Phosphinodithioate and phosphoramidodithioate hydrogen sulfide donors

Matthew Whiteman, Alexis Perry, Zongmin Zhou, Mariarosaria Bucci, Andreas Papapetropoulos, Guiseppe Cirino, Mark E. Wood

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Hydrogen sulfide is rapidly emerging as a key physiological mediator and potential therapeutic tool in numerous areas such as acute and chronic inflammation, neurodegenerative and cardiovascular disease, diabetes, obesity and cancer. However, the vast majority of the published studies have employed crude sulfide salts such as sodium hydrosulfide (NaSH) and sodium sulfide (Na2S) as H2S “donors” to generate H2S. Although these salts are cheap, readily available and easy to use, H2S generated from them occurs as an instantaneous and pH-dependent dissociation, whereas endogenous H2S synthesis from the enzymes cystathionine γ-lyase, cystathionine-β-synthase and 3-mercaptopyruvate sulfurtransferase is a slow and sustained process. Furthermore, sulfide salts are frequently used at concentrations (e.g. 100 μM to 10 mM) far in excess of the levels of H2S reported in vivo (nM to low μM). For the therapeutic potential of H2S is to be properly harnessed, pharmacological agents which generate H2S in a physiological manner and deliver physiologically relevant concentrations are needed. The phosphorodithioate GYY4137 has been proposed as “slow-release” H2S donors and has shown promising efficacy in cellular and animal model diseases such as hypertension, sepsis, atherosclerosis, neonatal lung injury and cancer. However, H2S generation from GYY4137 is inefficient necessitating its use at high concentrations/doses. However, structural modification of the phosphorodithioate core has led to compounds (e.g. AP67 and AP105) with accelerated rates of H2S generation and enhanced biological activity. In this review, the therapeutic potential and limitations of GYY4137 and related phosphorodithioate derivatives are discussed.

Original languageEnglish (US)
Pages (from-to)337-363
Number of pages27
JournalHandbook of Experimental Pharmacology
Volume230
DOIs
StatePublished - Jan 1 2015
Externally publishedYes

Fingerprint

Hydrogen Sulfide
Cystathionine
Salts
Sulfides
Animal Disease Models
Lyases
Lung Injury
Medical problems
Bioactivity
Neurodegenerative Diseases
Lung Neoplasms
Atherosclerosis
Animals
Chronic Disease
Cardiovascular Diseases
Therapeutics
Obesity
Pharmacology
Hypertension
Inflammation

Keywords

  • AP105
  • AP67
  • CGMP
  • GYY4137
  • Slow-release HS donor

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

Phosphinodithioate and phosphoramidodithioate hydrogen sulfide donors. / Whiteman, Matthew; Perry, Alexis; Zhou, Zongmin; Bucci, Mariarosaria; Papapetropoulos, Andreas; Cirino, Guiseppe; Wood, Mark E.

In: Handbook of Experimental Pharmacology, Vol. 230, 01.01.2015, p. 337-363.

Research output: Contribution to journalArticle

Whiteman, Matthew ; Perry, Alexis ; Zhou, Zongmin ; Bucci, Mariarosaria ; Papapetropoulos, Andreas ; Cirino, Guiseppe ; Wood, Mark E. / Phosphinodithioate and phosphoramidodithioate hydrogen sulfide donors. In: Handbook of Experimental Pharmacology. 2015 ; Vol. 230. pp. 337-363.
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