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Clopidogrel as a donor probe and thioenol derivatives as flexible promoieties for enabling H2S biomedicine

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      Abstract

      Hydrogen sulfide has emerged as a critical endogenous signaling transmitter and a potentially versatile therapeutic agent. The key challenges in this field include the lack of approved hydrogen sulfide-releasing probes for in human exploration and the lack of controllable hydrogen sulfide promoieties that can be flexibly installed for therapeutics development. Here we report the identification of the widely used antithrombotic drug clopidogrel as a clinical hydrogen sulfide donor. Clopidogrel is metabolized in patients to form a circulating metabolite that contains a thioenol substructure, which is found to undergo spontaneous degradation to release hydrogen sulfide. Model studies demonstrate that thioenol derivatives are a class of controllable promoieties that can be conveniently installed on a minimal structure of ketone with an α-hydrogen. These results can provide chemical tools for advancing hydrogen sulfide biomedical research as well as developing hydrogen sulfide-releasing drugs.

      Abstract

      Hydrogen sulphide (H 2S) is a gaseous signalling molecule, which has shown therapeutic value. Here, the authors show that a thioenol metabolite of the antithrombotic drug clopidogrel is an efficient H 2S donor and masked thioenols can be linked to existing compounds to develop H 2S-releasing agents.

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      Most cited references 62

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      H2S as a physiologic vasorelaxant: hypertension in mice with deletion of cystathionine gamma-lyase.

      Studies of nitric oxide over the past two decades have highlighted the fundamental importance of gaseous signaling molecules in biology and medicine. The physiological role of other gases such as carbon monoxide and hydrogen sulfide (H2S) is now receiving increasing attention. Here we show that H2S is physiologically generated by cystathionine gamma-lyase (CSE) and that genetic deletion of this enzyme in mice markedly reduces H2S levels in the serum, heart, aorta, and other tissues. Mutant mice lacking CSE display pronounced hypertension and diminished endothelium-dependent vasorelaxation. CSE is physiologically activated by calcium-calmodulin, which is a mechanism for H2S formation in response to vascular activation. These findings provide direct evidence that H2S is a physiologic vasodilator and regulator of blood pressure.
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        Two's company, three's a crowd: can H2S be the third endogenous gaseous transmitter?

         Rui Wang (2002)
        Bearing the public image of a deadly "gas of rotten eggs," hydrogen sulfide (H2S) can be generated in many types of mammalian cells. Functionally, H2S has been implicated in the induction of hippocampal long-term potentiation, brain development, and blood pressure regulation. By acting specifically on KATP channels, H2S can hyperpolarize cell membranes, relax smooth muscle cells, or decrease neuronal excitability. The endogenous metabolism and physiological functions of H2S position this gas well in the novel family of endogenous gaseous transmitters, termed "gasotransmitters." It is hypothesized that H2S is the third endogenous signaling gasotransmitter, besides nitric oxide and carbon monoxide. This positioning of H2S will open an exciting field-H2S physiology-encompassing realization of the interaction of H2S and other gasotransmitters, sulfurating modification of proteins, and the functional role of H2S in multiple systems. It may shed light on the pathogenesis of many diseases related to the abnormal metabolism of H2S.
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          Hydrogen sulphide and its therapeutic potential.

           Csaba Szabo (2007)
          Hydrogen sulphide (H2S) is increasingly being recognized as an important signalling molecule in the cardiovascular and nervous systems. The production of H2S from L-cysteine is catalysed primarily by two enzymes, cystathionine gamma-lyase and cystathionine beta-synthase. Evidence is accumulating to demonstrate that inhibitors of H2S production or therapeutic H2S donor compounds exert significant effects in various animal models of inflammation, reperfusion injury and circulatory shock. H2S can also induce a reversible state of hypothermia and suspended-animation-like state in rodents. This article overviews the physiology and biochemistry of H2S, summarizes the effects of H2S inhibitors or H2S donors in animal models of disease and outlines the potential options for the therapeutic exploitation of H2S.
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            Author and article information

            Affiliations
            [1 ]ISNI 0000 0001 0668 0420, GRID grid.267324.6, Department of Chemistry and Biochemistry, Border Biomedical Research Center, , The University of Texas at El Paso, ; El Paso, TX 79968 USA
            [2 ]Hypertension Center, Fuwai Hospital, CAMS-PUMC, State Key Laboratory of Cardiovascular Disease, Beijing, 102300 China
            [3 ]ISNI 0000000119573309, GRID grid.9227.e, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, , Chinese Academy of Sciences, ; 501 Haike Road, Shanghai, 201203 China
            [4 ]ISNI 0000 0001 0668 0420, GRID grid.267324.6, Department of Pharmaceutical Sciences, School of Pharmacy, , The University of Texas at El Paso, ; El Paso, TX 79902 USA
            [5 ]ISNI 0000 0001 2256 9319, GRID grid.11135.37, Analytical Instrumentation Center, College of Chemistry and Molecular Engineering, , Peking University, ; Beijing, 100871 China
            Contributors
            yzhu2@utep.edu
            Journal
            Nat Commun
            Nat Commun
            Nature Communications
            Nature Publishing Group UK (London )
            2041-1723
            27 September 2018
            27 September 2018
            2018
            : 9
            30262863
            6160475
            6373
            10.1038/s41467-018-06373-0
            © The Author(s) 2018

            Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

            Funding
            Funded by: FundRef https://doi.org/10.13039/100006545, U.S. Department of Health & Human Services | NIH | National Institute on Minority Health and Health Disparities (NIMHD);
            Award ID: 5G12MD007592
            Award Recipient :
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