Naphthoquinones Oxidize H2S to Polysulfides and Thiosulfate, Implications for Therapeutic Applications

Authors

Kenneth R Olson
Kasey J Clear
Paul J Derry
Yan Gao
Zhilin Ma
Nathaniel M Cieplik
Alyssa Fiume
Dominic J Gaziano
Stephen M Kasko
Kathleen Narloch
Cecilia L Velander
Ifeyinwa Nwebube
Collin J Pallissery
Ella Pfaff
Brian P Villa
Thomas A Kent
Gang Wu
Karl D Straub

Publication Date

10-31-2022

Journal

International Journal of Molecular Sciences

Abstract

1,4-Napththoquinones (NQs) are clinically relevant therapeutics that affect cell function through production of reactive oxygen species (ROS) and formation of adducts with regulatory protein thiols. Reactive sulfur species (RSS) are chemically and biologically similar to ROS and here we examine RSS production by NQ oxidation of hydrogen sulfide (H2S) using RSS-specific fluorophores, liquid chromatography-mass spectrometry, UV-Vis absorption spectrometry, oxygen-sensitive optodes, thiosulfate-specific nanoparticles, HPLC-monobromobimane derivatization, and ion chromatographic assays. We show that NQs, catalytically oxidize H2S to per- and polysulfides (H2Sn, n = 2−6), thiosulfate, sulfite and sulfate in reactions that consume oxygen and are accelerated by superoxide dismutase (SOD) and inhibited by catalase. The approximate efficacy of NQs (in decreasing order) is, 1,4-NQ ≈ juglone ≈ plumbagin > 2-methoxy-1,4-NQ ≈ menadione >> phylloquinone ≈ anthraquinone ≈ menaquinone ≈ lawsone. We propose that the most probable reactions are an initial two-electron oxidation of H2S to S0 and reduction of NQ to NQH2. S0 may react with H2S or elongate H2Sn in variety of reactions. Reoxidation of NQH2 likely involves a semiquinone radical (NQ·−) intermediate via several mechanisms involving oxygen and comproportionation to produce NQ and superoxide. Dismutation of the latter forms hydrogen peroxide which then further oxidizes RSS to sulfoxides. These findings provide the chemical background for novel sulfur-based approaches to naphthoquinone-directed therapies.

Keywords

Thiosulfates, Reactive Oxygen Species, Oxidation-Reduction, Naphthoquinones, Hydrogen Sulfide, Sulfur, Oxygen, reactive sulfur species, reactive oxygen species, antioxidants, juglone, plumbagin, vitamin K

DOI

10.3390/ijms232113293

PMID

36362080

PMCID

PMC9657496

PubMedCentral® Posted Date

10-31-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes