Biomedical subjects
Publications and source records attributed to M J Jung.
A new C-methyl flavonol glycoside, 5,7,8,4'-tetrahydroxy-3-methoxy-6-methylflavone 8-O-beta-D-glucopyranoside (1), has been isolated from the needles of Pinus densiflora, together with kaempferol 3-O-beta-(6"-acetyl)-galactopyranoside.
Doppler waveforms of the human fetal ductus arteriosus and the branch pulmonary artery are distinct in their shape and might reflect fetal cardiovascular hemodynamics and vessel wall characteristics. The waveform of ductus arteriosus had two peaks, a higher one in systole and a lower one in diastole. Both peaks had slow acceleration and deceleration and looked like two narrow base isosceles triangles. This unique waveform might be due to vessel wall characteristics and an instantaneous pressure gradient between the main pulmonary artery and descending aorta. The waveform of the branch pulmonary artery showed very steep acceleration with the onset of ejection followed by steep decline, then low velocity flow during diastole. The characteristic shape of the branch pulmonary artery might be related to high vascular resistance, decreased capacitance and the earlier reflection wave of pulmonary vessels.
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In 24 (0.98%) of 2457 patients with congenital heart disease the brachiocephalic vein was in an anomalous position below the aortic arch. This is a much higher proportion of such cases than reported so far. This high frequency may arise from differences in the study population and the method of diagnosis. This venous anomaly was more common in patients with tetralogy of Fallot or ventricular septal defect with pulmonary atresia. Patients with the venous anomaly were more likely to have a right aortic arch. The anomalous course of the brachiocephalic vein from the neck to the junction of the superior vena cava was shown by cross sectional echocardiography. In doubtful cases, Doppler study usually clarified the anatomical arrangement.
Renin inhibition has been evaluated for a new class of fluorinated ketones, true analogues of peptides that have been retroinverted at the C-terminal position. The readily formed hydrate of the ketone is proposed to mimic the tetrahedral intermediate that occurs during the enzyme-catalyzed hydrolysis of amide linkage. From this series of compounds it appears that the number of reverted amide bonds is crucial in terms of activity. Furthermore, a shortening of the C-terminal part of our peptide analogues and the replacement of the leucine residue in P1 by a cyclohexylalanine leads to the tripeptide analogue 12 a potent renin inhibitor (IC50 = 3.5 x 10(-9) M).
The syntheses of alpha-mono- and alpha-difluoromethyl derivatives of tryptophan and 5-hydroxytryptophan are described. In an attempt to selectively regulate serotonin synthesis, alpha-(mono- and difluoromethyl)tryptophan were tested in vivo as precursors (or prodrugs) of their 5-hydroxy analogues. Although alpha-(mono- and difluoromethyl)-5-hydroxytryptophans are potent irreversible inhibitors of aromatic amino acid decarboxylase (equipotent to alpha-difluoromethyl-Dopa), only alpha-(monofluoromethyl)tryptophan affects the level of serotonin in vivo (small decrease), alpha-(difluoromethyl)tryptophan being a very poor substrate of the activating (or helper) enzyme, tryptophan hydroxylase.
The syntheses of four derivatives of gamma-vinyl-GABA, in which vinylic hydrogen atoms were replaced by fluorine, are described. With use of 5-ethenyl-2-pyrrolidinone as starting material, the E and Z isomers of 4-amino-6-fluoro-5-hexenoic acid were prepared. The 6,6-difluoro and 5,6,6-trifluoro analogues could be synthesized from 4-oxobutanoic acid tert-butyl ester and (2,2-difluoroethenyl)- and (trifluoroethenyl)lithium correspondingly. The compounds were tested as inhibitors of GABA-T, and their in vitro and in vivo biochemistry is reported. The most active derivative was (Z)-4-amino-6-fluoro-5-hexenoic acid; the structure-activity relationship in the series is discussed.
beta-Difluoromethyl-beta-alanine (3-amino-4,4-difluorobutanoic acid) is a potent in vitro and in vivo inhibitor of GABA-T. The rate of inhibition of GABA-T is concentration- and time-dependent. The inactivation is active-site directed. No reactive species escapes from the active site before reacting with the enzyme. The inhibition is irreversible and stereospecific. The use of beta-2H-beta-difluoromethyl-beta-alanine results in a marked primary isotope effect in vitro and in vivo. The use of differently substituted dihalogeno derivatives of beta-alanine suggests that the rate of inhibition is dependent on the nature and position of the leaving group. The mechanism of inhibition is discussed on the basis of spectral changes.
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6-Fluoromevalonate blocks the incorporation of mevalonic acid, but not that of isopentenyl pyrophosphate, into non-saponifiable lipids in a rat liver multienzyme system. With 3H-labelled 6-fluoromevalonate, it was found that 6-fluoromevalonate is converted to its phospho and pyrophospho derivatives in this system. The kinetics of the two kinases were studied. 6-Fluoromevalonate 5-pyrophosphate is a potent competitive inhibitor of pyrophosphomevalonate decarboxylase (Ki 37 nM). In the multienzyme assay for cholesterol biosynthesis, there is accumulation of mevalonate 5-phosphate and mevalonate 5-pyrophosphate in the presence of 5 microM-6-fluoromevalonate, and 6-fluoromevalonate 5-pyrophosphate is more effective than 6-fluoromevalonate in inhibiting cholesterol biosynthesis. We suggest therefore that 6-fluoromevalonate blocks cholesterol biosynthesis at the level of pyrophosphomevalonate decarboxylase after being pyrophosphorylated.
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Incubation of rat brain or bacterial 4-aminobutyrate aminotransferase (EC 2.6.1.19) with both (S)-(+)- and (R)-(-)-enantiomers of 4- aminohex -5- ynoic acid results in a time-dependent irreversible loss of enzymatic activity. Rat brain glutamate decarboxylase (EC 4.1.1.15) is inactivated by the (S)-(+)-enantiomer while the bacterial glutamate decarboxylase is inactivated by the (R)-(-)-enantiomer. In addition, we demonstrate that (R)-(-)-4- aminohex -5- ynoic acid is a selective and effective inhibitor of rat brain 4-aminobutyrate aminotransferase in vivo.
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In rats, chronic infusion of alpha-fluoromethyl histidine, a selective irreversible inhibitor of mammalian histidine decarboxylase, caused a marked depletion of histamine in all tissues examined. There were no gross pharmacological effects associated with this depletion.
It was previously shown that 5-hexyne-1,4-diamine is a potent enzyme-activated irreversible inhibitor of mammalian ornithine decarboxylase. However this compound has secondary pharmacological effects owing to its in vivo oxidation to 4-aminohex-5-ynoic acid, an irreversible inhibitor of 4-aminobutyrate aminotransferase. The first step of this oxidation is catalysed by mitochondrial monamine oxidase. The monomethyl and dimethyl analogues of 5-hexyne-1,4-diamine, i.e. 6-heptyne-2,5-diamine and 2-methyl-6-heptyne-2,5-diamine, which cannot be substrate of monoamine oxidase, were tested as selective irreversible inhibitors of ornithine decarboxylase. Our results demonstrate that (2R,5R)-6-heptyne-2,5-diamine is greater than 10 times more potent, both in vitro and in vivo, than alpha-difluoromethylornithine, the most widely used irreversible inhibitor of this enzyme.
Cold and restraint stress in rats induced gastric mucosa lesions, increased gastric mucosa histidine decarboxylase activity and elevated hypothalamic content. Cimetidine did not modify the biochemical effects induced by stress but partially protected against gastric ulceration. alpha-Fluoromethyl histidine inhibited the increase of histidine decarboxylase activity in the gastric mucosa, inhibited the rise of hypothalamic histamine content and decreased the incidence of gastric lesions to the same extent as did cimetidine.