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

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 and Bin Geng
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Yaoqiu Zhu: The University of Texas at El Paso
Elkin L. Romero: The University of Texas at El Paso
Xiaodong Ren: The University of Texas at El Paso
Angel J. Sanca: The University of Texas at El Paso
Congkuo Du: State Key Laboratory of Cardiovascular Disease
Cai Liu: Chinese Academy of Sciences
Zubair A. Karim: The University of Texas at El Paso
Fatima Z. Alshbool: The University of Texas at El Paso
Fadi T. Khasawneh: The University of Texas at El Paso
Jiang Zhou: Peking University
Dafang Zhong: Chinese Academy of Sciences
Bin Geng: State Key Laboratory of Cardiovascular Disease

Nature Communications, 2018, vol. 9, issue 1, 1-9

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06373-0

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