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

Abstract

Three new thiosemicarbazones (TSCs) HL 1 – HL 3 as triapine analogues bearing a redox-active phenolic moiety at the terminal nitrogen atom were prepared. Reactions of HL 1 – HL 3 with CuCl 2 ·2H 2 O in anoxic methanol afforded three copper(II) complexes, namely, Cu(HL 1 )Cl 2 ( 1 ), [ Cu(L 2 )Cl] ( 2′ ), and Cu(HL 3 )Cl 2 ( 3 ), in good yields. Solution speciation studies revealed that the metal-free ligands are stable as HL 1 – HL 3 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 HL 1 and HL 2 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). HL 1 and 1 in the presence of 1,4-dithiothreitol are as potent inhibitors of mR2 ribonucleotide reductase as triapine.

Systematic Conversion of Photoinduced Intramolecular Electron Transfer in Trinuclear M-Ir-M (M = Re, Ir) Complexes to Intersystem Charge Transfer by Coupling to Gold Nanoclusters

“…41 The 1 H NMR spectra show the presence of the Z-isomer (∼20% for IrT, and 8−10% for IrTRe) in solution. 42,43 We tried to do the NMR of the complexes synthesized and purified under complete dark. However, for this system, it remains difficult to get 100% pure E isomer.…”

“…The photoinduced E/Z isomerization of the ethenyl/nitrile functionality is well studied and the TSCs are known to undergo such interconversion not only as free ligands but also upon coordination . The 1 H NMR spectra show the presence of the Z -isomer (∼20% for IrT, and 8–10% for IrTRe) in solution. , We tried to do the NMR of the complexes synthesized and purified under complete dark. However, for this system, it remains difficult to get 100% pure E isomer.…”

Proving the Antimicrobial Therapeutic Activity on a New Copper–Thiosemicarbazone Complex

“…Another pseudoreversible process at more positive potentials ( E ° 1/2 0.37 V in Ag/AgCl) has been displayed by the complex, which can be related to this Cu III/II process. Although it has been very difficult to establish a direct and/or accurate comparison with reported data (slight difference of the experimental setup), the obtained redox potential suggests that the Cu­(HL) 2 complex could display resistance to the in vivo reduction . Moreover, some authors have found similar values with copper square planar thiosemicarbazone (NNSS donors) complexes, suggesting also its ineffectiveness role for this redox activity …”

Simultaneous effect of different chromatographic conditions on the chromatographic retention of pentapeptide derivatives (HGRFG and NPNPT)

“…The acid dissociation constant (pKa) is an elementary parameter in the analysis of drugs and strongly affects their pharmacokinetics and biochemical properties by characterizing the degree of ionization of drug molecules in solution at different pH values ( Besleaga et al, 2021 ). pKa determines the existing form of compounds in the medium and their solubility, lipophilicity, permeability, bioaccumulation, and toxicity ( Konçe et al, 2019 ; Xie et al, 2022 ); these characteristics play a particularly important role in the drug development process ( Bergazin et al, 2021 ).…”