Biology and therapeutic potential of hydrogen sulfide and hydrogen sulfide-releasing chimeras

Abstract

Hydrogen sulfide, H2S, is a colorless gas with a strong odor that until recently was only considered to be a toxic environmental pollutant with little or no physiological significance. However, the past few years have demonstrated its role in many biological systems and it is becoming increasingly clear that H2S is likely to join nitric oxide (NO) and carbon monoxide (CO) as a major player in mammalian biology. In this review, we have provided an overview of the chemistry and biology of H2S and have summarized the chemistry and biological activity of some natural and synthetic H2S-donating compounds. The naturally occurring compounds discussed include, garlic, sulforaphane, erucin, and iberin. The synthetic H2S donors reviewed include, GYY4137; cysteine analogs; S-propyl cysteine, S-allyl cysteine, S-propargyl cysteine, and N-acetyl cysteine. Dithiolethione and its NSAID and other chimeras such as, L-DOPA, sildenafil, aspirin, diclofenac, naproxen, ibuprofen, indomethacin, and mesalamine have also been reviewed in detail. The newly reported NOSH-aspirin that releases both NO and H2S has also been discussed.

Figure 1

Metabolic pathways for H₂S biosynthesis (A) and degradation (B). Abbreviations: DHLA, dihydrolipoic acid; CAT, cysteine aminotransferase; CBS, cystathionine β-synthase; CSE, cystathionine γ-ligase; GSH, reduced glutathione; Rde, rhodanase; SDO, sulfur dioxygenase; SO, sulfite oxidase; SQR, sulfur:quinone oxidoreductase; ST, sulfur transferase; TR, thiosulfate reductase; Trx, thioredoxin; 3-MST, 3-mercaptopyruvate sulfur transferase.

Figure 2

Naturally occurring H₂S “donating” compounds.

Figure 3

Synthetic H₂S donating compounds.

Figure 4

Mechanisms of action of H₂S-releasing NSAIDs. When hydrolyzed, H₂S-releasing NSAIDs produce the parent NSAID and the H₂S-releasing moiety from which H₂S is released. The NSAID component inhibits COX-1 and COX-2 resulting in compromised mucosal defense mechanisms, which may lead to ulcers. NSAIDs can reduce renal perfusion, which can lead to increases in blood pressure (BP) leading to cardiovascular (CV) damage. The released H₂S counteracts many of the detrimental effects of NSAIDs. These protective effects appear to be mediated through activation of K_ATP channels. H₂S enhances the mucosal defense mechanisms; causes vasodilation thus reducing BP leading to cardioprotective effects. Both the NSAID and H₂S have anti-inflammatory effects, the former through inhibition of COX and latter through inhibition of nuclear transcription factor κB (NF-κB).

Figure 5

The chemical structures of NOSH compounds. NOSH-1: (4-(3-thioxo-3H-1, 2-dithiol-5-yl) phenyl 2-((4-(nitrooxy)butanoyl)oxy) benzoate); NOSH-2: (4-(nitrooxy)butyl (2-((4-(3-thioxo-3H-1,2-dithiol-5-yl)phenoxy)carbonyl)phenyl)); NOSH-3: (4-carbamothioylphenyl 2-((4-(nitrooxy)butanoyl)oxy)benzoate); and NOSH-4: (4-(nitrooxy)butyl 2-(5-((R)-1,2-dithiolan-3-yl)pentanoyloxy)benzoate).