Atropisomeric property of 1-(2,6-difluorobenzyl)-3-[(2R)-amino-2-phenethyl]-5-(2-fluoro-3-methoxyphenyl)-6-methyluracil

1-(2,6-Difluorobenzyl)-3-[(2R)-amino-2-phenethyl]-5-(2-fluoro-3-methoxyphenyl)-6-methyluracil (6), a potent and orally active antagonist of the human gonadotropin-releasing hormone receptor, exists as a pair of atropisomers in solution, which was detected by NMR spectroscopy, and separable by HPLC. In addition to a (R)-configured benzylamine, there is a second stereogenic element due to the presence of a chiral axis between the substituted 5-phenyl group and the uracil core. The rate constant of the interconversion (k = 5.07 x 10(-5) s(-1)) of these two atropisomers was determined by proton NMR analysis of a diastereoisomer-enriched sample in aqueous solution at 25 degrees C, and the corresponding Gibbs free energy DeltaG(#) of rotation barrier (97.4 kJ mol(-1)) was calculated using the Eyring equation. The diastereoisomer half-life at physiological temperature (37 degrees C) in aqueous media was estimated to be about 46 min.     

Anti-diabetic effects of sodium 4-amino-2,6-dipicolinatodioxovanadium(V) dihydrate in streptozotocin-induced diabetic rats

The evaluation of the anti-diabetic effects of an organic vanadium(V) complex in streptozotocin (STZ)-induced diabetic rats was investigated. The STZ-induced diabetic rats were orally administrated with sodium 4-amino-2,6-dipicolinatodioxovanadium(V) dihydrate (V5dipic-NH₂), a vanadium(V) coordination compound. The compound was administered through drinking water at a concentration of 0.1 mg/mL for 20 days, and then the concentration was increased to 0.3 mg/mL for the following 20 days. At the end of the experiment, V5dipic-NH₂ statistically significantly reduced the levels of blood glucose (P < 0.01), serum total cholesterol (P < 0.01), triglycerides (P < 0.01) and the activities of serum aspartate amino transferase (P < 0.05) and alkaline phosphatase (P < 0.01) compared to untreated diabetic animals. After treatment with 0.3 mg/mL V5dipic-NH₂, the oral glucose tolerance was improved in diabetic animals (P < 0.01). In addition, the daily intake of elemental vanadium was markedly decreased in V5dipic-NH₂-treated diabetic rats compared to vanadyl sulfate (VOSO₄)-treated diabetic rats, which suggested that the anti-diabetic activity of the element vanadium was elevated after being modified with an organic ligand. These results suggested that V5dipic-NH₂, as an organic vanadium compound, is more effective than inorganic vanadium salt at alleviating the symptoms of diabetes.     

Synthesis of 2,6-di(acylamino)-2,6-dideoxy-3-O-(d-2-propanoyl-l-alanyl-d-isoglutamine)-d-glucopyranoses

Five 2,6-di(acylamino)-2,6-dideoxy-3-O-(d-2-propanoyl-l-alanyl-d-isoglutamine)-d-glucopyranoses (lipophilic, muramoyl dipeptide analogs) were synthesized from benzyl 2-(benzyloxycarbonylamino)-3-O-(d-1-carboxyethyl)-2-deoxy-5,6-O-isopropylidene-β-dglucopyranoside (1). Methanesulfonylation of 3, derived from the methyl ester of 1 by O-deisopropylidenation, gave the 6-methanesulfonate (4). (Tetrahydropyran-2-yl)ation of 4 gave benzyl 2-(benzyloxycarbonylamino)-2-deoxy-3-O-[d-1-(methoxycarbonyl)ethyl]-6-O-(methylsulfonyl)-5-O-(tetrahydropyran-2-yl)-β-d- glucofuranoside, which was treated with sodium azide to give the corresponding 6-azido derivative (6). Condensation of benzyl 6-amino-2-(benzyloxycarbonyl-amino)-2,6-dideoxy-3-O-[d-1-(methoxycarbonyl)ethyl]-5-O-(tetrahydropyran-2-yl)-β-d-glucofuranoside, derived from 6 by reduction, with the activated esters of octanoic, hexadecanoic, and eicosanoic acid gave the corresponding 6-N-fatty acyl derivatives (8–10). Coupling of the 2-amino derivatives, obtained from compounds 8, 9, and 10 by catalytic reduction, with the activated esters of the fatty acids, gave the 2,6-(diacylamino)-2,6-dideoxy derivatives (11–15). Condensation of the acids, formed from 11–15 by de-esterification, with the benzyl ester of l-alanyl-d-isoglutamine, and subsequent hydrolysis, afforded benzyl 2,6-di(acylamino)-2,6-dideoxy-3-O-(d-2-propanoyl-l-alanyl-d-isoglutamine benzyl ester)-β-d-glucofuranosides. Hydrogenation of the dipeptide derivatives thus obtained gave the five lipophilic analogs of 6-amino-6-deoxymuramoyl dipeptide, respectively, in good yields.     

Synthesis of n-octyl 2,6-dideoxy-alpha-L-lyxo-hexopyranosyl-(1-->2)-3-amino-3-deoxy-beta-D-galactopyranoside, an analog of the H-disaccharide antigen

The synthesis of an analog of the H-disaccharide antigen (2), in which the galactopyranosyl moiety bears an amino group at C-3 and the fucopyranosyl residue is deoxygenated at C-2, is reported. The key reaction in the preparation of 2 was the glycosylation of an appropriately protected n-octyl 3-azido-3-deoxy-galactopyranoside derivative with a 2,6-dideoxy thioglycoside promoted by 1-(phenylsulfinyl)piperidine and triflic anhydride. Disaccharide 2 is of interest in studies directed towards understanding the molecular basis of substrate recognition by the blood group A and B glycosyltransferases.     

2-amino-2-desoxy-6-O-(D-glykofuranosylurono-6,3-lacton)-D-galaktopyranosen

Condensation of 2-amino-2-deoxy-D-galactopyranose with D-glucuronic acid or D-mannurono-6,3-lactone in the presence of hydrochloric acid gave the corresponding 2-amino-2-deoxy-6-O-(D-glycofuranosylurono-6,3-lactone)-D-galactopyranoses. The α-D configuration of the disaccharide derived from D-glucuronic acid was determined by its resistance towards β-D-glucuronidase.     

Orthric Rieske dioxygenases for degrading mixtures of 2,4-dinitrotoluene/naphthalene and 2-amino-4,6-dinitrotoluene/4-amino-2,6-dinitrotoluene

Pollutants are frequently found as mixtures yet it is difficult to engineer enzymes with broad substrate ranges on aromatics. Inspired by the archetypal nitroarene dioxygenase, which shares its electron transport with a salicylate monooxygenase, we have created an innovative and general approach to expand the substrate range of dioxygenase enzymes in a single cell. We have developed here a series of novel, hybrid dioxygenase enzymes that function with a single ferredoxin reductase and ferredoxin that are used to transport two electrons from nicotinamide adenine dinucleotide to the two independent terminal oxygenases. Each independent alpha-oxygenase may then be used simultaneously to create orthric enzymes that degrade mixtures of environmental pollutants. Specifically, we created a hybrid dioxygenase system consisting of naphthalene dioxygenase/dinitrotoluene dioxygenase to simultaneously degrade 2,4-dinitrotoluene and naphthalene (neither enzyme alone had significant activity on both compounds) and dinitrotoluene dioxygenase/nitrobenzene dioxygenase to simultaneously degrade the frequently encountered 2,4,6-trinitrotoluene reduction products 2-amino-4,6-dinitrotoluene and 4-amino-2,6-dinitrotoluene.     

Hypusine, N6-(4-amino-2-hydroxybutyl)-2,6-diaminohexanoic acid,in tissue proteins of mammals

Hypusine, N⁶-(4-amino-2-hydroxybutyl)-2,6-diaminohexanoic acid was isolated from proteins of bovine brain. Its identification was performed by comparison of its behavior in amino acid analysis, paper chromatography and electrophoresis to that of the authentic compound, and by periodic acid-permanganate oxidation which split hypusine into β-alanine and lysine. Hypusine was found in proteins of various organs of rabbits.Formation of hypusine from lysine was demonstrated by the intraperitoneal injection of labeled lysine into a rat and isolation of radioactive hypusine from the animal proteins. This findings indicates a possibility that hypusine is derived from the lysine residue of proteins through attachment of the 4-amino-2-hydroxybutyl moiety to the N⁶-amino radical of lysine.     

Enantioselective actions of 4-amino-3-hydroxybutanoic acid and (3-amino-2-hydroxypropyl)methylphosphinic acid at recombinant GABA(C) receptors

The R- and S-enantiomers of 4-amino-3-hydroxybutanoic acid (GABOB) were full agonists at human recombinant rho1 GABA(C) receptors. Their enantioselectivity (R>S) matched that reported for their agonist actions at GABA(B) receptors, but was the opposite to that reported at GABA(A) receptors (S>R). The corresponding methylphosphinic acid analogues proved to be rho1 GABA(C) receptor antagonists with R(+)-CGP44533 being more potent than S(-)-CGP44532, thus showing the opposite enantioselectivity to the agonists R(-)- and S(+)-GABOB. These studies highlight the different stereochemical requirements for the hydroxy group in these analogues at GABA(A), GABA(B) and GABA(C) receptors.     

Stereoselective synthesis of 2-amino-3-fluoro bicyclo[3.1.0]hexane-2,6-dicarboxylic acid.

(+)-2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740) is a conformationally restricted glutamate analogue that is a potent, selective and orally active group 2 metabotropic glutamate receptor agonist possessing anticonvulsant and anxiolytic properties. Herein, we describe a stereoselective and highly efficient synthesis of its 3-beta fluoro derivative using the Corey-Link methodology to create the amino acid stereogenic center.     

芦笋抗S—（2—氨乙基）—L—半胱氨酸（AEC）变异体的筛选

S-(2-氨乙基)-L-半胱氨酸(AEC)可抑制芦笋愈伤组织的生长,此抑制作用可被赖氨酸或甲硫氨酸部分解除。用0.5mmol/L的AEC进行筛选,得到抗性愈伤组织AR10并再生植株。AR10愈伤组织经一年多的继代培养,在离开选择剂组培继代两代后仍保持对AEC的抗性。抗性系愈伤组织还表现出对2mmol/L的半胱氨酸具交叉抗性,对1mmol/L的赖氨酸加苏氨酸表现部分交叉抗性。AR10再生植株一部分保持对AEC的抗性,而一部分则无抗性。对抗性愈伤组织及其再生植株的氨基酸分析表明,愈伤组织内游离赖氨酸、苏氨酸、甲硫氨酸都有增加,而在再生植株内却发现半胱氨酸和赖氨酸的特异性增加,分别是对照植株的5.4和4.6倍。     

Isolation of 4-(1'-D-ribitylamino)-5-amino-2,6-dihydroxypyrimidine from a riboflavin-adenine-deficient mutant of Bacillus subtilis.

Studies were carried out to determine possible intermediates involved in the biosynthetic pathway of riboflavin, using resting cells of a riboflavin-adenine-deficient mutant, Bacillus subtilis AJ1988. The cells excreted 6,7-dimethyl-8-ribityllumazine, the end product in the biosynthetic pathway, into the incubation medium in large amounts. The addition of glyoxal caused a large accumulation of a green fluorescent compound; an inverse relation was observed between the formation of the lumazine and the concentration of glyoxal. Furthermore, added [2-14C]guanine effectively incorporated into the lumazine and the fluorescent compound in the same specific activity during incubation. The fluorescent compound was isolated, purified, and identified by paper chromatographic, fluorometric, and spectrophotometric analyses. It was proved to be 8-(1'-D-ribityl)lumazine, which appeared to have been formed by a reaction between glyoxal and a possible intermediate in the cells. Accordingly, 4-(1'-D-ribitylamino)-5-amino-2,6-dihydroxypyrimidine was concluded to be an immediate precursor of 6,7-dimethyl-8-ribityllumazine.     

Distribution of ciliatine (2-aminoethylphosphonic acid) and phosphonoalanine (2-amino-3-phosphonopropionic acid) in human tissues

Ciliatine (2-aminoethylphosphonic acid) was detected in the human brain, heart, kidney, liver, intestine, spleen, adrenal glands, and aorta. Phosphonoalanine (2-amino-3-phosphonopropionic acid) was found in the human liver, intestine and spleen. Tissue homogenates were extracted with trichloroacetic acid and a chloroform-methanol mixture. After hydrolysis, each fraction was subfractionated by ion-exchange chromatography and examined by paper chromatography and electrophoresis using a specific ninhydrin-molybdate staining procedure to detect the phosphonic acids. The acids were found bound either to lipid or to protein; no free phosphonic acid was detected.