Copper(I) complexes with homoscorpionate tris(azolyl)borate and auxiliary monodentate phosphine ligands: synthesis and in vitro and in vivo Anticancer Activity

The research on copper(I,II) coordination compounds as antiproliferative agents it’s one of the main research line of our group since years [1]. Hydrophilic, monocationic [M(L)4]PF6 complexes (M = Cu, Ag or Au; L: thp = tris(hydroxymethyl)phosphine, L: PTA = 1,3,5-triaza-7- phosphaadamantane, L: thpp = tris(hydroxypropyl)phosphine) were synthesized and tested as cytotoxic agents against a panel of several human tumour cell lines also including a defined cisplatin resistant cell line [2]. The best results in terms of in vitro antitumour activity were achieved with metal-thp species and, among the coinage metal complexes, copper derivatives were found to be the most efficient drugs [2]. As a natural development of this research line, 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 by means of NMR and ESI-MS, and XAS-EXAFS, 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 complex [HB(pz)3]Cu(PCN) was validated in the murine Lewis Lung Carcinoma (LLC) model [3].