Clopidogrel As a Donor Probe and Thioenol Derivatives As Flexible Promoieties for Enabling HS Biomedicine

Overview

Journal Nat Commun

Specialty Biology

Date 2018 Sep 29

PMID 30262863

Citations 7

Authors

Yaoqiu Zhu

Elkin L Romero

Xiaodong Ren

Angel J Sanca

Congkuo Du

Cai Liu

Zubair A Karim

Fatima Z Alshbool

Fadi T Khasawneh

Jiang Zhou

Dafang Zhong

Bin Geng

Affiliations

Soon will be listed here.

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.

Citing Articles

Pleiotropic effects of clopidogrel.

Kuszynski D, Lauver D Purinergic Signal. 2022; 18(3):253-265.

PMID: 35678974 PMC: 9391547. DOI: 10.1007/s11302-022-09876-0.

Clopidogrel treatment inhibits P2Y-Mediated constriction in the rabbit middle cerebral artery.

Kuszynski D, Christian B, Dorrance A, Lauver D Eur J Pharmacol. 2021; 911:174545.

PMID: 34606835 PMC: 8577565. DOI: 10.1016/j.ejphar.2021.174545.

Pharmacokinetic, pharmacodynamic, and pharmacogenetic assays to monitor clopidogrel therapy.

Alvitigala B, Gooneratne L, Constantine G, Wijesinghe R, Ashanthi Menuka Arawwawala L Pharmacol Res Perspect. 2020; 8(6):e00686.

PMID: 33200888 PMC: 7670852. DOI: 10.1002/prp2.686.

SG1002 and Catenated Divalent Organic Sulfur Compounds as Promising Hydrogen Sulfide Prodrugs.

Gojon G, Morales G Antioxid Redox Signal. 2020; 33(14):1010-1045.

PMID: 32370538 PMC: 7578191. DOI: 10.1089/ars.2020.8060.

Activatable Small-Molecule Hydrogen Sulfide Donors.

Levinn C, Cerda M, Pluth M Antioxid Redox Signal. 2019; 32(2):96-109.

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References

Wang R . Two's company, three's a crowd: can H2S be the third endogenous gaseous transmitter?. FASEB J. 2002; 16(13):1792-8. DOI: 10.1096/fj.02-0211hyp. View

Yang C, Chen L, Xu S, Day J, Li X, Xian M . Recent Development of Hydrogen Sulfide Releasing/Stimulating Reagents and Their Potential Applications in Cancer and Glycometabolic Disorders. Front Pharmacol. 2017; 8:664. PMC: 5623001. DOI: 10.3389/fphar.2017.00664. View

Bradley J, Organ C, Lefer D . Garlic-Derived Organic Polysulfides and Myocardial Protection. J Nutr. 2016; 146(2):403S-409S. PMC: 4725427. DOI: 10.3945/jn.114.208066. View

Velusamy N, Binoy A, Bobba K, Nedungadi D, Mishra N, Bhuniya S . A bioorthogonal fluorescent probe for mitochondrial hydrogen sulfide: new strategy for cancer cell labeling. Chem Commun (Camb). 2017; 53(62):8802-8805. DOI: 10.1039/c7cc05339h. View

Zhao Y, Yang C, Organ C, Li Z, Bhushan S, Otsuka H . Design, Synthesis, and Cardioprotective Effects of N-Mercapto-Based Hydrogen Sulfide Donors. J Med Chem. 2015; 58(18):7501-11. PMC: 4766970. DOI: 10.1021/acs.jmedchem.5b01033. View

Sestito S, Nesi G, Pi R, Macchia M, Rapposelli S . Hydrogen Sulfide: A Worthwhile Tool in the Design of New Multitarget Drugs. Front Chem. 2017; 5:72. PMC: 5623673. DOI: 10.3389/fchem.2017.00072. View

Dansette P, Rosi J, Bertho G, Mansuy D . Cytochromes P450 catalyze both steps of the major pathway of clopidogrel bioactivation, whereas paraoxonase catalyzes the formation of a minor thiol metabolite isomer. Chem Res Toxicol. 2011; 25(2):348-56. DOI: 10.1021/tx2004085. View

Polhemus D, Lefer D . Emergence of hydrogen sulfide as an endogenous gaseous signaling molecule in cardiovascular disease. Circ Res. 2014; 114(4):730-7. PMC: 3951140. DOI: 10.1161/CIRCRESAHA.114.300505. View

Powell C, Foster J, Okyere B, Theus M, Matson J . Therapeutic Delivery of HS via COS: Small Molecule and Polymeric Donors with Benign Byproducts. J Am Chem Soc. 2016; 138(41):13477-13480. PMC: 5074078. DOI: 10.1021/jacs.6b07204. View

10.

Tuffal G, Roy S, Lavisse M, Brasseur D, Schofield J, Delesque Touchard N . An improved method for specific and quantitative determination of the clopidogrel active metabolite isomers in human plasma. Thromb Haemost. 2011; 105(4):696-705. DOI: 10.1160/TH10-09-0582. View

11.

Szabo C, Papapetropoulos A . International Union of Basic and Clinical Pharmacology. CII: Pharmacological Modulation of HS Levels: HS Donors and HS Biosynthesis Inhibitors. Pharmacol Rev. 2017; 69(4):497-564. PMC: 5629631. DOI: 10.1124/pr.117.014050. View

12.

Steiger A, Pardue S, Kevil C, Pluth M . Self-Immolative Thiocarbamates Provide Access to Triggered H2S Donors and Analyte Replacement Fluorescent Probes. J Am Chem Soc. 2016; 138(23):7256-9. PMC: 4911618. DOI: 10.1021/jacs.6b03780. View

13.

Nishio R, Shinke T, Otake H, Nakagawa M, Inoue T, Hariki H . Paraoxonase-1 activity affects the clopidogrel response in CYP2C19 loss-of-function carriers. Thromb Res. 2013; 132(5):558-64. DOI: 10.1016/j.thromres.2013.09.008. View

14.

Zheng Y, Yu B, De La Cruz L, Roy Choudhury M, Anifowose A, Wang B . Toward Hydrogen Sulfide Based Therapeutics: Critical Drug Delivery and Developability Issues. Med Res Rev. 2017; 38(1):57-100. DOI: 10.1002/med.21433. View

15.

Zheng Y, Ji X, Ji K, Wang B . Hydrogen sulfide prodrugs-a review. Acta Pharm Sin B. 2015; 5(5):367-77. PMC: 4629439. DOI: 10.1016/j.apsb.2015.06.004. View

16.

Alshbool F, Karim Z, Vemana H, Conlon C, Lin O, Khasawneh F . The regulator of G-protein signaling 18 regulates platelet aggregation, hemostasis and thrombosis. Biochem Biophys Res Commun. 2015; 462(4):378-82. DOI: 10.1016/j.bbrc.2015.04.143. View

17.

Wu Z, Liang D, Tang X . Visualizing Hydrogen Sulfide in Mitochondria and Lysosome of Living Cells and in Tumors of Living Mice with Positively Charged Fluorescent Chemosensors. Anal Chem. 2016; 88(18):9213-8. DOI: 10.1021/acs.analchem.6b02459. View

18.

Karazniewicz-Lada M, Danielak D, Burchardt P, Kruszyna L, Komosa A, Lesiak M . Clinical pharmacokinetics of clopidogrel and its metabolites in patients with cardiovascular diseases. Clin Pharmacokinet. 2013; 53(2):155-64. PMC: 3899497. DOI: 10.1007/s40262-013-0105-2. View

19.

Zhao Y, Wang H, Xian M . Cysteine-activated hydrogen sulfide (H2S) donors. J Am Chem Soc. 2010; 133(1):15-7. PMC: 3073703. DOI: 10.1021/ja1085723. View

20.

Pereillo J, Maftouh M, Andrieu A, Uzabiaga M, Fedeli O, Savi P . Structure and stereochemistry of the active metabolite of clopidogrel. Drug Metab Dispos. 2002; 30(11):1288-95. DOI: 10.1124/dmd.30.11.1288. View