Browse
Submit Data
Databases
API
Help

Dataset Information

18 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

New acyloxy nitroso compounds with improved water solubility and nitroxyl (HNO) release kinetics and inhibitors of platelet aggregation.

ABSTRACT: New acyloxy nitroso compounds, 4-nitrosotetrahydro-2H-pyran-4-yl 2,2,2-trichloroacetate and 4-nitrosotetrahydro-2H-pyran-4-yl 2,2-dichloropropanoate were prepared. These compounds release HNO under neutral conditions with half-lives between 50 and 120min, identifying these HNO donors as kinetically intermediate to the much slower acetate derivative and the faster trifluoroacetic acid derivative. These compounds or HNO-derived from these compounds react with thiols, including glutathione, thiol-containing enzymes and heme-containing proteins in a similar fashion to other acyloxy nitroso compounds. HNO released from these acyloxy nitroso compounds inhibits activated platelet aggregation. These acyloxy nitroso compounds augment the range of release for this group of HNO donors and should be valuable tools in the further study of HNO biology.

SUBMITTER: Mohamed HA

PROVIDER: S-EPMC4554820 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

New acyloxy nitroso compounds with improved water solubility and nitroxyl (HNO) release kinetics and inhibitors of platelet aggregation.

Mohamed Heba A H HA Abdel-Aziz Mohamed M Abuo-Rahma Gamal El-Din A A Gel-D King S Bruce SB

Bioorganic & medicinal chemistry 20150416 17

New acyloxy nitroso compounds, 4-nitrosotetrahydro-2H-pyran-4-yl 2,2,2-trichloroacetate and 4-nitrosotetrahydro-2H-pyran-4-yl 2,2-dichloropropanoate were prepared. These compounds release HNO under neutral conditions with half-lives between 50 and 120min, identifying these HNO donors as kinetically intermediate to the much slower acetate derivative and the faster trifluoroacetic acid derivative. These compounds or HNO-derived from these compounds react with thiols, including glutathione, thiol-c ...[more]

PMID: 26228501

Similar Datasets

Acyloxy nitroso compounds as nitroxyl (HNO) donors: kinetics, reactions with thiols, and vasodilation properties.

Project description:Acyloxy nitroso compounds hydrolyze to nitroxyl (HNO), a nitrogen monoxide with distinct chemistry and biology. Ultraviolet-visible spectroscopy and mass spectrometry show hydrolysis rate depends on pH and ester group structure with the observed rate being trifluoroacetate (3) > acetate (1) > pivalate (2). Under all conditions, 3 rapidly hydrolyzes to HNO. A combination of spectroscopic, kinetic, and product studies show that addition of thiols increases the decomposition rate of 1 and 2, leading to hydrolysis and HNO. Under conditions that favor thiolates, the thiolate directly reacts with the nitroso group, yielding oximes without HNO formation. Biologically, 3 behaves like Angeli's salt, demonstrating thiol-sensitive nitric oxide-mediated soluble guanylate cyclase-dependent vasorelaxation, suggesting HNO-mediated vasorelaxation. The slow HNO-donor 1 demonstrates weak thiol-insensitive vasorelaxation, indicating HNO release kinetics determine HNO bioavailability and activity. These results show that acyloxy nitroso compounds represent new HNO donors capable of vasorelaxation depending on HNO release kinetics.

| S-EPMC3041856 | biostudies-other

Water soluble acyloxy nitroso compounds: HNO release and reactions with heme and thiol containing proteins.

Project description:Nitroxyl (HNO) has gained interest as a potential treatment of congestive heart failure through the ability of the HNO donor, Angeli's salt (AS), to evoke positive inotropic effects in canine cardiac muscle. The release of nitrite during decomposition limits the use of AS requiring other HNO sources. Acyloxy nitroso compounds liberate HNO and small amounts of nitrite upon hydrolysis and the synthesis of the water-soluble 4-nitrosotetrahydro-2H-pyran-4-yl acetate and pivalate allows for pig liver esterase (PLE)-catalysis increasing the rate of decomposition and HNO release. The pivalate derivative does not release HNO, but the addition of PLE catalyzes hydrolysis (t(1/2)=39 min) and HNO formation (65% after 30 min). In the presence of PLE, this compound converts metmyoglobin (MetMb) to iron nitrosyl Mb and oxyMb to metMb indicating that these compounds only react with heme proteins as HNO donors. The pivalate in the presence and the absence of PLE inhibits aldehyde dehydrogenase (ALDH) with IC(50) values of 3.5 and 3.3 ?M, respectively, in a time-dependent manner. Reversibility assays reveal reversible inhibition of ALDH in the absence of PLE and partially irreversible inhibition with PLE. Liquid chromatography-mass spectrometry (LC-MS) reveals formation of a disulfide upon incubation of an ALDH peptide without PLE and a mixture of disulfide and sulfinamide in the presence of PLE. A dehydroalanine residue forms upon incubation of this peptide with excess AS. These results identify acyloxy nitroso compounds as unique HNO donors capable of thiol modification through direct electrophilic reaction or HNO release.

| S-EPMC3518590 | biostudies-literature

Direct and nitroxyl (HNO)-mediated reactions of acyloxy nitroso compounds with the thiol-containing proteins glyceraldehyde 3-phosphate dehydrogenase and alkyl hydroperoxide reductase subunit C.

Project description:Nitroxyl (HNO) reacts with thiols, and this reactivity requires the use of donors with 1-nitrosocyclohexyl acetate, pivalate, and trifluoroacetate, forming a new group. These acyloxy nitroso compounds inhibit glyceraldehyde 3-phosphate dehydrogenase (GAPDH) by forming a reduction reversible active site disulfide and a reduction irreversible sulfinic acid or sulfinamide modification at Cys244. Addition of these acyloxy nitroso compounds to AhpC C165S yields a sulfinic acid and sulfinamide modification. A potential mechanism for these transformations includes nucleophilic addition of the protein thiol to a nitroso compound to yield an N-hydroxysulfenamide, which reacts with thiol to give disulfide or rearranges to sulfinamides. Known HNO donors produce the unsubstituted protein sulfinamide as the major product, while the acetate and pivalate give substituted sulfinamides that hydrolyze to sulfinic acids. These results suggest that nitroso compounds form a general class of thiol-modifying compounds, allowing their further exploration.

| S-EPMC3798158 | biostudies-literature

Ring expansions of acyloxy nitroso compounds.

Project description:Treatment of cyclopentanone and cyclobutanone-derived oximes with lead (IV) tetraacetate gives the bright blue acyloxy nitroso compounds, which upon basic hydrolysis yields the ring expansion product cyclic hydroxamic acids in 12-81% yield. Reactions of substituted cyclopentanones provide ring expanded products where the -NOH group regioselectively inserts to the more substituted position and gives a better yield compared to the treatment of the same ketone with a basic solution of Piloty's acid. Reaction of phosphines with acyloxy nitroso compounds generally generates a ring-expanded Beckmann rearrangement product that can be hydrolyzed to the corresponding lactam. Acyloxy nitroso compounds that undergo rapid hydrolysis to HNO do not show this ring expansion reactivity. These results further demonstrate the versatility of acyloxy nitroso compound to yield structurally complex materials.

| S-EPMC4671303 | biostudies-literature

Rapid and selective nitroxyl (HNO) trapping by phosphines: kinetics and new aqueous ligations for HNO detection and quantitation.

Project description:Recent studies distinguish the biological and pharmacological effects of nitroxyl (HNO) from its oxidized/deprotonated product nitric oxide (·NO), but the lack of HNO detection methods limits the understanding its in vivo mechanisms and the identification of endogenous sources. We previously demonstrated that reaction of HNO with triarylphosphines provides aza-ylides and HNO-derived amides, which may serve as stable HNO biomarkers. We now report a kinetic analysis for the trapping of HNO by phosphines, ligations of enzyme-generated HNO, and compatibility studies illustrating the selectivity of phosphines for HNO over other physiologically relevant nitrogen oxides. Quantification of HNO using phosphines is demonstrated using an HPLC-based assay and ligations of phosphine carbamates generate HNO-derived ureas. These results further demonstrate the potential of phosphine probes for reliable biological detection and quantification of HNO.

| S-EPMC3145035 | biostudies-literature

Nitroxyl (HNO): A novel approach for the acute treatment of heart failure.

Project description:The nitroxyl (HNO) donor, Angeli's salt, exerts positive inotropic, lusitropic, and vasodilator effects in vivo that are cAMP independent. Its clinical usefulness is limited by chemical instability and cogeneration of nitrite which itself has vascular effects. Here, we report on effects of a novel, stable, pure HNO donor (CXL-1020) in isolated myoctyes and intact hearts in experimental models and in patients with heart failure (HF).CXL-1020 converts solely to HNO and inactive CXL-1051 with a t1/2 of 2 minutes. In adult mouse ventricular myocytes, it dose dependently increased sarcomere shortening by 75% to 210% (50-500 ?mol/L), with a ?30% rise in the peak Ca(2+) transient only at higher doses. Neither inhibition of protein kinase A nor soluble guanylate cyclase altered this contractile response. Unlike isoproterenol, CXL-1020 was equally effective in myocytes from normal or failing hearts. In anesthetized dogs with coronary microembolization-induced HF, CXL-1020 reduced left ventricular end-diastolic pressure and myocardial oxygen consumption while increasing ejection fraction from 27% to 40% and maximal ventricular power index by 42% (both P<0.05). In conscious dogs with tachypacing-induced HF, CXL-1020 increased contractility assessed by end-systolic elastance and provided venoarterial dilation. Heart rate was minimally altered. In patients with systolic HF, CXL-1020 reduced both left and right heart filling pressures and systemic vascular resistance, while increasing cardiac and stroke volume index. Heart rate was unchanged, and arterial pressure declined modestly.These data show the functional efficacy of a novel pure HNO donor to enhance myocardial function and present first-in-man evidence for its potential usefulness in HF.URL: http://www.clinicaltrials.gov. Unique identifiers: NCT01096043, NCT01092325.

| S-EPMC4110196 | biostudies-literature

Induction of caveolin-3/eNOS complex by nitroxyl (HNO) ameliorates diabetic cardiomyopathy.

Project description:Nitroxyl (HNO), one-electron reduced and protonated sibling of nitric oxide (NO), is a potential regulator of cardiovascular functions. It produces positive inotropic, lusitropic, myocardial anti-hypertrophic and vasodilator properties. Despite of these favorable actions, the significance and the possible mechanisms of HNO in diabetic hearts have yet to be fully elucidated. H9c2 cells or primary neonatal mouse cardiomyocytes were incubated with normal glucose (NG) or high glucose (HG). Male C57BL/6 mice received intraperitoneal injection of streptozotocin (STZ) to induce diabetes. Here, we demonstrated that the baseline fluorescence signals of HNO in H9c2 cells were reinforced by both HNO donor Angeli's salt (AS), and the mixture of hydrogen sulfide (H2S) donor sodium hydrogen sulfide (NaHS) and NO donor sodium nitroprusside (SNP), but decreased by HG. Pretreatment with AS significantly reduced HG-induced cell vitality injury, apoptosis, reactive oxygen species (ROS) generation, and hypertrophy in H9c2 cells. This effect was mediated by induction of caveolin-3 (Cav-3)/endothelial nitric oxide (NO) synthase (eNOS) complex. Disruption of Cav-3/eNOS by pharmacological manipulation or small interfering RNA (siRNA) abolished the protective effects of AS in HG-incubated H9c2 cells. In STZ-induced diabetic mice, administration of AS ameliorated the development of diabetic cardiomyopathy, as evidenced by improved cardiac function and reduced cardiac hypertrophy, apoptosis, oxidative stress and myocardial fibrosis without affecting hyperglycemia. This study shed light on how interaction of NO and H2S regulates cardiac pathology and provide new route to treat diabetic cardiomyopathy with HNO.

| S-EPMC7078438 | biostudies-literature

Mechanisms Associated to Nitroxyl (HNO)-Induced Relaxation in the Intestinal Smooth Muscle.

Project description:The pharmacological properties of nitroxyl (HNO) donors in the gastrointestinal tract are unknown. We investigated the properties of this molecule in the regulation of gastrointestinal contractility focusing on its possible interaction with other gaseous signaling molecules such as NO and H2S. Organ bath, Ca2+ imaging, and microelectrode recordings were performed on rat intestinal samples, using Angeli's salt as HNO donor. Angeli's salt caused a concentration-dependent relaxation of longitudinal or circular muscle strips of the ileum and the proximal colon. This relaxation was strongly inhibited by the Rho-kinase inhibitor Y-27632 (10 μM), by the reducing agent DTT or by the inhibitor of soluble guanylate cyclase (sGC) ODQ (10 μM) alone or in combination with the inhibitors of the endogenous synthesis of H2S β-cyano-L-alanine (5 mM) and amino-oxyacetate (5 mM). Preventing endogenous synthesis of NO by the NO synthase inhibitor L-NAME (200 μM) did not affect the relaxation induced by HNO. HNO induced an increase in cytosolic Ca2+ concentration in colonic myocytes. It also elicited myocyte membrane hyperpolarization that amounted to -10.6 ± 1.1 mV. ODQ (10 μM) and Apamin (1 μM), a selective inhibitor of small conductance Ca2+-activated K+ channels (SKca), strongly antagonized this effect. We conclude that HNO relaxes the gastrointestinal tract musculature by hyperpolarizing myocytes via activation of the sGC/cGMP pathway similarly to NO, not only inhibiting the RhoK and activating MLCP as do both NO and H2S but also increasing cytosolic Ca2+ for activation of SK C a contributing to hyperpolarization.

| S-EPMC7283591 | biostudies-literature

Nitroxyl (HNO) targets phospholamban cysteines 41 and 46 to enhance cardiac function.

Project description:Nitroxyl (HNO) positively modulates myocardial function by accelerating Ca2+ reuptake into the sarcoplasmic reticulum (SR). HNO-induced enhancement of myocardial Ca2+ cycling and function is due to the modification of cysteines in the transmembrane domain of phospholamban (PLN), which results in activation of SR Ca2+-ATPase (SERCA2a) by functionally uncoupling PLN from SERCA2a. However, which cysteines are modified by HNO, and whether HNO induces reversible disulfides or single cysteine sulfinamides (RS(O)NH2) that are less easily reversed by reductants, remain to be determined. Using an 15N-edited NMR method for sulfinamide detection, we first demonstrate that Cys46 and Cys41 are the main targets of HNO reactivity with PLN. Supporting this conclusion, mutation of PLN cysteines 46 and 41 to alanine reduces the HNO-induced enhancement of SERCA2a activity. Treatment of WT-PLN with HNO leads to sulfinamide formation when the HNO donor is in excess, whereas disulfide formation is expected to dominate when the HNO/thiol stoichiometry approaches a 1:1 ratio that is more similar to that anticipated in vivo under normal, physiological conditions. Thus, 15N-edited NMR spectroscopy detects redox changes on thiols that are unique to HNO, greatly advancing the ability to detect HNO footprints in biological systems, while further differentiating HNO-induced post-translational modifications from those imparted by other reactive nitrogen or oxygen species. The present study confirms the potential of HNO as a signaling molecule in the cardiovascular system.

| S-EPMC6571998 | biostudies-literature

Comparison of Reductive Ligation-Based Detection Strategies for Nitroxyl (HNO) and S-Nitrosothiols.

Project description:Phosphine-based detection strategies for both nitroxyl (HNO) and S-nitrosothiols (RSNO) were investigated and compared. Phosphorus NMR studies show that azaylides derived from HNO or organic RSNO efficiently participate in subsequent reductive ligation required for fluorescence generation in properly substituted substrates. S-Azaylides derived from biological RSNO containing free amine and carboxylic acid groups primarily yield phosphine oxides suggesting these groups facilitate nonligation pathways such as hydrolysis. The fluorescence response of a phosphine-based fluorophore toward the same RSNO confirms these differences and indicates that these probes selectively react with HNO. Flow cytometry experiments in HeLa cells reinforce the reactivity difference and offer a potential fast screening approach for endogenous HNO sources.

| S-EPMC4906479 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data