Chemistry and antitumor investigations of new Cu(I) complexes of bis(pyrazol-1-yl)acetate ligands functionalized with an NMDA receptor antagonist

Copper complexes are coming out as metal-based drug candidates for the treatment of cancer, due to their wide structural variability, biologically accessible redox properties and bioavailability. They display broader spectra of activities and lower toxicity, thereby providing the possibility of circumventing the problems encountered by clinically approved platinum drugs. In the search for Cu-based anticancer agents, over the last decades our attention has been focused on the design and synthesis of copper complexes of bis(azol-1-yl)carboxylate heteroscorpionate ligands of general formula [HC(COOH)(az)2], with az = pyrazole or 1,2,4-triazole. Here we report copper(I) complexes of bis(pyrazol-1-yl)carboxylic acid (LH), bis(3,5- dimethylpyrazol-1-yl)carboxylic acid (L2H) as well as of bis(pyrazol-1-yl)acetates conjugated with the NMDA receptor antagonist 6,6-diphenyl-1,4-dioxan-2-yl)methanamine, named NMDA-ANT for briefness (LNMDA and L2NMDA) and phosphane ligands (triphenylphosphine and 1,3,5-triaza-7-phosphaadamantane, PTA) were synthesized. The selection of an NMDA antagonist for the coupling with LH and L2H was suggested by the observation that NMDA receptors are expressed an play a role in different types of cancer models. All the new complexes showed significant antitumor activity on a panel of human tumor cell lines of different histology and cisplatin sensitive or resistant or with Multi-Drug Resistant phenotype, being significantly more active than cisplatin even in 3D spheroids of H157 and BxPC3 cancer cells. Finally, morphological analysis revealed that the most representative complex [(L2NMDA)Cu(PTA)2]PF6 induced a massive swelling of the endoplasmic reticulum (ER) membrane, which is a clear sign of ER stress.