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.