Alkylamine-Substituted Perthiocarbamates: Dual Precursors to Hydropersulfide and Carbonyl Sulfide with Cardioprotective Actions

J Am Chem Soc. 2020 Mar 4;142(9):4309-4316. doi: 10.1021/jacs.9b12180. Epub 2020 Feb 25.

Abstract

The recent discovery of hydropersulfides (RSSH) in mammalian systems suggests their potential roles in cell signaling. However, the exploration of RSSH biological significance is challenging due to their instability under physiological conditions. Herein, we report the preparation, RSSH-releasing properties, and cytoprotective nature of alkylamine-substituted perthiocarbamates. Triggered by a base-sensitive, self-immolative moiety, these precursors show efficient RSSH release and also demonstrate the ability to generate carbonyl sulfide (COS) in the presence of thiols. Using this dually reactive alkylamine-substituted perthiocarbamate platform, the generation of both RSSH and COS is tunable with respect to half-life, pH, and availability of thiols. Importantly, these precursors exhibit cytoprotective effects against hydrogen peroxide-mediated toxicity in H9c2 cells and cardioprotective effects against myocardial ischemic/reperfusion injury, indicating their potential application as new RSSH- and/or COS-releasing therapeutics.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cardiotonic Agents / chemical synthesis
  • Cardiotonic Agents / pharmacology*
  • Cell Line
  • Disulfides / chemical synthesis
  • Disulfides / pharmacology*
  • Mice
  • Myocardial Reperfusion Injury / prevention & control*
  • Rats
  • Sulfides / metabolism*
  • Sulfur Oxides / metabolism*
  • Thiocarbamates / chemical synthesis
  • Thiocarbamates / pharmacology*

Substances

  • Cardiotonic Agents
  • Disulfides
  • Sulfides
  • Sulfur Oxides
  • Thiocarbamates
  • persulfides
  • carbonyl sulfide