Electrochemical and Mechanistic Study of Superoxide Elimination by Mesalazine through Proton-Coupled Electron Transfer

Tatsushi Nakayama; Ryo Honda

doi:10.3390/ph14020120

Electrochemical and Mechanistic Study of Superoxide Elimination by Mesalazine through Proton-Coupled Electron Transfer

Pharmaceuticals (Basel). 2021 Feb 4;14(2):120. doi: 10.3390/ph14020120.

Authors

Tatsushi Nakayama¹, Ryo Honda²

Affiliations

¹ Department of Pharmacy, Gifu Pharmaceutical University, 1-25-4, Daigaku-nishi, Gifu 501-1196, Japan.
² United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.

Abstract

The elimination of superoxide radical anions (O₂^•-) by 5-amino-2-hydroxybenzoic acid (mesalazine, 5-ASA), 4-amino-2-hydroxybenzoic acid (4-ASA), and related compounds used for ulcerative colitis treatment was investigated using cyclic voltammetry and electron spin resonance (ESR) analyses aided by density functional theory (DFT) calculations. Quasi-reversible O₂/O₂^•- redox was found to be modified by the compounds, suggesting that an acid-base reaction in which a hydroperoxyl radical (HO₂^•) is formed from O₂^•- occurs. However, the deprotonated 5-ASA anion can eliminate O₂^•- through proton-coupled electron transfer (PCET), forming a radical product. This electron transfer (ET) was confirmed by ESR analysis. The 4-aminophenol moiety in 5-ASA plays an important role in the PCET, involving two proton transfers and one ET based on π-conjugation. The electrochemical and DFT results indicated that O₂^•- elimination by 5-ASA proceeds efficiently through the PCET mechanism after deprotonation of the 1-carboxyl group. Thus, 5-ASA may act as an anti-inflammatory agent in the alkali intestine through PCET-based O₂^•- elimination.

Keywords: cyclic voltammetry; electron spin resonance; mesalazine; proton-coupled electron transfer; superoxide radical anion; ulcerative colitis.