Design, Synthesis, and Cardioprotective Effects of N-Mercapto-Based Hydrogen Sulfide Donors

Yu Zhao; Chuntao Yang; Chelsea Organ; Zhen Li; Shashi Bhushan; Hiro Otsuka; Armando Pacheco; Jianming Kang; Hector C Aguilar; David J Lefer; Ming Xian

doi:10.1021/acs.jmedchem.5b01033

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Design, Synthesis, and Cardioprotective Effects of N-Mercapto-Based Hydrogen Sulfide Donors

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Design, Synthesis, and Cardioprotective Effects of N-Mercapto-Based Hydrogen Sulfide Donors

Yu Zhao, Chuntao Yang, Chelsea Organ, Zhen Li, Shashi Bhushan, Hiro Otsuka, Armando Pacheco, Jianming Kang, Hector C Aguilar, David J Lefer, …

Journal of medicinal chemistry, Vol.58(18), pp.7501-7511

09/24/2015

DOI: https://doi.org/10.1021/acs.jmedchem.5b01033

Handle:

https://hdl.handle.net/2376/105194

PMCID: PMC4766970

PMID: 26317692

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https://doi.org/10.1021/acs.jmedchem.5b01033View

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Abstract

Hydrogen Sulfide - metabolism

L-Lactate Dehydrogenase - metabolism

Heart Ventricles - cytology

Oxidative Stress

Sulfhydryl Compounds - pharmacology

Male

Structure-Activity Relationship

Membrane Potential, Mitochondrial - drug effects

Cardiotonic Agents - chemical synthesis

Drug Design

Sulfhydryl Compounds - chemistry

Benzamides - pharmacology

Myoblasts, Cardiac - drug effects

Myocardial Reperfusion Injury - drug therapy

Benzamides - chemistry

Cell Line

Myoblasts, Cardiac - cytology

Mice, Inbred C57BL

Hydrogen Peroxide - pharmacology

Rats

Cardiotonic Agents - chemistry

Cardiotonic Agents - pharmacology

Sulfhydryl Compounds - chemical synthesis

Benzamides - chemical synthesis

Animals

Hydrogen sulfide (H2S) is a signaling molecule which plays regulatory roles in many physiological and/or pathological processes. Therefore, regulation of H2S levels could have great potential therapeutic value. In this work, we report the design, synthesis, and evaluation of a class of N-mercapto (N-SH)-based H2S donors. Thirty-three donors were synthesized and tested. Our results indicated that controllable H2S release from these donors could be achieved upon structural modifications. Selected donors (NSHD-1, NSHD-2, and NSHD-6) were tested in cellular models of oxidative damage and showed significant cytoprotective effects. Moreover, NSHD-1 and NSHD-2 were also found to exhibit potent protective effects in a murine model of myocardial ischemia reperfusion (MI/R) injury.

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Title: Design, Synthesis, and Cardioprotective Effects of N-Mercapto-Based Hydrogen Sulfide Donors
Creators: Yu Zhao - Department of Chemistry, Washington State University , Pullman, Washington 99164, United States
Chuntao Yang - Department of Physiology, Guangzhou Medical University , Guangzhou 511436, China
Chelsea Organ - Cardiovascular Center of Excellence, Louisiana State University Health Science Center , New Orleans, Louisiana 70112, United States
Zhen Li - Cardiovascular Center of Excellence, Louisiana State University Health Science Center , New Orleans, Louisiana 70112, United States
Shashi Bhushan - Cardiovascular Center of Excellence, Louisiana State University Health Science Center , New Orleans, Louisiana 70112, United States
Hiro Otsuka - Cardiovascular Center of Excellence, Louisiana State University Health Science Center , New Orleans, Louisiana 70112, United States
Armando Pacheco - Department of Chemistry, Washington State University , Pullman, Washington 99164, United States
Jianming Kang - Department of Chemistry, Washington State University , Pullman, Washington 99164, United States
Hector C Aguilar - Paul G. Allen School for Global Animal Health, Washington State University , Pullman, Washington 99164, United States
David J Lefer - Cardiovascular Center of Excellence, Louisiana State University Health Science Center , New Orleans, Louisiana 70112, United States
Ming Xian - Department of Chemistry, Washington State University , Pullman, Washington 99164, United States
Publication Details: Journal of medicinal chemistry, Vol.58(18), pp.7501-7511
Academic Unit: Chemistry, Department of
Publisher: United States
Grant note: R01 HL116571 / NHLBI NIH HHS R01 AI109022 / NIAID NIH HHS R01HL116571 / NHLBI NIH HHS
Identifiers: 99900546570801842
Language: English
Resource Type: Journal article