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

ABSTRACT: 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.

SUBMITTER: Zhao Y

PROVIDER: S-EPMC4766970 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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

Zhao Yu Y Yang Chuntao C Organ Chelsea C Li Zhen Z Bhushan Shashi S Otsuka Hiro H Pacheco Armando A Kang Jianming J Aguilar Hector C HC Lefer David J DJ Xian Ming M

Journal of medicinal chemistry 20150904 18

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 ...[more]

PMID: 26317692

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Project description:Non-steroidal anti-inflammatory drugs (NSAIDs) are among the frontline treatments for inflammation and pain. Hydrogen sulfide (H2S) and related persulfide (RS-SH) are important mediators of antioxidant response and protect cells from oxidative stress. Hybrids of these pharmacological agents have shown promise in clinical trials and are superior to the parent NSAID. Here, we report a new class of NSAID-H2S hybrids, where a strategic placement of a sulfhydryl group adjacent to a carbonyl of a NSAID facilitates the enzymatic generation of H2S. We show that α-mercapto-nabumetone, a derivative of the clinical drug nabumetone, is a substrate for 3-mercaptopyruvate sulfurtransferase (3-MST), an enzyme involved in H2S biosynthesis. The key step of 3-MST catalysis is the cleavage of a C-S bond adjacent to a carbonyl group, which generates an enolate and 3-MST persulfide, which in turn is cleaved under reducing conditions to generate H2S. Guided by a molecular docking study with 3-MST, we prepared two mercapto-nabumetone derivatives, protected as their thioacetates. In the presence of 3-MST, both mercapto-nabumetone derivatives generated H2S and the NSAID in a nearly quantitative yield, produced glutathione persulfide (GS-SH), an important mediator of cellular antioxidant response, and permeated cells to generate H2S. Lastly, to gain insights into the scope of this strategy, we prepared mercapto-NSAID derivatives containing a carboxylic acid. We found that the propensity to generate H2S depended on the nature of the enol that is produced during the transformation of the mercapto-NSAID into the parent NSAID. This offers new insights into 3-MST catalysis and how reaction outcomes can be modulated by the keto-enol equilibrium. Taken together, the atom economical transformation of a clinical NSAID with one strategically placed sulfhydryl group to generate H2S presents new opportunities to enhance the properties of NSAIDs through participation in endogenous H2S biosynthesis.

Project description:Traditionally, hydrogen sulfide (H2S) was simply considered as a toxic and foul smelling gas, but recently H2S been brought into the spot light of cardiovascular research and development. Since the 1990s, H2S has been mounting evidence of physiological properties such as immune modification, vascular relaxation, attenuation of oxidative stress, inflammatory mitigation, and angiogenesis. H2S has since been recognized as the third physiological gaseous signaling molecule, along with CO and NO [65,66]. H2S is produced endogenously through several key enzymes, including cystathionine β-lyase (CBE), cystathionine γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (MST)/cysteine aminotransferase (CAT). These specific enzymes are expressed accordingly in various organ systems and CSE is the predominant H2S-producing enzyme in the cardiovascular system. The cystathionine γ-lyase (CSE)/H2S pathway has demonstrated various cardioprotective effects, including anti-atherosclerosis, anti-hypertension, pro-angiogenesis, and attenuation of myocardial ischemia-reperfusion injury. CSE exhibits its anti-atherosclerotic effect through 3 mechanisms, namely reduction of chemotactic factor inter cellular adhesion molecule-1 (ICAM-1) and CX3CR1, inhibition of macrophage lipid uptake, and induction of smooth muscle cell apoptosis via MAPK pathway. The CSE/H2S pathway's anti-hypertensive properties are demonstrated via aortic vasodilation through several mechanisms, including the direct stimulation of KATP channels of vascular smooth muscle cells (VSMCs), induction of MAPK pathway, and reduction of homocysteine buildup. Also, CSE/H2S pathway plays an important role in angiogenesis, particularly in increased endothelial cell growth and migration, and in increased vascular network length. In myocardial ischemia-reperfusion injuries, CSE/H2S pathway has shown a clear cardioprotective effect by preserving mitochondria function, increasing antioxidant production, and decreasing infarction injury size. However, CSE/H2S pathway's role in inflammation mitigation is still clouded, due to both pro and anti-inflammatory results presented in the literature, depending on the concentration and form of H2S used in specific experiment models.

Dataset Information

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

Publications

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

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