Rational design and biological evaluation of novel conjugated heteroscorpionate ligands and related Copper(I/II) complexes

Polydentate nitrogen-containing donor ligands derived from poly(pyrazol-1-yl)methanes bearing organic functional groups on the bridging carbon have recently attracted considerable attention and their coordination chemistry towards main group and transition metals have been extensively studied [1]. Recently we designed and synthetized two carboxylated heteroscorpionate ligands (LH, [HC(CO2H)(pz)2] and LMe, [HC(CO2H)(pzMe2)2]), and the related 5-nitroimidazole conjugated heteroscorpionate ligands named LHMN and LMeMN [2] (Fig. 1) by direct coupling of preformed side chain acid with 5-nitroimidazole. In particular the copper(II) complexes (LRMN)2CuCl2 and the water soluble copper(I) complexes [(LRMN)Cu(PTA)2](PF6) (R = H or Me) have been prepared and evaluated for their cytotoxic activity towards a panel of several human tumour cell lines [3]. The ligands LH and LMe have also been functionalized with the potent NMDA receptor antagonist (6,6-diphenyl-1,4-dioxan-2-yl)methanamine, which showed a significant cytotoxic activity on MCF7 human breast cancer cell lines, highly expressing NMDA receptors [4], affording the conjugated derivatives LHNMDA and LMeNMDA (Fig. 1) used for the preparation of stable Cu(I/II) complexes. All the compounds were evaluated against a panel of human tumor cell lines derived from solid tumors. The research results suggest that these Cu(I/II) complexes might act through synergistic mechanisms of action due to the presence of the NMDA ligands and copper in the same chemical entity.