Copper complexes of bis(pyrazolyl)acetates conjugated with biologically active molecules as potential anticancer and antiviral agents

Copper complexes show broader spectra of activities and lower toxicity, thereby providing the possibility of circumventing the problems encountered by platinum drugs, such as dose-limiting toxicity and inherent/acquired resistance [1]. We have recently reported copper complexes with heteroscorpionate ligands conjugated with the derivatives of the antineoplastic drug lonidamine (L1-L4, Fig. 1), endowed with cytotoxic activity toward a panel of human tumor cell lines [2]. Here we describe the synthesis and biological evaluation of new Cu(I) and Cu(II) complexes functionalized with the antiviral agent amantadine (L5 and L6, Fig. 1). The bis(pyrazol-1-yl)acetic acids were selected as bifunctionalizable coordinating agents for the synthesis of the ligands due to the presence of a carboxylic function suitable for the coupling with primary amine groups. All the complexes with amantadine-conjugated ligands were primarily evaluated for their cytotoxicity on two mammalian immortalized cell lines, such as HaCaT and Vero E6 cells, by MTT cell viability assay. The results highlighted that all the Cu(II) complexes and the Cu(I)-PTA complexes showed good biocompatibility profiles at both the studied cell lines and have been selected to be tested in vitro for their antiviral activity by using lentiviral vectors expressing luciferase in Vero E6 cells.