Design, synthesis and biological evaluation of chemical swiss tools to treat tumors

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. We have synthesized three carboxylated heteroscorpionate ligands, [HC(CO2H)(pzMe2)2], [HC(CO2H)(pz)2] and [HC(CO2H)(tz)2] and we have studied their coordination chemistry towards copper(II), copper(I) and silver(I) acceptors. We have also investigated the use of nitroimidazole (2-methyl-5-nitro-imidazole) as biomolecule to link to scorpionate ligands, as nitroimidazole conjugates of bis(thiosemicarbazonato)copper(II) showed additive or synergistic selectivity for tumor hypoxia compared to their individual components. In particular, we designed two new nitroimidazole conjugated heteroscorpionate ligands, 2,2-bis(3,5-dimethyl-1H-pyrazol-1-yl)-N-(2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl)acetamide (LMN) and 2,2-bis(1H-pyrazol-1-yl)-N-(2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl)acetamide (LMN’), useful for the synthesis of novel copper(I) and copper(II) derivatives to be evaluated for their cytotoxic activity.3 The ligands [HC(CO2H)(pzMe2)2] and [HC(CO2H)(pz)2] 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 Some new copper(II) complexes as well as the corresponding uncoordinated ligands were evaluated for their cytotoxic activity towards a panel of several human tumour cell lines.