Background-The potential biological significance of hydrogen sulfide (H 2 S) has attracted growing interest in recent years. The aim of this study was to characterize a novel, water-soluble, slow-releasing H 2 S compound [morpholin-4-ium 4 methoxyphenyl(morpholino) phosphinodithioate (GYY4137)] and evaluate its use as a tool to investigate the cardiovascular biology of this gas. Methods and Results-The acute vasorelaxant effect of drugs was assessed in rat aortic rings and perfused rat kidney in vitro and in the anesthetized rat in vivo. The chronic effect of GYY4137 on blood pressure in normotensive and spontaneously hypertensive rats was determined by tail-cuff plethysmography. GYY4137 released H 2 S slowly both in aqueous solution in vitro and after intravenous or intraperitoneal administration in anesthetized rats in vivo. GYY4137 caused a slow relaxation of rat aortic rings and dilated the perfused rat renal vasculature by opening vascular smooth muscle K ATP channels. GYY4137 did not affect rat heart rate or force of contraction in vitro. GYY4137 exhibited antihypertensive activity as evidenced by ability to reduce N G -nitro-L-arginine methyl ester-evoked hypertension in the anesthetized rat and after chronic (14-day) administration in spontaneously hypertensive rats. Conclusions-These results identify GYY4137 as a slow-releasing H 2 S compound with vasodilator and antihypertensive activity. GYY4137 is likely to prove useful in the study of the many and varied biological effects of H 2 S. GYY4137 may also prove of therapeutic value in cardiovascular disease.
The role of hydrogen sulfide (H 2 S) in inflammation is controversial, with both pro-and antiinflammatory effects documented. Many studies have used simple sulfide salts as the source of H 2 S, which give a rapid bolus of H 2 S in aqueous solutions and thus do not accurately reflect the enzymatic generation of H 2 S. We therefore compared the effects of sodium hydrosulfide and a novel slow-releasing H 2 S donor (GYY4137) on the release of pro-and antiinflammatory mediators in lipopolysaccharide (LPS)-treated murine RAW264.7 macrophages. For the first time, we show that GYY4137 significantly and concentration-dependently inhibits LPS-induced release of proinflammatory mediators such as IL-1b, IL-6, TNF-a, nitric oxide ( NO), and PGE 2 but increased the synthesis of the antiinflammatory chemokine IL-10 through NF-kB=ATF-2=HSP-27-dependent pathways. In contrast, NaHS elicited a biphasic effect on proinflammatory mediators and, at high concentrations, increased the synthesis of IL-1b, IL-6, NO, PGE 2 and TNF-a. This study clearly shows that the effects of H 2 S on the inflammatory process are complex and dependent not only on H 2 S concentration but also on the rate of H 2 S generation. This study may also explain some of the apparent discrepancies in the literature regarding the pro-versus antiinflammatory role of H 2 S.
The slow-releasing hydrogen sulfide (H2S) donor, GYY4137, caused concentration-dependent killing of seven different human cancer cell lines (HeLa, HCT-116, Hep G2, HL-60, MCF-7, MV4-11 and U2OS) but did not affect survival of normal human lung fibroblasts (IMR90, WI-38) as determined by trypan blue exclusion. Sodium hydrosulfide (NaHS) was less potent and not active in all cell lines. A structural analogue of GYY4137 (ZYJ1122) lacking sulfur and thence not able to release H2S was inactive. Similar results were obtained using a clonogenic assay. Incubation of GYY4137 (400 µM) in culture medium led to the generation of low (<20 µM) concentrations of H2S sustained over 7 days. In contrast, incubation of NaHS (400 µM) in the same way led to much higher (up to 400 µM) concentrations of H2S which persisted for only 1 hour. Mechanistic studies revealed that GYY4137 (400 µM) incubated for 5 days with MCF-7 but not IMR90 cells caused the generation of cleaved PARP and cleaved caspase 9, indicative of a pro-apoptotic effect. GYY4137 (but not ZYJ1122) also caused partial G2/M arrest of these cells. Mice xenograft studies using HL-60 and MV4-11 cells showed that GYY4137 (100–300 mg/kg/day for 14 days) significantly reduced tumor growth. We conclude that GYY4137 exhibits anti-cancer activity by releasing H2S over a period of days. We also propose that a combination of apoptosis and cell cycle arrest contributes to this effect and that H2S donors should be investigated further as potential anti-cancer agents.
Background and Purpose Atherosclerosis is associated with reduced vascular hydrogen sulfide (H2S) biosynthesis. GYY4137 is a novel slow‐releasing H2S compound that may effectively mimic the time course of H2S release in vivo. However, it is not known whether GYY4137 affects atherosclerosis. Experimental Approach RAW 264.7 cells and human blood monocyte‐derived macrophages were incubated with oxidized low density lipoprotein (ox‐LDL) with/without GYY4137. ApoE−/− mice were fed a high‐fat diet for 4 weeks and administered GYY4137 for 30 days. Lipid and atherosclerotic lesions were measured by oil red O staining. Endothelium‐dependent relaxation was assessed in response to acetylcholine. Superoxide production was detected by dihydroethidium staining. Expression of mRNA and protein were evaluated by quantitative real‐time PCR and Western blot. Key Results GYY4137 inhibited ox‐LDL‐induced foam cell formation and cholesterol esterification in cultured cells. GYY4137 decreased the expression of lectin‐like ox‐LDL receptor‐1, iNOS, phosphorylated IκBα, NF‐κB, ICAM‐1, VCAM‐1 and chemokines, including CXCL2, CXCR4, CXCL10 and CCL17, but increased the scavenger protein CD36, in ox‐LDL‐treated RAW 264.7 cells. In vivo, GYY4137 decreased aortic atherosclerotic plaque formation and partially restored aortic endothelium‐dependent relaxation in apoE−/− mice. GYY4137 decreased ICAM‐1, TNF‐α and IL‐6 mRNA expression as well as superoxide (O2−) generation in aorta. In addition, GYY4137 increased aortic eNOS phosphorylation and expression of PI3K, enhanced Akt Ser473 phosphorylation and down‐regulated the expression of LOX‐1. Conclusion and Implications GYY4137 inhibits lipid accumulation induced by ox‐LDL in RAW 264.7 cells. In vivo, GYY4137 decreased vascular inflammation and oxidative stress, improved endothelial function and reduced atherosclerotic plaque formation in apoE−/− mice.
Visible light induced oxidative C-H functionalisation of tertiary amines catalysed by the combination of graphene oxide and Rose Bengal was developed. This reaction avoids the use of stoichiometric amounts of peroxy compounds as terminal oxidants. This reaction is useful for tri-alkyl amines including chiral tertiary amines. Both cyanide and trifluoromethyl nucleophiles were shown to participate in this reaction, providing a-cyano-and a-trifluoromethylated tertiary amines.Graphene oxide (GO), a two-dimensional carbon sheet, is traditionally used as a precursor to prepare graphene. Its unique physical and chemical properties have attracted the attention of chemists due to potential applications in plastic electronics, optical materials, solar cells and biosensors, 1 but its potential as a catalyst in organic transformation remains relatively unexplored. 2,3 The feasibility and potential of GO as catalyst were demonstrated by the seminal work of Bielawski and co-workers on the use of GO for the oxidation of alcohols and hydration of alkynes. 3a Subsequently, RGO was reported to catalyse the hydrogenation of nitrobenzene at room temperature. 3b The use of GO and reduced graphene oxide (RGO) as "carbocatalyst" in organic transformations is a nascent area and should lead to exciting discoveries.On a different note, the use of visible light in organic synthesis has attracted the attention of various synthetic organic chemists recently. 4 The groups of MacMillan, 5 Yoon, 6 and Stephenson 7 have showed the ability of metal-based photosensitizers, such as Ru(bpy) 3 Cl 2 (tris(2,2¢-bipyridine)-ruthenium(II) chloride) (Fig. 1), as photoredox catalysts for organic transformations under visible light irradiation. 8 Organic dyes, which are often Fig. 1 Ruthenium bipyridyl complex and Rose Bengal.used in dye-sensitized solar cells, are considered to be cheaper and easier to modify relative to metal-based photosensitizers, 9 thus they are attractive alternatives as photoredox catalysts. The viability of organic dyes as photoredox catalysts has been demonstrated by several groups. 10 For example, Zeitler et al. reported eosin Y catalysed dehalogenation and enantioselective a-alkylation using a combination of photoredox catalyst and organocatalyst. 10a Fukuzumi reported a selective aerobic bromination catalysed by 9-mesityl-10-methylacridinium perchlorate (Acr + -Mes). 10b We have also demonstrated that Rose Bengal (RB, Fig. 1) was able to photocatalyse a-oxyamination of 1,3-dicarbonyl compounds and 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) using visible light. 10c Although GO has been reported as a photocatalyst for hydrogen production from water under UV irradiation, 11 the potential application of GO in synthetic photochemistry has not been explored. Therefore we wish to report the combination of GO and RB which works in synergy to efficiently catalyse the a-functionalisation of tertiary amines in the presence of visible light. The oxidative a-functionalisation of tertiary amines through highly reactive iminium intermedia...
We report that chiral bicyclic guanidine 1 is found to catalyze the isomerization of alkynes to chiral allenes with high enantioselectivities. This Brønsted base catalyzed 1,3-proton shift reaction, an efficient and atom economical reaction, proceeds through deprotonation and protonation sequences. The axial chirality of the allenes is efficiently transferred to functionalized butenolides and cycloaddition products. We also successfully demonstrate the stereospecific synthesis of butenolide through allenoate cyclization with a catalytic cationic Au(I) complex.
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