cu(HB(pz)3)(PCN)] (HB(pz)3 = tris(pyrazolyl) borate, PCN = tris-cyanoethylphoshine), showed IC50 values up to 15-fold lower than those recorded with the reference compound, demostrating a particular efficacy against human 2008 ovarian adenocarcinoma and A431 cervix carcinoma cells. The correlation between cytotoxicity, liphophilicity and steric hindrance of the ligands as well as final charge of the complexes is discussed.