Copper(I) heteroleptic ‘3+1’ complexes: ligand effect on their in vitro cytotoxicity

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. They showed a remarkable in vitro cytotoxic activity also towards cisplatin sensitive and resistant cell lines suggesting a DNA-independent mechanism of action. By comparison of ‘2+1+1’ and ‘3+1’ complexes, the latter seemed by far the most active. For this reason we have prepared and screened a series of (3+1) [CuLP]0/+ copper(I) compounds containing a tridentate tris(azolyl)borate ligand (L) and an auxiliary monodentate phosphine (P), whose hydrophilicity and steric hindrance were systematically changed trying to find a structure-activity relationship. Among them, [Cu(HB(pz)3)(PCN)] (HB(pz)3 = tris(pyrazolyl) borate, PCN = tris-cyanoethylphosphine) showed IC50 values up to 15-fold lower than those recorded with the reference metallodrug cisplatin. Mechanistic studies revealed that cancer cells treated with [Cu(HB(pz)3)(PCN)] died via a paraptotic cell death coherent with the impairment of cell proteolytic system. In vivo studies on syngeneic murine Lewis Lung Carcinoma (LLC) confirmed the antitumor efficacy of [Cu(HB(pz)3)(PCN)]