GYY4137, a Novel Water-Soluble, H2S-Releasing Molecule

Rose, Peter; Dymock, Brian; Moore, Philip K.

doi:10.1016/bs.mie.2014.11.014

Cited by 91 publications

(69 citation statements)

References 86 publications

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“…Plant biologists will, of course, cherish these developments and intensify their search for RSS or RSS releasing agents as secondary metabolites in plants, fungi and other microbes. Likewise, from a pharmaceutical perspective, there is increasing interest in developing drugs which generate RSS (or modulate current RSS signalling) with the promise of developing new drugs for the treatment of conditions such as inflammation, cardiovascular disease and cancer [124,125]. …”

Section: Discussionmentioning

confidence: 99%

The Reactive Sulfur Species Concept: 15 Years On

et al. 2017

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Fifteen years ago, in 2001, the concept of “Reactive Sulfur Species” or RSS was advocated as a working hypothesis. Since then various organic as well as inorganic RSS have attracted considerable interest and stimulated many new and often unexpected avenues in research and product development. During this time, it has become apparent that molecules with sulfur-containing functional groups are not just the passive “victims” of oxidative stress or simple conveyors of signals in cells, but can also be stressors in their own right, with pivotal roles in cellular function and homeostasis. Many “exotic” sulfur-based compounds, often of natural origin, have entered the fray in the context of nutrition, ageing, chemoprevention and therapy. In parallel, the field of inorganic RSS has come to the forefront of research, with short-lived yet metabolically important intermediates, such as various sulfur-nitrogen species and polysulfides (Sx2−), playing important roles. Between 2003 and 2005 several breath-taking discoveries emerged characterising unusual sulfur redox states in biology, and since then the truly unique role of sulfur-dependent redox systems has become apparent. Following these discoveries, over the last decade a “hunt” and, more recently, mining for such modifications has begun—and still continues—often in conjunction with new, innovative and complex labelling and analytical methods to capture the (entire) sulfur “redoxome”. A key distinction for RSS is that, unlike oxygen or nitrogen, sulfur not only forms a plethora of specific reactive species, but sulfur also targets itself, as sulfur containing molecules, i.e., peptides, proteins and enzymes, preferentially react with RSS. Not surprisingly, today this sulfur-centred redox signalling and control inside the living cell is a burning issue, which has moved on from the predominantly thiol/disulfide biochemistry of the past to a complex labyrinth of interacting signalling and control pathways which involve various sulfur oxidation states, sulfur species and reactions. RSS are omnipresent and, in some instances, are even considered as the true bearers of redox control, perhaps being more important than the Reactive Oxygen Species (ROS) or Reactive Nitrogen Species (RNS) which for decades have dominated the redox field. In other(s) words, in 2017, sulfur redox is “on the rise”, and the idea of RSS resonates throughout the Life Sciences. Still, the RSS story isn’t over yet. Many RSS are at the heart of “mistaken identities” which urgently require clarification and may even provide the foundations for further scientific revolutions in the years to come. In light of these developments, it is therefore the perfect time to revisit the original hypotheses, to select highlights in the field and to question and eventually update our concept of “Reactive Sulfur Species”.

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Section: Discussionmentioning

confidence: 99%

The Reactive Sulfur Species Concept: 15 Years On

et al. 2017

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“…Finally, although unrelated to mTOR inhibition, a potential cytoprotective approach, by activating the AMP‐activated protein kinase/mTOR signaling pathway, is worth mentioning here; H 2 S releasing morpholinium‐morpholine derivative 19 (GYY4137; Figure ), was developed as a slow‐releasing H 2 S agent with vasodilatory, antihypertensive, cardioprotective properties, as well as other cardiovascular effects attributed to H 2 S via the mTOR pathway …”

Section: Pharmacological Activity Of Morpholine Derivatives On Varioumentioning

confidence: 99%

Morpholine as a privileged structure: A review on the medicinal chemistry and pharmacological activity of morpholine containing bioactive molecules

Kourounakis

Xanthopoulos

Tzara

2019

Medicinal Research Reviews

171

114

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Morpholine is a heterocycle featured in numerous approved and experimental drugs as well as bioactive molecules. It is often employed in the field of medicinal chemistry for its advantageous physicochemical, biological, and metabolic properties, as well as its facile synthetic routes. The morpholine ring is a versatile and readily accessible synthetic building block, it is easily introduced as an amine reagent or can be built according to a variety of available synthetic methodologies. This versatile scaffold, appropriately substituted, possesses a wide range of biological activities. There are many examples of molecular targets of morpholine bioactive in which the significant contribution of the morpholine moiety has been demonstrated; it is an integral component of the pharmacophore for certain enzyme active‐site inhibitors whereas it bestows selective affinity for a wide range of receptors. A large body of in vivo studies has demonstrated morpholine's potential to not only increase potency but also provide compounds with desirable drug‐like properties and improved pharamacokinetics. In this review we describe the medicinal chemistry/pharmacological activity of morpholine derivatives on various therapeutically related molecular targets, attempting to highlight the importance of the morpholine ring in drug design and development as well as to justify its classification as a privileged structure.

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“…5, A and B). 2) H 2 S levels were rescued in vessels from obese animals by treatment with the H 2 S donor GYY4137 (43).…”

Section: Discussionmentioning

confidence: 98%

“…We next examined the relationship between obesitydependent H 2 S depletion and changes in remodeling gene expression by experimentally increasing H 2 S levels in mesenteric arterioles. Isolated vessels were placed in tissue culture overnight with or without the H 2 S donor GYY4137 (43), and the expression levels of remodeling genes were determined on the following day by qRT-PCR. Incubation with GYY4137 significantly reduced the expression of fibronectin, collagen types I and III, CTGF, and MMP9 in vessels from the obese mice (Fig.…”

Section: Exogenous H 2 S Reverses the Effect Of Obesity On Expressionmentioning

confidence: 99%

Hydrogen sulfide depletion contributes to microvascular remodeling in obesity

Candela

Velmurugan

White

2016

American Journal of Physiology-Heart and Circulatory Physiology

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Structural remodeling of the microvasculature occurs during obesity. Based on observations that impaired H2S signaling is associated with cardiovascular pathologies, the current study was designed to test the hypothesis that altered H2S homeostasis is involved in driving the remodeling process in a diet-induced mouse model of obesity. The structural and passive mechanical properties of mesenteric resistance arterioles isolated from 30-wk-old lean and obese mice were assessed using pressure myography, and vessel H2S levels were quantified using the H2S indicator sulfidefluor 7-AM. Remodeling gene expression was assessed using quantitative RT-PCR, and histological staining was used to quantify vessel collagen and elastin. Obesity was found to be associated with decreased vessel H2S concentration, inward hypertrophic remodeling, altered collagen-to-elastin ratio, and reduced vessel stiffness. In addition, mRNA levels of fibronectin, collagen types I and III, matrix metalloproteinases 2 and 9, and tissue inhibitor of metalloproteinase 1 were increased and elastin was decreased by obesity. Evidence that decreased H2S was responsible for the genetic changes was provided by experiments in which H2S levels were manipulated, either by inhibition of the H2S-generating enzyme cystathionine γ-lyase with dl-propargylglycine or by incubation with the H2S donor GYY4137. These data suggest that, during obesity, depletion of H2S is involved in orchestrating the genetic changes underpinning inward hypertrophic remodeling in the microvasculature.

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GYY4137, a Novel Water-Soluble, H2S-Releasing Molecule

Cited by 91 publications

References 86 publications

The Reactive Sulfur Species Concept: 15 Years On

The Reactive Sulfur Species Concept: 15 Years On

Morpholine as a privileged structure: A review on the medicinal chemistry and pharmacological activity of morpholine containing bioactive molecules

Hydrogen sulfide depletion contributes to microvascular remodeling in obesity

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