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.
Highlights
United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Abstract: The elimination of superoxide radical anions (O2 − ) by 5-amino-2-hydroxybenzoic acid, 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
We reported that O2 − is eliminated by polyphenols [11], diphenols, and mono-phenols including p-AP [12] through the proton-coupled electron transfer (PCET) mechanism
A DMF solution containing 0.1 mol dm−3 tetrapropylammonium perchlorate (TPAP) as a supporting electrolyte was saturated with O2 by air-bubbling the gas for ca. 2−3 min, and the gas was passed over the solutions during the electrochemical and ESR measurements to maintain the concentration of O2 at a constant level
Summary
5-amino-2-hydroxybenzoic acid (mesalazine, 5-ASA) is a medication used to treat inflammatory bowel conditions including ulcerative colitis and Crohn’s disease that can be taken orally or rectally [1,2]. It has been reported that both SASP and 5-ASA are poorly absorbed from the digestive tract [1] This indicates that their therapeutic action is based on ROS elimination from the intestine and the surface of the gastrointestinal tract rather than cyclooxygenase inhibition after absorption, which is the main mode of action for typical NSAIDs. In addition, the reason that 5-ASA administered orally is not absorbed but instead degraded in the gastrointestinal tract is thought to be related to oxidation by ROS. We reported that O2 − is eliminated by polyphenols [11], diphenols (hydroquinone [10] and catechol [13]), and mono-phenols including p-AP [12] through the PCET mechanism. The mechanism of O2 − elimination in relation to PCET has been electrochemically investigated with aid of density functional theory (DFT) calculations
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