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

Three new thiosemicarbazones (TSCs) HL¹-HL³ as triapine analogues bearing a redox-active phenolic moiety at the terminal nitrogen atom were prepared. Reactions of HL¹-HL³ with CuCl₂·2H₂O in anoxic methanol afforded three copper(II) complexes, namely, Cu(HL¹)Cl₂ (1), [Cu(L²)Cl] (2'), and Cu(HL³)Cl₂ (3), in good yields. Solution speciation studies revealed that the metal-free ligands are stable as HL¹-HL³ at pH 7.4, while being air-sensitive in the basic pH range. In dimethyl sulfoxide they exist as a mixture of E and Z isomers. A mechanism of the E/Z isomerization with an inversion at the nitrogen atom of the Schiff base imine bond is proposed. The monocationic complexes [Cu(L^1-3)]⁺ are the most abundant species in aqueous solutions at pH 7.4. Electrochemical and spectroelectrochemical studies of 1, 2', and 3 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 HL¹ and HL² as well as 1 and 2' afforded several two-electron and four-electron oxidation products, which were isolated and comprehensively characterized. Complexes 1 and 2' showed an antiproliferative activity in Colo205 and Colo320 cancer cell lines with half-maximal inhibitory concentration values in the low micromolar concentration range, while 3 with the most closely related ligand to triapine displayed the best selectivity for cancer cells versus normal fibroblast cells (MRC-5). HL¹ and 1 in the presence of 1,4-dithiothreitol are as potent inhibitors of mR2 ribonucleotide reductase as triapine.