Triapine Analogues and Their Copper(II) Complexes: Synthesis, Characterization, Solution Speciation, Redox Activity, Cytotoxicity, and mR2 RNR Inhibition.

Three new thiosemicarbazones (TSCs) - as triapine analogues bearing a redox-active phenolic moiety at the terminal nitrogen atom were prepared. Reactions of - with CuCl·2HO in anoxic methanol afforded three copper(II) complexes, namely, (), [ (), and (), in good yields. Solution speciation studies revealed that the metal-free ligands are stable as - at pH 7.4, while being air-sensitive in the basic pH range. In dimethyl sulfoxide they exist as a mixture of and isomers. A mechanism of the isomerization with an inversion at the nitrogen atom of the Schiff base imine bond is proposed. The monocationic complexes are the most abundant species in aqueous solutions at pH 7.4. Electrochemical and spectroelectrochemical studies of , , and confirmed their redox activity in both the cathodic and the anodic region of potentials. The one-electron reduction was identified as metal-centered by electron paramagnetic resonance spectroelectrochemistry. An electrochemical oxidation pointed out the ligand-centered oxidation, while chemical oxidations of and as well as and afforded several two-electron and four-electron oxidation products, which were isolated and comprehensively characterized. Complexes and showed an antiproliferative activity in Colo205 and Colo320 cancer cell lines with half-maximal inhibitory concentration values in the low micromolar concentration range, while with the most closely related ligand to triapine displayed the best selectivity for cancer cells versus normal fibroblast cells (MRC-5). and in the presence of 1,4-dithiothreitol are as potent inhibitors of mR2 ribonucleotide reductase as triapine.