Faculty Collaboration Database

Boronate-Based Oxidant-Responsive Derivatives of Acetaminophen as Proinhibitors of Myeloperoxidase. Chem Res Toxicol 2023 Aug 21;36(8):1398-1408

Date

08/03/2023

Pubmed ID

37534491

Pubmed Central ID

PMC10445283

DOI

10.1021/acs.chemrestox.3c00140

Scopus ID

2-s2.0-85168427662 (requires institutional sign-in at Scopus site)   1 Citation

Abstract

Myeloperoxidase (MPO) is an important component of the human innate immune system and the main source of a strong oxidizing and chlorinating species, hypochlorous acid (HOCl). Inadvertent, misplaced, or excessive generation of HOCl by MPO is associated with multiple human inflammatory diseases. Therefore, there is a considerable interest in the development of MPO inhibitors. Here, we report the synthesis and characterization of a boronobenzyl derivative of acetaminophen (AMBB), which can function as a proinhibitor of MPO and release acetaminophen, the inhibitor of chlorination cycle of MPO, in the presence of inflammatory oxidants, i.e., hydrogen peroxide, hypochlorous acid, or peroxynitrite. We demonstrate that the AMBB proinhibitor undergoes conversion to acetaminophen by all three oxidants, with the involvement of the primary phenolic product intermediate, with relatively long half-life at pH 7.4. The determined rate constants of the reaction of the AMBB proinhibitor with hydrogen peroxide, hypochlorous acid, or peroxynitrite are equal to 1.67, 1.6 × 10⁴, and 1.0 × 10⁶ M^-1 s^-1, respectively. AMBB showed lower MPO inhibitory activity (IC₅₀ > 0.3 mM) than acetaminophen (IC₅₀ = 0.14 mM) toward MPO-dependent HOCl generation. Finally, based on the determined reaction kinetics and the observed inhibitory effects of two plasma components, uric acid and albumin, on the extent of AMBB oxidation by ONOO^- and HOCl, we conclude that ONOO^- is the most likely potential activator of AMBB in human plasma.

Author List

Pierzchała K, Pięta J, Pięta M, Rola M, Zielonka J, Sikora A, Marcinek A, Michalski R

Author

Jacek M. Zielonka PhD Assistant Professor in the Biophysics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Acetaminophen
Humans
Hydrogen Peroxide
Hypochlorous Acid
Oxidants
Oxidation-Reduction
Peroxidase
Peroxynitrous Acid