The chemistry and biogenesis of the S-containing metabolites of vinyl chloride in rats.

In order to determine whether vinyl chloride yields chloroethylene oxide in vivo, the biogenesis of the various urinary S-containing metabolites in rats has been investigated.N-Acetyl-S-(2-hydroxyethyl)cysteine is a major vinyl chloride metabolite in rats, but according to the method of protective esterification that is used, so either N-acetyl-S-(2-chloroethyl)cysteine or N-acetyl-S-(2-hydroxyethyl)cysteine may be isolated from the body fluids. N-Acetyl-S-vinylcysteine is a second related metabolite. These S-containing vinyl chloride metabolites are not mutagenic in S. typhimurium. Neutral methanol methylates N-acetyl-S-(2-hydroxyethyl)cysteine. N-Acetyl-S-(2-methoxyethyl)cysteine plus N-acetyl-S-vinylcysteine degrade to give the volatile S-(2-methoxyethyl)(prop-1 or 2-enyl)sulphide.Administration of several vinyl chloride metabolites and closely related compounds to rats shows that chloroacetaldehyde and S-(carboxymethyl)cysteine, but not chloroacetic acid, lie on a pathway or pathways connecting vinyl chloride with thiodiglycollic acid. The fact (a) that chloroacetaldehyde affords both thiodiglycollic acid and N-acetyl-S-(2-hydroxyethyl)cysteine in the animal and (b) that S-(carboxymethyl)cysteine has been identified amongst the hydrolytic products from an hepatic extract prepared from vinyl chloride-treated animals is consistent with the formation of chloroacetaldehyde, and with the reaction of chloroethylene oxide or chloroacetaldehyde with glutathione in the presence of a glutathione S-epoxide transferase to give the identified S-containing metabolites.     

Synthesis of kojitetraose and kojipentaose

Kojitriose [α-d-Glcp-(1→2)-α-d-Glcp-(1→2)-d-Glcp], kojitetraose, and koji-pentaose have been synthesised by silver perchlorate-promoted Koenigs-Knorr type condensations, using 3,4,6-tri-O-acetyl-2-O-allyl-β-d-glucopyranosyl chloride and hepta-O-acetyl-β-kojibiosyl chloride as the key intermediates. The synthesis of α-β-Glcp-(1→2)-α-d-Glcp-(1→3)-d-Glcp is also described.     

Bongkrekic acid and atractyloside inhibits chloride channels from mitochondrial membranes of rat heart

The aim of this work was to characterize the effect of bongkrekic acid (BKA), atractyloside (ATR) and carboxyatractyloside (CAT) on single channel properties of chloride channels from mitochondria. Mitochondrial membranes isolated from a rat heart muscle were incorporated into a bilayer lipid membrane (BLM) and single chloride channel currents were measured in 250/50 mM KCl cis/trans solutions. BKA (1-100 μM), ATR and CAT (5-100 μM) inhibited the chloride channels in dose-dependent manner. The inhibitory effect of the BKA, ATR and CAT was pronounced from the trans side of a BLM and it increased with time and at negative voltages (trans-cis). These compounds did not influence the single channel amplitude, but decreased open dwell time of channels. The inhibitory effect of BKA, ATR and CAT on the mitochondrial chloride channel may help to explain some of their cellular and/or subcellular effects.     

Electron-impact mass spectrometry of methyl O-methylglucopyranosiduranamides

6-O-Acetyl-2,4-diazido-3-O-benzyl-2,4-dideoxy-β-D-glucopyranosyl chloride and 2,6-diazido-3,4-di-O-benzyl-2,6-dideoxy-β-D-glucopyranosyl chloride are two valuable building units suitable for the synthesis of α-linked disaccharides containing 2,4-diamino-2,4-dideoxy- or 2,6-diamino-2,6-dideoxy-D-glucose as nonreducing moieties. The glycoside synthesis is accomplished stereoselectively under mild conditions in the presence of silver perchlorate. The α-(1→3)-linked disaccharides 2,4-diacetamido-2,4-dideoxy-3-O-(2,4-diacetamido-2,4-dideoxy-α-D-glucopyranosyl)-D-glucopyranose and 2-acetamido-2-deoxy-3-O-(2,6-diacetamido-2,6-dideoxy-α-D-glucopyranosyl)-D-glucopyranose have been prepared.     

Synthesis of a tetrasaccharide donor corresponding to the O-specific polysaccharide of Shigella dysenteriae type 1

O-(2,4-Di-O-chloroacetyl-α-l-rhamnopyranosyl)-(1 → 2)-O-(3,4,6-tri-O-benzoyl-α-d-galactopyranosyl)-(1 → 3)-O-(2-acetamido-4,6-di-O-acetyl-2-deoxy-α-d-glycopyranosyl)-(1 → 3)-2,4-di-O-benzoyl-α-l-rhamnopyranosyl trichloroacetimidate (1) was synthesized in a stepwise manner, using the following monosaccharide units: 2-(trimethylsilyl)ethyl 2,4-di-O-benzoyl-α-l-rhamnopyranoside, 2-azido-4,6-O-benzylidene-3-O-chloroacetyl-2-deoxy-β-d-glycopyranosyl chloride, methyl 3,4,6-tri-O-benzoyl-2-O-(4-methoxybenzyl)-1-thio-β-d-galactopyranoside, and 2,4-di-O-benzoyl-3-O-chloroacetyl-α-l-rhamnopyranosyl chloride. Compound 1 corresponds to a complete tetrasaccharide repeating unit of the O-specific polysaccharide of the lipopolysaccharide of Shigella dysenteriae type 1.     

Syntheses of some purine nucleosides by the fusion method,by the condensation of acetylated chlorides,and from 1-acetates in the presence of titanium tetrachloride: a comparison

9-(2-Acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-d-glucopyranosyl)-6-benzamidopurine (9) and 6-benzamido-9-(2,3,4,6-tetra-O-acetyl-β-d-glucopyranosyl)purine (11) have been prepared by three synthetic routes: (a) the fusion procedure, (b) direct condensation of 6-benzamido(chloromercuri)purine with the acetylated chloride, or (c) with the chloride formed in situ from the 1-acetate in the presence of titanium tetrachloride. The results obtained are briefly discussed; the direct condensation of the mercuri salt with chlorides proved to be the most convenient.Whereas, in the condensation with acetylated chlorides, only products having the β-d anomeric configuration were isolated, the chloride protected with non-participating groups (benzyl) afforded both anomers. The removal of the benzyl groups should be preceded by hydrolytic cleavage of the benzamido group. A simple procedure for fractionation, on small columns of silica gel, of reaction mixtures obtained in the fusion reactions is described.     

Preparation of an enantiomerically pure, highly porous metalloorganic crystal

We report the synthesis and the structure determination of tris-(4,5-diazo-spiro-bifluorene)ruthenium(II) chloride, a chiral building block whose racemic mixture solution spontaneously resolves and forms two crystalline, enantiomerically pure, porous networks composed exclusively of the Λ or Δ atropisomers. The extended chiral channels are occupied by water molecules (approximately 20% by weight) and the chloride counter-ions.     

N-methyl-2-anilino-6-naphthalenesulfonyl hydrazine (2,6-mansyl hydrazine): A new sensitive fluorometric reagent for carbonyl compounds

An almost quantitative synthesis of N-methyl-2-anilino-6-naphthalenesulfonyl hydrazine (2,6-mansyl hydrazine) from sulfonyl chloride and hydrazinlum hydroxide is described. The 2,6-mansyl chloride was prepared by different methods from 6-hydroxynaphthalene-2-sulfonic acid (overall yield: 69%). The N- and the O-mansylation of suitable compounds (e.g., amines, amino acids, and phenolic steroids) with 2,6-mansyl chloride and the preparation of oxosteroid-2,6-mansyl hydrazones are deseribed, and the derivatives obtained, their uv spectra, and methods for their thin-layer chromatographic separation are compared with the corresponding data for dansylated compounds.     

The chemical synthesis of polysaccharides : Part III. Synthesis of 6-O-α-D-mannopyranosyl-D-mannose and 4-O-α-D-mannopyranosyl-D-mannose. Isolation of A (1→6)-linked D-mannan

When 1,2,3,4-tetra-O-acetyl-α-D-mannopyranose was fused with a catalytic amount of toluene-p-sulphonic acid, 6-O-α-D-mannopyranosyl-D-mannose and 4-O-α-D-mannopyranosyl-D-mannose were isolated after deacetylation of the reaction mixture. No β-D-linked disaccharide was detected in the reaction mixture. When the corresponding β-D-tetra-acetate was fused with zinc chloride as catalyst, higher oligomers were formed, and a D-mannan was isolated and shown to be mainly an α-(1→6)-linked polymer having d.p. of 10. With 5% of zinc chloride, the α-D-tetra-acetate showed oligosaccharide formation, and yielded a smaller proportion of a (1→6)-linked D-mannan.     

Enhancement of divalent anion transport across the human red blood cell membrane by the water-soluble dansyl chloride derivative 2-(N-piperidine)ethylamine-1-naphtyl-5-sulfonylchloride (PENS-Cl)

Sulfate transport across the red cell membrane is enhanced by the newly synthesised, water-soluble and nonpenetrating dansyl chloride derivative 2-(N-piperidine)ethylamine-1-napththyl-5-sulfonylchloride (PENS-Cl). The transport is only enhanced if the potentiating agent 2-(4-aminophenyl-3-sulfonic acid)-6-methylbenzothiazol-7-sulfonic acid (APMB)is present during incubation with PENS-Cl. The enhanced flux is reduced by the anion-transport inhibitor 4,4′-diisothiocyanatodihydrostilbene-2,2′-disulfonate (H₂ DIDS) to about the same low level as in untreated controls. In contrast to dansyl chloride, PENS-Cl does not increase cation leakage from the red cells. The effects of PENS-Cl on sulfate transport resemble those produced by dansyl chloride. However, it can be shown that PENS-Cl only reacts with one subset of sites that are modified by dansyl chloride and involved in bringing about the enhancement of sulfate transport. This subset does not include the sites accessible to dansyl chloride in the absence of APMB. It comprises only a fraction of the sites exposed to dansyl chloride in the presence of APMB. Very little labelling of proteins of the red cell membrane can be seen after exposure of ghosts to the PENS-Cl, while dansyl chloride labels all major proteins.     

Discovery of N-ethylpyridine-2-carboxamide derivatives as a novel scaffold for orally active γ-secretase modulators

Gamma-secretase modulators (GSMs) are promising disease-modifying drugs for Alzheimer’s disease because they can selectively decrease pathogenic amyloid-β42 (Aβ42) levels. Here we report the discovery of orally active N-ethylpyridine-2-carboxamide derivatives as GSMs. The isoindolinone moiety of 5-[8-(benzyloxy)-2-methylimidazo[1,2-a]pyridin-3-yl]-2-ethyl-2,3-dihydro-1H-isoindol-1-one hydrogen chloride (1a) was replaced with a picolinamide moiety. Optimization of the benzyl group significantly improved GSM activity and mouse microsomal stability. 5-{8-[([1,1′-Biphenyl]-4-yl)methoxy]-2-methylimidazo[1,2-a]pyridin-3-yl}-N-ethylpyridine-2-carboxamide hydrogen chloride (1v) potently reduced Aβ42 levels with an IC₅₀ value of 0.091 µM in cultured cells without inhibiting CYP3A4. Moreover, 1v demonstrated a sustained pharmacokinetic profile and significantly reduced brain Aβ42 levels in mice.     

Nanoheterogeneous catalytic hydrogenation of N-, O- or S-heteroaromatic compounds by re-usable aqueous colloidal suspensions of rhodium(0)

The hydrogenation of various nitrogen-, oxygen- or sulfur-heterocyclic aromatic compounds by various surfactant-stabilized aqueous rhodium(0) colloidal suspensions was investigated. The nanocatalysts in the size range of 2.1-2.4 nm have been synthesized by reducing RhCl₃ · 3H₂O with sodium borohydride and were stabilized by highly water soluble N,N-dimethyl-N-cetyl-N-(2-hydroxyethyl)ammonium bromide or chloride salts. The catalytic reactions were performed under mild reaction conditions, namely room temperature and under atmospheric hydrogen pressure. The influence of the bromide or chloride nature of the surfactant counter-ion on the recycling of the aqueous phase containing the Rh(0) particles was studied.     

Pisum sativum stress metabolites: Two cinnamylphenols and a 2′-methoxychalcone

An HPLC study of copper(II) chloride treated Pisum sativum has shown that the cinnamylphenols obtustyrene [E-1-(4-hydroxy-2-methoxybenzyl)-2-phenylethylene] and xenognosin [E-1-(4-hydroxy-2-metboxy-benzyl)-2- (4-hydroxyphenyl)ethylene] as well as the chalcone 4,4′-dihydroxy-2′-methoxychalcone accumulate as de novo metabolites in the stressed plant. This chalcone has not previously been identified from a plant source. The biosynthetic and stress response relationships of these compounds are discussed.     

Synthesis and reactions of some hydrazones of dehydro-l-ascorbic acid

l-threo-2,3-Hexodiulosono-1,4-lactone 2-(3-chlorophenylhydrazone) and 4- (2-acetoxyethylidene)-4-hydroxy-2,3-dioxobutano-1,4-lactone 2-(3-chlorophenylhydrazone) were prepared. The two geometric isomers of the corresponding bis(hydrazone) underwent an intramolecular rearrangement to 1-(3-chlorophenyl)- 3-(l-threo-glycerol-1-yl)-4,5-pyrazoledione 4-(3-chlorophenylhydrazone), which gave a tri-O-acetyl derivative upon acetylation and the anticipated formyl derivative upon periodate oxidation. Oxidation of the bis(hydrazone) with cupric chloride afforded the bicyclic compound 3,6-anhydro-3-C-(3-chlorophenylazo)-l- xylo-2-hexulosono-1,4-lactone 2-(3-chlorophenylhydrazone), whose acetylation afforded the mono-O-acetyl derivative.     

Enumeration of Particle-Bound and Unattached Respiring Bacteria in the Salt Marsh Environment

Proportions of respiring bacteria determined with a 2-(p-iodophenyl)-3-(p-nitrophenyl)-5-phenyl tetrazolium chloride dye-epifluorescent technique were significantly elevated in the 300-μm surface layer of a salt marsh estuary. Almost all the detectably respiring bacteria in the particle-laden surface layer and a significant proportion in subsurface waters were attached to particles.     

Interaction of enantiomeric alkylacyl and diacylglycerophosphocholines with cholesterol in bilayer membranes

The sn-1 and sn-3 isomers of dioleoylglycerophosphocholine form vesicles of the same size as the racemic lipid. Identical permeability coefficients were found for the diffusion of glucose and chloride across bilayer membranes of vesicles consisting of these lipids. Vesicles made of mixtures of enantiomeric or racemic dioleoyllecithin with 30 mol% cholesterol have identical radii. Cholesterol reduces the permeability of bilayers for glucose and chloride irrespective of the steric configuration of the constituent phospholipid. Increasing concentrations of cholesterol (17, 33 and 50 mol%, respectively) broaden the (CH₂)_n signal in the ¹H-NMR-spectra (90 MHz) of unilamellar vesicles containing sn-1, sn-3 or rac alkyloleoylglycerophosphocholine to the same extent. These results indicate that the steric configuration of phospholipids has no gross effect on the arrangement of phospholipids and cholesterol in bilayer membranes.     

Synthèse des 2-acé-tamido-2-désoxy-6-O-α-et β-D-xylopyranosyl-α-D-glucopyranose

2-Acetamido-2- deoxy-6-O-, -xylopyranosyl-O-D-glucopyranose has been synthesized in crystalline form by condensation of 2,3,4-tri-O-acetyl-α-D-xylopyranosyl chloride (1) with benzyl 2-acetamido-3,4-di-O-acetyl-2-deoxy-β-D-glucopyranoside (2), followed by O-deacetylation and catalytic hydrogenation. Condensation of 2 with 2,3,4-tri-O-chlorosulfonyl-β-D-xylopyranosyl chloride, followed by dechlorosulfonylation and acetylation, gave benzyl 2-acetamido-3,4-di-O-acetyl-2-deoxy-6-O-(2,3,4-tri-O-acetyl-α-D-xylopyranosyl)β-D-glucopyranoside in crystalline form. O-Deacetylation, followed by catalytic hydrogenation, gave 2-acetamido-2-deoxy-6-O-α-D-xylopyranosyl-α-D-glucopyranose in crystalline form.     

Isolation and synthesis of trans- and cis-(−)-clovamides and their deoxy analogues from the bark of Dalbergia melanoxylon

N-(3′,4′-Dihydroxy-trans-cinnamoyl)-3-(3,4-dihydroxyphenyl)-L-alanine [(?)-clovamide], the major phenolic metabolite (0.1%) in the bark of Dalbergia melanoxylon, is associated with minor proportions of its cis-isomer, and similar pairs of geometrical isomers of their deoxy analogues N-(4′-hydroxycinnamoyl)-3-(3,4-dihydroxyphenyl)-L-alanine and N-(4′-hydroxycinnamoyl)-3-(4-hydroxyphenyl)-L-alanine. (?)-Trans-clovamide is synthesized by direct condensation of the acid chloride of caffeic acid with L-DOPA. Diagnostic CD spectra of these compounds and ¹³C spectra of (?)-trans- and (?)-cis-clovamides are recorded.     

1,2-O-cyanoalkylidene derivatives of furanoses as 1,2-trans-glycosylating agents

Treatment of acetylated l-arabinofuranose, d-galactofuranose, and d-glucofuranose with trimethylsilyl cyanide in acetonitrile in the presence of stannous chloride gave the respective 1,2-O-(1-cyanoethylidene) derivatives. Triphenyl-methylium perchlorate-catalysed glycosylation of trityl ethers of monosaccharides by the above cyanoethylidene derivatives and by 3,5-di-O-benzoyl-1,2-O-(α-cyanobenzylidene)-β-l-arabinofuranose gave high yields of protected disaccharides containing a 1,2-trans-glycofuranosidic bond.     

Preparation of 1-aryl-2-(benzylthio)-(1,2-dideoxy-d-glycero-β-l-gluco-heptofurano)[1,2-d]-2-imidazolines,and new,acyclic C-nucleosides of the imidazole

The reaction of 1-aryl-(1,2-dideoxy-d-glycero-β-l-gluco-heptofurano)[1,2-d]imidazolidine-2-thiones with benzyl chloride and an equivalent amount of sodium hydrogencarbonate yields 1-aryl-2-(benzylthio)-(1,2-dideoxy-d-glycero-β-l-gluco-heptofurano)[1,2-d]-2-imidazolines (2). If the reaction is carried out in the absence of sodium hydrogencarbonate, the 1-aryl-2-(benzylthio)-4-(d-galacto-pentitol-1-yl)imidazoles are obtained. These compounds are also obtained by acid-catalyzed isomerization of compounds 2.