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At least 955 records · Page 53Linked to original sources
PubMed2005

Hydroxyimine NO-donors; FK409 and derivatives.

FK409 was discovered during a screening program for prostaglandin like compounds from microbial products by measuring inhibition of platelet aggregation and vasodilation. FK409, a semisynthetic compound derived from acidic nitrosation of microbial broth, was shown to be a potent vasodilator with a similar pharmacological profile to organic nitrates such as nitroglycerin (NTG). FK409 dilated the larger diameter coronary vascular vessels more potently than those with a smaller diameter in vitro, and was more potent than NTG in a dog angina pectoris model. Clinical development of FK409 for angina pectoris included a preliminary open efficacy study in about twenty patients with angina pectoris showing an improvement in 60-70 % of patients. Anemia proved a drug related adverse event. A new study was carried out on around 20 patients with ischemic heart disease, but in the longer term the anemia remained. It was concluded that FK409 had a comparable efficacy to organic nitrates, but an undesirable adverse effect, and development was terminated. Back-up compounds for FK409, explored improvement of the pharmacokinetic profile: an increase in duration of action and a reduction of the risk of anemia. The pharmacological action of FK409 was associated with increased cGMP levels in aortic smooth muscle; and release of NO was observed by physicochemical methods. Synthesis of chemically more stable derivatives of FK409 with slower NO release was aimed at longer pharmacokinetic profiles and a lower incidence of anemia. FR144220 and FR146881 were identified as chemically more stable compounds with a longer duration of pharmacological action.

Anemia↗
PubMed1975

A novel diazonium-sulfhydryl reaction in the inactivation of yeast alcohol dehydrogenase by diazotized 3-aminopyridine adenine dinucleotide.

Diazotized 3-aminopyridine adenine dinucleotide has been found to modify four sulfhydryl groups per molecule of enzyme during the complete inactivation of yeast alcohol dehydrogenase. The reaction of sulfhydryl groups was indicated by titration studies with 5,5-dithiobis(2-nitrobenzoic acid) as well as isolation and quantitation of the cysteinyl derivative released by acid hydrolysis of the modified enzyme. The cysteinyl derivative was identified as S-(3-pyridyl)cysteine. Authentic S-(3-pyridyl)cystein was synthesized and structurally characterized for these studies. Diazonium-sulfhydryl reactions were demonstrated for a number of diazonium derivatives with cysteine, homocysteine, glutathione, and mercaptoethanol at 0-4 degrees and neutral pH. Second order rate constants were determined in reactions of these sulfhydryl compounds with diazotized 1-methyl-3-aminopyridinium chloride, diazotized 3-aminopyridine adenine dinucleotide, and diazotized 3-aminopyridine adenine dinucleotide phosphate.

Alcohol Oxidoreductases↗
PubMed1984

Conversion of 3-nitropropanol (miserotoxin aglycone) to 3-nitropropionic acid in cattle and sheep.

The metabolism of intravenously administered 3-nitropropanol (miserotoxin aglycone) was examined in cattle and sheep using high-pressure liquid chromatography (HPLC) to determine nitrocompounds in plasma. 3-Nitropropanol (NPOH) showed a rapid rate of decay and simultaneously, 3-nitropropionic acid (NPA) was detected at comparable levels in plasma. In animals dosed with NPOH, the observed NPA decayed at a slower rate than NPOH. Nitrite levels in plasma were more closely related to NPA than to NPOH. Therefore, metabolism of NPOH is linked to NPA and this could provide a common basis for the toxicity of these compounds in cattle and sheep.

1-Propanol↗
PubMed2001

Tolerance towards explosives, and explosives removal from groundwater in treatment wetland mesocosms.

A short-term study was performed to determine the feasibility of using constructed wetlands to remove explosives from groundwater, and to assess accumulation of parent explosives compounds and their known degradation compounds in wetland plants. Tolerance towards explosives in submersed and emergent plants was screened over a range of 0 to 40 mg L(-1). Tolerance varied per compound, with TNT evoking the highest, 2NT the lowest, and 24DNT, 26DNT, and RDX an intermediate growth reducing effect. Submersed plants were more sensitive to TNT than emergent ones. A small-scale 4-month field study was carried out at the Volunteer Army Ammunition Plant, Chattanooga, TN. In this surface-flow, modular system, the influent contained high levels (>2.1 mg L(-1)) of TNT, 2,4DNT, 2,6DNT, 2NT, 3NT, and 4NT, and the HRT was 7 days. The performance criteria of US EPA treatment goals for local discharge of 2,4DNT concentration <0.32 mg L(-1), and 26DNT concentration <0.55 mg L(-1) were not met at the end of the experiment, although explosives levels were greatly reduced. Low levels of 2ADNT and 4ADNT were transiently observed in the plant biomass. Results of two other, older, constructed wetlands, however, indicated that in these systems treatment goals were met most of the time, residues of explosives parent compounds and known degradation compounds in plant tissues were low and/or transient, and in substrates were low.

Biomass↗
PubMed2003

Neuroprotective effects of (+/-)-huprine Y on in vitro and in vivo models of excitoxicity damage.

We have investigated the neuroprotective effects of (+/-)-huprine Y on excitotoxic lesions in rat cerebellar granule cells (CGCs). (+/-)-Huprine Y prevented cell death induced by 100 microM glutamate, as well as, 10 microM MK-801, a NMDA receptor antagonist, in a significant manner. On the other hand, intracellular calcium increase induced by NMDA (200 microM), measured by fura-2 fluorescence, was prevented by (+/-)-huprine Y with an EC(50) of 12.44 microM, which evidences the modulatory action of this compound on NMDA-induced calcium currents. In vivo, we have studied (+/-)-huprine Y neuroprotective effects on striatal lesions induced by the subacute administration of the mitochondrial toxin 3-nitropropionic acid (3-NP, 30 mg/kg, ip, for 10 days). We have assessed that both the behavioral and the morphological consequences of the lesion were prevented by pretreatment with (+/-)-huprine Y (2.5 mg/kg/twice a day, ip). Striatal gliosis induced by 3-NP treatment was prevented by (+/-)-huprine Y pretreatment, as demonstrated by the attenuation of both the increase in [(3)H]PK 11195 specific binding indicative of microgliosis and the expression of hsp27 kDa, a chaperone expressed mainly in astrocytes. In conclusion, (+/-)-huprine Y attenuated excitotoxic-induced lesions, both in vitro and in vivo, and further evidence is provided for the potential use of this compound in the prevention of neurodegenerative disorders.

Aminoquinolines↗
PubMed1982

Mutagenicity of N-hydroxy-2-acetylaminofluorene and N-hydroxy-phenacetin and their respective deacetylated metabolites in nitroreductase deficient Salmonella TA98FR and TA100FR.

The mutagenicity of N-hydroxy-2-acetylaminofluorene and N-hydroxyphenacetin and their respective deacetylated metabolites, N-hydroxy-2-aminofluorene and 2-nitrosofluorene, and N-hydroxyphenetidine and rho-nitrosophenetole was determined in nitroreductase deficient Salmonella tester strains TA 98FR and TA100FR. The mutagenicity of N-hydroxy-2-acetylaminofluorene medicated by either rat liver microsomes or rat liver 105 000 g supernatant fractions was no different in either TA98 (nitroreductase proficient) or TA98FR (nitroreductase deficient). Similarly the mutagenicity of N-hydroxyphenacetin mediated by hamster liver microsomes was not affected by either the presence or absence of nitroreductase activity in TA100. N-Hydroxy-2-aminofluorene and 2-nitrosofluorene were equipotent direct acting mutagens in both TA98 and TA98FR, as were both N-hydroxyphenetidine and rho-nitrosophenetole in TA100 and TA 100FR. Ascorbate (5 mM) and NADPH (1 mM) had no significant effect on the mutagenicity of either N-hydroxy-2-acetylaminofluorene, N-hydroxy-2-aminofluorene, or 2-nitrosofluorene in TA98 or TA98FR whereas ascorbate and NADPH markedly inhibited the mutagenicity of both N-hydroxyphenetidine and rho-nitrosophenetole in both TA100 and TA100FR. Ascorbate appears to be inhibiting the mutagenicity of N-hydroxyphenetidine and rho-nitrosophenetole as a result of the nonenzymatic chemical reduction of these compounds to non-mutagenic derivatives.

2-Acetylaminofluorene↗
PubMed2006

In vitro metabolism of (nitrooxy)butyl ester nitric oxide-releasing compounds: comparison with glyceryl trinitrate.

We investigated the in vitro metabolism of two (nitrooxy)butyl ester nitric oxide (NO) donor derivatives of flurbiprofen and ferulic acid, [1,1'-biphenyl]-4-acetic acid-2-fluoro-alpha-methyl-4-(nitrooxy)butyl ester (HCT 1026) and 3-(4-hydroxy-3-methoxyphenyl)-2-propenoic acid 4-(nitrooxy)butyl ester (NCX 2057), respectively, in rat blood plasma and liver subcellular fractions compared with (nitrooxy)butyl alcohol (NOBA) and glyceryl trinitrate (GTN). HCT 1026 and NCX 2057 undergo rapid ubiquitous carboxyl ester hydrolysis to their respective parent compounds and NOBA. The nitrate moiety of this latter is subsequently metabolized to inorganic nitrogen oxides (NOx), predominantly in liver cytosol by glutathione S-transferase (GST) and to a lesser extent in liver mitochondria. If, however, in liver cytosol, the carboxyl ester hydrolysis is prevented by an esterase inhibitor, the metabolism at the nitrate moiety level does not occur. In blood plasma, HCT 1026 and NCX 2057 are not metabolized to NOx, whereas a slow but sustained NO generation in deoxygenated whole blood as detected by electron paramagnetic resonance indicates the involvement of erythrocytes in the bioactivation of these compounds. Differently from NOBA, GTN is also metabolized in blood plasma and more quickly metabolized by different GST isoforms in liver cytosol. The cytosolic GST-mediated denitration of these organic nitrates in liver limits their interaction with other intracellular compartments to possible generation of NO and/or their subsequent availability and bioactivation in the systemic circulation and extrahepatic tissues. We show the possibility of modulating the activity of hepatic cytosolic enzymes involved in the metabolism of (nitrooxy)butyl ester compounds, thus increasing the therapeutic potential of this class of compounds.

Animals↗