New Cu(I) Complexes of Bis(pyrazol-1-yl)acetate Ligands Functionalized with an NMDA Receptor Antagonist with Cytotoxic Activity

Among transition metals, copper is one of the most versatile elements to obtain metal-based drugs, due to the wide structural variability, biologically accessible redox properties and bioavailability. In the attempt to find potential Cu-based antitumor agents, our efforts have been recently focused on the design and synthesis of copper compounds of bis(azolyl)acetate heteroscorpionate ligands of general formula [(az)2CH(COOH)], where az = pyrazole, 3,5-dimethylpyrazole and 1,2,4-triazole. Cu(I) compounds have been synthesized employing bis(pyrazol-1-yl)acetic acid (LH), bis(3,5-dimethylpyrazol-1-yl)acetic acid (L2H) and the same ligands conjugated with the NMDA receptor antagonist (6,6-diphenyl-1,4-dioxan-2-yl)methanamine (LNMDA and L2NMDA). The selection of an NMDA antagonist for the coupling with LH and L2H has been suggested by the observation that NMDA receptors are expressed and play a role in several types of cancer models. Phospanes as coligands (triphenylphosphine, PPh3, and 1,3,5-triaza-7-phosphaadamantane, PTA) have also been used in order to stabilize the Cu(I) centre in the +1 oxidation state. All the new complexes have shown significant antitumor activity on a panel of human tumor cell lines of different histology, with cisplatin-sensitive, cisplatin-resistant or multi-drug-resistant phenotype. Their half-maximal inhibitory concentration (IC50) values have been in the low- and sub-micromolar range and, in general, significantly lower than that of cisplatin. Interestingly, the fact that all the complexes have proved to be significantly more active than cisplatin even in three-dimensional (3D) spheroids of H157 and BxPC3 cancer cells has increased the relevance of the in vitro results.