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Effects of combined exposure to noise and toxic substances--critical review of the literature.

A number of studies have been conducted in recent years investigating the potential effects on various health endpoints of the combination of noise and a variety of different industrial substances. This review indicates that the information available in both animals and humans on this subject is limited particularly with respect to assessing occupational risk. Most studies have focused on auditory effects in animals, although investigations have been performed for other toxicological endpoints. For some substances, notably toluene, the information from animals studies does suggest an interaction but these were performed only at exposure levels to both noise and chemicals which were each individually ototoxic. Single simultaneous exposure to noise and styrene did not result in any enhancement of auditory impairment above that produced by noise or styrene alone. Single simultaneous exposure to noise and carbon monoxide (CO), however, showed some evidence of enhancement of ototoxicity beyond that produced by noise or carbon monoxide alone, although only at high atmospheric concentrations of CO. When 1,3-dinitrobenzene was administered parentally at neurotoxic dose levels with continuous noise exposure, there was an increased severity of effects in the brain stem. Combined exposure to noise and lead and/or cadmium resulted in histopathological heart lesions of undefined severity, a finding which was not observed for either of those agents in isolation. Dermal exposure to dimethylformamide and noise or inhalation exposure to xylene and noise resulted in some biochemical changes in cardiac muscle which were of doubtful toxicological significance. In developing mice, there was evidence that combined exposure to cadmium sulphate and noise caused an increased incidence of external and skeletal malformations but only at dose levels of cadmium which would have induced developmental effects. Overall, for each of these chemicals and endpoints observed there is a suggestion of some interaction with noise exposure. From the data that are currently available, however, inferences cannot be drawn on whether or not interactions would have occurred at lower, more occupationally relevant, levels of exposure. A number of studies have investigated human populations exposed to both noise and industrial chemicals. Due to confounding factors, however, it was concluded that these data were inadequate for assessing the combined effects of noise and chemical exposure on hearing.

Animals↗

Water-miscible organic cosolvents enhance phosphatidylinositol-specific phospholipase C phosphotransferase as well as phosphodiesterase activity.

Phosphatidylinositol-specific phospholipase C (PI-PLC) from Bacillus thuringiensis catalyzes the hydrolysis of phosphatidylinositol (PI) in a Ca(2+)-independent two-step mechanism: (i) an intramolecular phosphotransferase reaction to form inositol 1,2-(cyclic)-phosphate (cIP), followed by (ii) a cyclic phosphodiesterase activity that converts cIP to inositol 1-phosphate (I-1-P). Moderate amounts of water-miscible organic solvents have previously been shown to dramatically enhance the cyclic phosphodiesterase activity, that is, hydrolysis of cIP. Cosolvents [isopropanol (iPrOH), dimethylsufoxide (DMSO), and dimethylformamide (DMF)] also enhance the phosphotransferase activity of PI-PLC toward PI initially presented in vesicles, monomers, or micelles. Although these water-miscible organic cosolvents caused large changes in PI particle size and distribution (monitored with pyrene-labeled PI fluorescence, 31P NMR spectroscopy, gel filtration, and electron microscopy) that differed with the activating solvent, the change in PI substrate structure in different cosolvents was not correlated with the enhanced catalytic efficiency of PI-PLC toward its substrates. PI-PLC stability was decreased in water/organic cosolvent mixtures (e.g., the T(m) for PI-PLC thermal denaturation decreased linearly with added iPrOH). However, the addition of myo-inositol, a water-soluble inhibitor of PI-PLC, helped stabilize the protein. At 30% iPrOH and 4 degrees C (well below the T(m) for PI-PLC in the presence of iPrOH), cosolvent-induced changes in protein secondary structure were minimal. iPrOH and diheptanoylphosphatidylcholine, each of which activates PI-PLC for cIP hydrolysis, exhibited a synergistic effect for cIP hydrolysis that was not observed with PI as substrate. This behavior is consistent with a mechanism for cosolvent activation that involves changes in active site polarity along with small conformational changes involving the barrel rim tryptophan side chains that have little effect on protein secondary structure.

Bacillus thuringiensis↗

A photoreactive competitive inhibitor of the human lysosomal neuraminidase in cultured skin fibroblasts.

A photoreactive, potent, competitive inhibitor of the human lysosomal neuraminidase in cultured skin fibroblasts has been prepared. The starting material, 2,3 dehydro-N-acetyl neuraminic acid methyl ester, was selectively tosylated at the C-9 position with tosyl chloride and subsequently peracetylated with acetic anhydride. The tosyl group was displaced with potassium thio acetate in dimethylformamide at 60 degrees C for 80 min. 4-fluoro-3-nitrophenylazide was incorporated by reaction with the thio acetate product and equimolar sodium methoxide in methanol followed by reacetylation. Base hydrolysis gave the final product, 9-S-(4-azido-2-nitrophenyl)-5-acetamido-2,6 anhydro-2,3,5,9-tetradeoxy-9-thio-D-glycero-D-galacto-non-2-enonic acid (W5). The yields at each step were 50-70%. Competitive inhibition kinetics were observed when W5 was tested with the fibroblast neuraminidase using 4-methylumbelliferyl-N-acetyl-neuraminic acid as substrate giving an apparent Ki of about 10 microM. These results suggest that the terminal hydroxyl group at C-9 may not be important in the recognition and binding of the substrate by the enzyme. Also, the compounds prepared here may be useful as photoaffinity probes or ligands for affinity chromatography for purification.

Affinity Labels↗

Transformation of actin-encapsulating liposomes induced by cytochalasin D.

Liposomes encapsulating actin filaments were prepared by swelling at 0 degrees C lipid film consisting of a mixture of dimyristoyl phosphatidylcholine and cardiolipin (equal amounts by weight) in 100 microM rabbit skeletal muscle actin and 0.5 mM CaCl2 followed by polymerization of actin at 30 degrees C. Liposomes initially assumed either disk or dumbbell shape, but when cytochalasin D was added to the medium surrounding the liposomes, they were found to become spindle shaped. Liposomes containing bovine serum albumin that were given cytochalasin D and actin-containing liposomes that were given dimethylformamide, the solvent for cytochalasin D, did not transform. These results indicated actin-cytochalasin interaction is involved in the transformation process. Falling-ball viscometry and sedimentation analysis of actin solution indicated that cytochalasin cleaved actin filaments and caused depolymerization. The observation of polarized fluorescence of encapsulated actin labeled with acrylodan indicated that the actin filaments in the transformed liposomes aligned along the long axis of the liposomes. Because the actin filaments in the disk- or dumbbell-shaped liposomes formed bundles running along the liposome contour, the transformation was likely to be accompanied by the change in the actin filament arrangement in the liposomes, which was induced by actin-cytochalasin interaction.

Actins↗

Solvent hydrogen-bond network in protein self-assembly: solvation of collagen triple helices in nonaqueous solvents.

Forces between type I collagen triple helices are studied in solvents of varying hydrogen-bonding ability. The swelling of collagen fibers in reconstituted films is controlled by the concentration of soluble polymers that are excluded from the fibers and that compete osmotically with collagen for available solvent. The interaxial spacing between the triple helices as a function of the polymer concentration is measured by x-ray diffraction. Exponential-like changes in the spacing with increasing osmotic stress, qualitatively similar to the forces previously found in aqueous solution, are also seen in formamide and ethylene glycol. These are solvents that, like water, are capable of forming three-dimensional hydrogen-bond networks. In solvents that either cannot form a network or have a greatly impaired ability to form a hydrogen-bonded network, strikingly different behavior is observed. A hard-wall repulsion is seen with collagen solvated by ethanol, 2-propanol, and N,N-dimethylformamide. The spacing between helices hardly changes with increasing polymer concentration until the stress exceeds some threshold where removal of the solvent becomes energetically favorable. No solvation of collagen is observed in dimethoxyethane. In solvents with an intermediate ability to form hydrogen-bonded networks, methanol, 2-methoxyethanol, or N-methylformamide, the change in spacing with polymer concentration is intermediate between exponential-like and hard-wall. These results provide direct evidence that the exponential repulsion observed between collagen helices at 0-8-A surface separations in water is due to the energetic cost associated with perturbing the hydrogen-bonded network of solvent molecules between the collagen surfaces.

Animals↗

Fast wave activity in the rat rhinencephalon: elicitation by the odors of phytochemicals, organic solvents, and a rodent predator.

Recent research has shown that bursts of approximately 20 Hz fast waves are elicited in rhinencephalic cortex in rats by the odors of a number of different organic solvents and of components of the secretions of predators such as the weasel and the fox. We now show that a number of phytochemicals (benzyl alcohol, carvacrol, eucalyptol, and salicylaldehyde) will elicit fast wave bursts of about 20 Hz in the rat pyriform cortex. Additional organic solvents (carbon tetrachloride, chloroform, diethyl ether, 1, 2-dimethoxyethane, n-heptane, mesitylene, methylcyclohexane, and commercial gasoline and kerosene, but not N,N-dimethylformamide or dimethyl sulfoxide) and another component of fox secretions (isopentenylmethyl sulfide) were also effective. Many of these compounds will also elicit fast wave bursts of about 20 Hz in the dentate gyrus. The effectiveness of benzyl alcohol, camphor, carvacrol, eucalyptol, isopentenylmethyl sulfide, 2-propylthietane, salicylaldehyde, toluene, and trimethylthiazoline (all of which elicit rhinencephalic fast waves in rats) in suppressing feeding in various small herbivores suggests that the recording of odor-induced rhinencephalic fast waves may provide an easy means of identifying new antifeedants. We found no evidence that the bursts of 20-Hz activity seen in the rat rhinencephalon were kindling-induced seizure-like reactions of the olfactory brain to the vapors of toxic chemicals.

Aldehydes↗

A synthesis of 3',4'-dideoxykanamycin B.

3',4',-Dideoxykanamycin B, the kanamycin B derivative that is active against resistant bacteria, was prepared from kanamycin B via N-tosylation, 3',4'-O-sulphonylation, 3',4'-unsaturation, and hydrogenation. The unsaturated intermediate was obtained from the 3',4'-di-O-sulphonyl derivatives by the action of sodium iodide in N,N-dimethylformamide; if zinc dust was added in this reaction, aziridine derivatives were formed. Removal of the tosyl group was successfully performed by using sodium in ammonia-ethylamine.

Dibekacin↗

Synthesis of p-nitrobenzyl and p-nitrophenyl 1-thioglycopyranosides.

Reaction of 2,3,4-trio-O-acetyl-alpha-L-fucopyranosyl bromide (1) with thiourea (2), followed by reductive cleavage of the product, gave 2,3,4-tri-O-acetyl-1-thio-beta-L-fucopyranose (4). Reaction of 4 with p-nitrobenzyl bromide followed by O-deacylation yielded p-nitrobenzyl 1-thio-beta-L-fucopyranoside (6). Similar reaction conditions were used for the synthesis of p-nitrobenzyl 1-thio-beta-D-fucopyranoside (11) and 1-thio-alpha-D-mannopyranoside (16). A facile preparation of O-acylated p-nitrophenyl 1-thioglycopyranosides was achieved by condensing the appropriate glycosyl halide with sodium p-nitrobenzenethioxide in N,N-dimethylformamide.

Magnetic Resonance Spectroscopy↗

Synthesis and stereochemistry of 6-deoxy-6-halogeno-D-glucofuranose cyclic phosphates.

1, 2-O-Cyclohexylidene- and 1, 2-O-isopropylidene-alpha-D-glucofuranose react with hexa-alkylphosphorous triamides to give the corresponding 3, 5, 6-phosphites. Treatment of the latter compounds with chlorine and bromine affords 1, 2-substituted 6-deoxy-6-halogeno-alpha-D-glucofuranose 3, 5-phosphorohalogenidates. Replacement of halogen at phsophorus by hydroxyl and amino groups has been investigated. Cyclic phosphorohalogenidates isomerize in N, N-dimethylformamide. The stereochemistry of the compounds investigated was established by using 1H- and 13C-n.m.r. data.

Glucose↗

[Synthesis of 2-acetamido-2-deoxy-4-O-alpha-L-fucopyranosyl-alpha-D-glucopyranose].

Condensation of 2,3,4-tri-O-benzyl-alpha-L-fucopyranosyl bromide with benzyl 2-acetamido-3,6-di-O-benzyl-alpha-D-glucopyranoside in dichloromethane-N,N-dimethylformamide, in the presence of tetraethylammonium bromide, diisopropylethylamine, and molecular sieve (halide ion-catalyzed reaction), gave benzyl 2-acetamido-3,6-di-O-benzyl-2 deoxy-4-O-(2,3,4-tri-O-benzyl-alpha-L-fucopyranosyl)-alpha-D-glucopyranoside in crystalline form in 82% yield. Hydrogenolysis of the benzyl groups gave the title disaccharide, in crystalline form in 90% yield, which was characterized by a crystalline peracetylated alpha-D derivative.

Benzyl Compounds↗

An alternative synthesis of 4-deoxy-4-fluoro-D-glucose and its transport in the human erythrocyte.

Treatment of methyl 4-O-mesy-alpha-D-galactopyranoside with benzyl bromide in N,N-dimethylformamide in the presence of silver oxide yielded methyl 2,3,6-tri-O-benzyl-4-O-mesyl-alpha-D-galactopyranoside which with tert-butylammonium fluoride at reflux underwent nucleophilic displacement to give methyl 2,3,6-tri-O-benzyl-4-deoxy-4-fluoro-alpha-D-glucopyranoside. This compound on hydrogenolysis provided crystalline methyl 4-deoxy-4-fluoro-alpha-D-glucopyranoside (9). The structure of 9 was established by its conversion to the 2,3,6-tri-O-acetyl derivative and by n.m.r. and m.s. analysis. Acid hydrolysis of 9 gave 4-deoxy-4-fluoro-D-glucose (1). A modification of an established synthesis of 4-deoxy-D-xylo-hexose (2) from methyl 2,3,6-tri-O-benzoyl-alpha-D-galactopyranoside is described. A systematic comparison was made of the transport parameters (Kx and Vmax) of D-glucose, 2, and 1 in human erythrocytes. The Kx values observed for the above sugars are: 4.0mM, 4.5mM, and 4.6mM, respectively. These results indicate that O-4 in beta-D-glucopyranose is not involved in hydrogen bonding to the carrier protein associated with the transport of D-glucose in the erythrocyte.

Biological Transport↗

Synthesis of prumycin and related compounds.

Prumycin (1) and related compounds have been synthesized from benzyl 2-(benzyloxycarbonyl)amino-2-deoxy-5,6-O-isopropylidene-beta-D-glucofuranoside (4). Benzoylation of 4, followed by deisopropylidenation, gave benzyl 3-O-benzoyl-2-(benzyloxycarbonyl)amino-2-deoxy-beta-D-glucofuranoside (6), which was converted, via oxidative cleavage at C-5-C-6 and subsequent reduction, into the related benzyl beta-D-xylofuranoside derivative (7). Benzylation of 3-O-benzoyl-2-(benzyloxycarbonyl)-amino-2-deoxy-D-xylopyranose (8), derived from 7 by hydrolysis, afforded the corresponding DERIVATIVES (9,11) of beta-and alpha-D-xylopyranoside, and compound 7 as a minor product. Treatment of benzyl 3-O-benzoyl-2(benzyloxycarbonyl)amino-2-deoxy-4-O-mesyl-beta-D-xylopyranoside (10), formed by mesylation of 9, with sodium azide in N,N-dimethylformamide gave benzyl 4-azido-3-O-benzoyl-2-(benzyloxycarbonyl)amino-2,4-dideoxy-alpha-L-arabinopyranoside (13), which was debenzoylated to compound 14. Selective reduction of the azide group in 14, and condensation of the 4-amine with N-[N-benzyloxycarbonyl)-D-alaninoyloxy]succinimide, gave the corresponding derivative (15) of 1. Reductive removal of the protecting groups of 15 afforded 1. Prumycin analogs were also synthesized from compound 14. Evidence in support of the structures assigned to the new derivatives is presented.

Aminoglycosides↗

Enantiomeric forms of 9-(5-deoxy-beta-erythro-pent-4-enofuranosyl)adenine and a new preparation of 5-deoxy-D-lyxose.

Methyl 5-deoxy-5-iodo-2,3-O-isopropylidene-beta-D-ribofuranoside (3) was obtained in three steps from D-ribose. Exchange of the isopropylidene group for benzoate groups and acetolysis gave 1-O-acetyl-2,3-di-O-benzoyl-5-deoxy-5-iodo-D-ribofuranose which was coupled with 6-benzamidochloromercuripurine by the titanium tetrachloride method to afford the blocked nucleoside. Treatment with 1,5-diazabicyclo[5.4.0]undec-5-ene in N,N-dimethylformamide and removal of the blocking groups have 9-(5-deoxy-beta-D-erythro-pent-4-enofuranosyl)adenine (9). A similar route starting from methyl 5-deoxy-5-iodo-2,3-O-isopropylidene-alpha-D-lyxofuranoside (14) afforded the enantiomeric nucleoside, 9-(5-deoxy-beta-L-erythro-pent-4-enofuranosyl)adenine (20). Methyl 2,3-O-isopropylidene-alpha-D-mannofuranoside was treated with sodium periodate and then with sodium borohydride to give methyl 2,3-O-isopropylidene-alpha-D-lyxofuranoside (11). Acid hydrolysis afforded D-lyxose. Tosylation of 11 gave methyl 2,3-O-isopropylidene-5-O-p-tolylsulfonyl-alpha dp-lyxofuranoside (12) which was converted into 14 with sodium iodide in acetone. Reduction of 12 gave methyl 5-deoxy-2,3-O-isopropylidene-alpha-D-lyxofuranoside which was hydrolyzed to give 5-deoxy-D-lyxose.

Anti-Bacterial Agents↗

A precursor to the beta-pyranosides of 3-amino-3,6-dideoxy-D-mannose (mycosamine).

SN2-type reaction of 3-O-(1-imidazyl)sulfonyl-1,2:5,6-di-O-isopropylidene-alpha-D-gluco furanose with benzoate gave the 3-O-benzoyl-alpha-D-allo derivative 2, which was hydrolysed to give the 5,6-diol 3. Compound 3 was converted into the 6-deoxy-6-iodo derivative 4 which was reduced with tributylstannane, and then position 5 was protected by benzyloxymethylation, to give 3-O-benzoyl-5-O-benzyloxymethyl-6-deoxy-1,2-O-isopropylidene-alpha -D- allofuranose (6). Debenzoylation of 6 gave 7, (1-imidazyl)sulfonylation gave 8, and azide displacement gave 3-azido-5-O-benzyloxymethyl-3,6-dideoxy- 1,2-O-isopropylidene-alpha-D-glucofuranose (9, 85%). Acetolysis of 9 gave 1,2,4-tri-O-acetyl-3-azido-3,6-dideoxy-alpha,beta-D-glucopyranose (10 and 11). Selective hydrolysis of AcO-1 in the mixture of 10 and 11 with hydrazine acetate (----12), followed by conversion into the pyranosyl chloride 13, treatment with N,N-dimethylformamide dimethyl acetal in the presence of tetrabutylammonium bromide, and benzylation gave 3-azido-4-O-benzyl-3,6-dideoxy-1,2-O-(1-methoxyethylidene)-alpha-D -glucopyranose (15). Treatment of 15 with dry acetic acid gave 1,2-di-O-acetyl-3-azido-4-O-benzyl-3,6-dideoxy-beta-D-glucopyranose (16, 86% yield) that was an excellent glycosyl donor in the presence of trimethylsilyl triflate, allowing the synthesis of cyclohexyl 2-O-acetyl-3-azido-4-O-benzyl-3,6-dideoxy-beta-D-glucopyranoside (17, 90%).(ABSTRACT TRUNCATED AT 250 WORDS)

Amphotericin B↗

Positional isomers of thioxylobiose, their synthesis and inducing ability for D-xylan-degrading enzymes in the yeast Cryptococcus albidus.

Isomeric S-linked 2-thioxylobiose 10, 3-thioxylobiose 17, and 4-thioxylobiose 19 were conveniently prepared by SN2 displacement of suitable triflylglycoses with the sodium salt of 2,3,4-tri-O-acetyl-1-thio-beta-D-glucopyranose, either in N,N-dimethylformamide, or in oxolan in the presence of a sodium complexing agent. Allyl 3,5-O-isopropylidene-2-O-trifluoromethanesulfonyl-beta-D-lyxofu ranoside was a convenient electrophilic precursor for 10, which was smoothly obtained after a short sequence of deprotection involving conversion to the 1-propenyl glycoside. 1,2:5,6-Di-O-isopropylidene-3-O-trifluoromethylsulfonyl-alpha-D-++ +allofuranose and 1,2,3-tri-O-benzoyl-4-O-trifluoromethylsulfonyl-beta-L-arabinop yranose were the respective precursors for 17 and 19. 4-Thioxylobiose has a highly stimulatory effect on the synthesis of enzymes of the xylanolytic system in the yeast Cryptococcus albidus when applied to the cells in the presence of the natural disaccharide inducer (1----4)-beta-D-xylobiose.

Carbohydrate Sequence↗

Synthesis of the isomeric trisaccharides, methyl O-alpha-L-fucopyranosyl- (1----3, 4, and 6)-O-(2-acetamido-2-deoxy-beta-D-glucopyranosyl)-(1----3)-beta- D-galactopyranoside.

Benzylation of methyl 3-O-(2-acetamido-4,6-O-benzylidene-2-deoxy-beta-D- glucopyranosyl)-2,4,6-tri-O-benzyl-beta-D-galactopyranoside with benzyl bromide in N,N-dimethylformamide in the presence of sodium hydride afforded methyl 3-O- (2-acetamido-3-O-benzyl-4,6-O-benzylidene-2-deoxy-beta-D-glucopyranosyl) -2,4,6- tri-O-benzyl-beta-D-galactopyranoside (3). Reductive ring-opening of the benzylidene group of 3 gave methyl 3-O-(2-acetamido-3,6-di-O-benzyl-2-deoxy-beta-D- glucopyranosyl)- 2,4,6-tri-O-benzyl-beta-D-galactopyranoside (4). Cleavage of the 4,6-acetal group of 3 with hot, 80% aqueous acetic acid afforded the diol (5). Compounds 3, 4, and 5 were each subjected to halide ion-catalyzed glycosylation with 2,3,4-tri-O-benzyl-alpha-L-fucopyranosyl bromide to produce the corresponding trisaccharide derivatives, which, on catalytic hydrogenation, furnished the title trisaccharides, respectively.

Oligosaccharides↗

Anticoagulant properties of dextranmethylcarboxylate benzylamide sulfate (DMCBSu); a new generation of bioactive functionalized dextran.

Dextranmethylcarboxylate benzylamide sulfate (DMCBSu), a functionalized dextran, exhibits anticoagulant properties. Its synthesis involves three steps: a carboxymethylation with monochloroacetic acid in alkaline water-iso-propanol, a benzylamidification of some of the methylcarboxylate groups with benzylamine in the presence of a water soluble carbodiimide and a partial sulfation of the remaining hydroxyl groups with SO3-pyridine in dimethylformamide. This procedure yields reproducibly DMCBSu with degrees of substitution in methylcarboxylate (MC), benzylamide (B) and sulfate (Su) groups, respectively, up to 1.61, 0.35 and 1.5, each obtained in one step. For a degree of substitution of methylcarboxylate ca. 1, the presence of sulfate groups is absolutely necessary to confer anticoagulant activities to the samples. In addition, the anticoagulant ability is higher for derivatives bearing benzylamide groups. The anticoagulant ability of DMCBSu increases with the degree of sulfation, reaching 20% of heparin activity for a degree of substitution of Su groups about 1.3.

Anticoagulants↗

A simple access to the D-mannosidase inhibitor, 1-deoxymannojirimycin.

Crystalline 1,3,4,5-tetra-O-acetyl-6-bromo-6-deoxy-keto-D-fructose was prepared by reaction of 1,3,4,5-tetra-O-acetyl-D-fructopyranose with triphenylphosphane dibromide in dichloromethane. Subsequent deprotection followed by reaction of the free 6-bromodeoxyfructofuranose with sodium azide in N,N-dimethylformamide furnished the corresponding 6-azidodeoxyketose. Catalytic hydrogenation led to 1-deoxymannojirimycin in 27% overall yield from 1,3,4,5-tetra-O-acetyl-D-fructopyranose. This access is simple, inexpensive, high-yielding and clearly suitable for multigram preparations.

1-Deoxynojirimycin↗