ELECTROCHEMICAL ANALYSIS OF 1-METHYL-2-NITROIMIDAZOLE IN THE PRESENCE OF WEAK ACIDS
Samvel Avagyan, Diane Smith.
San Diego State University, San Diego, CA.
1-methyl-2-nitroimidazole (2-NI) and its derivatives are highly active biological compounds that can be used for therapeutic purposes. Benznidazole, a 2-NI derivative, is 1 of only 2 drugs used for the treatment of Chagas disease. In cancer treatment, 2-NI has also been studied as a radiosensitizer of hypoxic cells. In both cases, the reduced, radical intermediates are believed to be toxic to cells. The 2e- reduction product of the 2-NI forms 1-methyl-2-nitrosoimidazole (nitroso) which is the active form of the pro-drug. Aromatic nitrosos are known to be active compounds which react cysteine residues to inactivate enzymes and shift the redox balance of the cells. The fact that an initial reduction of the 2-NI is required makes electrochemical methods a powerful tool to study the 2-NI. Our aim is to gain a qualitative understanding of the specific redox pathways of 2-NI in the presence of weak acids. Cyclic voltammetry (CV) experiments of 2-NI have been conducted in aqueous and aprotic solvents. In an aqueous system, we use the L-cysteine•HCl (CysHCl) as the guest. In aprotic solution, we use 2-naphthol (naphthol) and N-tertbutoxycarbonyl-L-cysteine-methyl-ester (Cys) as the guests. In an aqueous environment, the 2-NI is reduced to the hydroxylamine/nitroso rodox pairs, without any guests. In experiments with naphthol, the 2-NI also forms the hydroxylamine/nitroso rodox pairs. In aqueous and aprotic environments, CysHCl and Cys react with the nitroso to form an amino-thioether compund. This shows that nitroso is the more active form of the reduced 2-NI, which reacts with cysteine.