Phosphinodithioate and Phosphoramidodithioate Hydrogen Sulfide Donors

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.

The novel mitochondria-targeted hydrogen sulfide (H 2 S) donors AP123 and AP39 protect against hyperglycemic injury in microvascular endothelial cells in vitro

“…The need for slow-release H 2 S donor compounds was recognised since higher concentrations of the gas are toxic, the half-life of H 2 S is very short and simple salts like sodium hydrosulfide (NaSH) and sodium sulfide (Na 2 S) can only provide instantaneous H 2 S generation [43], [44], [45]. Anethole dithiolethione (ADT-OH) and 4-hydroxythiobenzamide (HTB) represent two simple moieties that release H 2 S slowly.…”

“…H 2 S is volatile and has short half-life in vivo , thus for long-term treatment its preferable to use donor molecules (prodrugs) that release H 2 S at a controlled rate. Several H 2 S donor compounds have been developed over the last couple of years and various H 2 S producing chemistries have been implicated but the control of H 2 S generation is still not perfect [43], [52], [53]. A further problem may arise from the side effects caused by the by-products that are formed during H 2 S release, thus in chronic diseases it is necessary to reduce the concentration of the donors as much as possible since very long treatment periods are anticipated.…”

Delayed Treatment with Sodium Hydrosulfide Improves Regional Blood Flow and Alleviates Cecal Ligation and Puncture (CLP)-Induced Septic Shock

“…If the toxicity of H 2 S is primarily determined by its peak concentration, then one way of extending its therapeutic index would be to use slow-release donors; another potential direction may be to employ H 2 S donors that specifically target certain subcellular compartments (e.g. mitochondria); a further approach may involve multifunctional drugs where a H 2 S donating component is combined with a scaffold which has its own independent pharmacological actions (34,35). …”

The dichotomous role of H2S in cancer cell biology? Déjà vu all over again

“…The therapeutic potential of H 2 S-donating compounds have been described in the cardiovascular system [288, 289], urology [290], neuroinflammation [291], and ophthalmology [292]. These general areas have been thoroughly reviewed elsewhere [34, 109, 293].…”

“…It should be noted that commercial preparations of GYY4137 are sold as a dichloromethane complex, and it has been reported that dichloromethane is metabolized to carbon monoxide (CO) [304, 305] an important gasotransmitter. Since CO is reported to have similar biological effects as H 2 S [306–308], it is possible that some of the observed effects of GYY4137 could also be due, at least in part, to a contribution by CO [289]. …”