Syntheses, biological and catalytic studies of copper complexes bearing bis(azol-1-yl)-acetato heteroscorpionate ligands

During the last decades, in our quest to find suitable ligands in the search for copper-based anticancer agents and inorganic catalysts, we focused our attention on the design and synthesis of copper complexes of bis(azol-1-yl)carboxylate heteroscorpionate ligands of general formula [HC(az)2X] (az = N-heterocyclic ring; X = neutral or anionic donor group with pendant donor arms, such as carboxylate, alkoxide, phenoxide, acetamidate, thioacetamidate, ether, thioether and correlated groups). In these last years, we have worked on the development of bis(pyrazolyl)acetic acid [HC(COOH)(pz)2] (LH) and bis(3,5-pyrazolyl)acetic acid [HC(COOH)(pzMe2)2] (L2H) and their corresponding esterified compounds with numerous alcohols (methanol, ethanol, isopropanol and hexanol). All the esterified ligands have been used to synthesize Cu(II) complexes by reaction with CuCl2 acceptor and to obtain Cu(I) complexes by reaction of Cu(CH3CN)4PF6 and triphenylphosphine, 1,3,5-triaza-7-phosphaadamantane and tris(hydroxymethyl)phosphine. In addition, Cu(II) complexes of bis(pyrazol-1-yl)- and bis(triazol-1-yl)-acetate heteroscorpionate ligands have been synthesized by the reaction of Cu(ClO4)2 with the ligands LH, L2H and bis(1,2,4-triazol-1-yl)acetic acid [HC(COOH)(tz)2]. Moreover, LH and L2H have been bioconjugated with the NMDA receptor antagonist (±)-(6,6-diphenyl-1,4-dioxan-2-yl)methanamine and the resultant ligands have been employed in order to obtain the corresponding Cu(II) and Cu(I) complexes. All novel copper complexes and the related free ligands have been studied in order to evaluate the cytotoxic activity against 2D monolayer cultures of a panel of human tumor cell lines and the most interesting ones against 3D-cultured HCT-15 colon cancer spheroids. Finally, among the complexes bearing esterified LH and L2H ligands, the compounds that have shown the best solubility profile have been chosen to investigate the radical allylic oxidation of olefins by means of the catalytic cycle of the Kharasch-Sosnovsky reaction.