Clopidogrel as a donor probe and thioenol derivatives as flexible promoieties for enabling H ₂S biomedicine

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.