TY - JOUR
T1 - Naphthoquinones Oxidize H2S to Polysulfides and Thiosulfate, Implications for Therapeutic Applications
AU - Olson, Kenneth R.
AU - Clear, Kasey J.
AU - Derry, Paul J.
AU - Gao, Yan
AU - Ma, Zhilin
AU - Cieplik, Nathaniel M.
AU - Fiume, Alyssa
AU - Gaziano, Dominic J.
AU - Kasko, Stephen M.
AU - Narloch, Kathleen
AU - Velander, Cecilia L.
AU - Nwebube, Ifeyinwa
AU - Pallissery, Collin J.
AU - Pfaff, Ella
AU - Villa, Brian P.
AU - Kent, Thomas A.
AU - Wu, Gang
AU - Straub, Karl D.
N1 - Funding Information:
This research was supported in part by National Science Foundation Grant NO. IOS2012106 (KRO), National Institute of Health Grant NO R01NS094535 (TAK, PJD), Welch Foundation Grant BE-0048 (TAK) and Biomedical Research Foundation at Central Arkansas Veteran’s Healthcare System (KDS).
Publisher Copyright:
© 2022 by the authors.
PY - 2022/10/31
Y1 - 2022/10/31
N2 - 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.
AB - 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.
KW - antioxidants
KW - juglone
KW - plumbagin
KW - reactive oxygen species
KW - reactive sulfur species
KW - vitamin K
KW - Reactive Oxygen Species/metabolism
KW - Oxidation-Reduction
KW - Sulfur/metabolism
KW - Thiosulfates/pharmacology
KW - Oxygen/metabolism
KW - Hydrogen Sulfide/metabolism
KW - Naphthoquinones/pharmacology
UR - http://www.scopus.com/inward/record.url?scp=85141571248&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85141571248&partnerID=8YFLogxK
U2 - 10.3390/ijms232113293
DO - 10.3390/ijms232113293
M3 - Article
C2 - 36362080
AN - SCOPUS:85141571248
SN - 1661-6596
VL - 23
JO - International journal of molecular sciences
JF - International journal of molecular sciences
IS - 21
M1 - 13293
ER -