TY - JOUR
T1 - Alkylamine-Substituted Perthiocarbamates
T2 - Dual Precursors to Hydropersulfide and Carbonyl Sulfide with Cardioprotective Actions
AU - Khodade, Vinayak S.
AU - Pharoah, Blaze M.
AU - Paolocci, Nazareno
AU - Toscano, John P.
N1 - Funding Information:
We gratefully acknowledge the National Science Foundation (CHE-1900285 to J.P.T.), the National Institutes of Health (T32 GM080189 for support of B.M.P.; R01 HL136918 and R01 HL063030 to N.P.), and Johns Hopkins University (Magic-That-Matters Fund to N.P.) for generous support for this research. We also thank Dr. Stephen Chelko (Johns Hopkins University) for providing access to a cell culture facility and Drs. Jon Fukuto and Joseph Lin (Sonoma State University) for advice on the cell viability studies.
Publisher Copyright:
© 2020 American Chemical Society.
PY - 2020/3/4
Y1 - 2020/3/4
N2 - 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.
AB - 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.
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U2 - 10.1021/jacs.9b12180
DO - 10.1021/jacs.9b12180
M3 - Article
C2 - 32058717
AN - SCOPUS:85081147378
SN - 0002-7863
VL - 142
SP - 4309
EP - 4316
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
IS - 9
ER -