Anticancer Activity of Copper(I) Complexes with Homoscorpionate Tris(pyrazolyl)borate and Auxiliary Monodentate Phosphine Ligands

The altered metabolism of cancer cells and the different response between normal and tumor cell to copper have laid the basis for the development of copper complexes as anticancer agents. In previous studies, we found that stable tetrahedral, heteroleptic copper(I) complexes were obtained by combining the property of scorpionates with the reducing ability of tertiary phosphines. Recently, tetrahedral copper(I) TpCuP complexes, where Tp is a N,N,N-tris(azolyl)borate and P is a tertiary phosphine, have been synthesized and characterized (Figure 1) by means of NMR, ESI-MS and X-ray diffraction analyses on the representative complexes [HB(pz)3]Cu(PCN) and [HB(3-(NO2)pz)3]Cu(PCN).3 All copper(I) complexes were evaluated for their antiproliferative activity against a panel of human cancer cell lines (including cisplatin and multidrug-resistant sublines). The two most effective complexes [HB(pz)3]Cu(PCN) and [HB(pz)3]Cu(PTA) showed selectivity toward tumor vs normal cells, inhibition of 26S proteasome activity associated with endoplasmic reticulum stress, and unfolded protein response activation. No biochemical hallmarks of apoptosis were detected, and morphology studies revealed an extensive cytoplasmic vacuolization coherently with a paraptosis-like cell death mechanism. Finally, the antitumor efficacy of [HB(pz)3]Cu(PCN) was validated in the murine Lewis Lung Carcinoma model.