Double-headed acyclo C-nucleoside analogues. Functionalized 1,2-bis-(1,2,4-triazol-3-yl)ethane-1,2-diol

Reaction of L-tartaric acid with thiocarbohydcrazide afforded (1R, 2S)-1,2-bis(4-amino-5-mercapto-1,2,4-triazol-3-yl)-ethane-1,2-diol (3). The functional groups in 3 allowed the construction of fused heterocycles on the 1,2,4-triazole rings, mainly of the 1,2,4-triazolo[3,4-b][1,3,4]thiadiazine type as in 4, 5, 7, 10, 13 and 1,2,4-triazolo[3,4-b][1,3,4]thiadiazole type as in 14.     

A new bacterial sphingophospholipid containing 3-aminopropane-1,2-diol

1. A new sphingophospholipid has been isolated from the bacterial fraction of sheep rumen contents. 2. This new lipid has been characterized as a ceramide phosphate moiety esterified to 3-aminopropane-1,2-diol through the primary alcohol group. 3. Mass spectrometry has shown the intact lipid to contain a vicinal hydroxyl amino grouping, and oxidation with periodate converts it quantitatively into a new phospholipid which is probably ceramide phosphorylglycolaldehyde. 4. The sphingophospholipid contains a mixture of saturated long-chain bases mainly with branched-chain alkyl groups, which are typical of a microbial origin. 5. A Gram-negative bacterium isolated from rumen contents contains about 30% of the new lipid in its phospholipids when grown in pure culture.     

3-Monochloropropane-1,2-diol (alpha-chlorohydrin) disrupts spermatogenesis and causes spermatotoxicity in males of the Egyptian fruit-bat (Rousettus aegyptiacus)

We evaluated the sterilizing effect of 3-monochloropropane-1, 2-diol (3-MCPD) in male Egyptian fruit bats (Rousettus aegyptiacus). We used three groups. One was treated with 70 mg/kg 3-MCPD for 4 days. The second group was treated with 3-MCPD as a bait formulation (known concentration of 3-MCPD mixed with a known amount of food). The third group was untreated controls. We compared the weights of the reproductive organs, histology of the testes, occurrence of spermatogenesis, and the count, motility and abnormalities of epididymal sperm of treated males with those of the untreated control group. 3-MCPD caused significantly decreased weights of reproductive organs, several testicular histological alterations and spermatogenic arrest accompanied by significant decreases in sperm count and motility, and significantly increased number of abnormal sperm. 3-MCPD bait was readily accepted by the animals. 3-MCPD, even in low doses and after limited exposure, disrupted spermatogenesis in males of the Egyptian fruit bat. Our findings have potential value for public health and agricultural authorities, and for vertebrate pest managers. 3-MCPD may have application for control of this pest.     

Bacterial metabolism of propane-1,2-diol

The pathway of propane-1,2-diol metabolism by a species of Flavobacterium able to grow on the diol as the sole source of carbon was influenced by the degree of aeration of the growth medium. Under strongly aerobic conditions the diol was exclusively catabolised to lactaldehyde by an initial diol oxidase, subsequently metabolised to pyruvate and then oxidised to CO₂ by the tricarboxylic acid cyle. Under microaerophilic conditions some propane-1,2-diol was catabolised by the oxidase-initiated pathway, but some diol was alternatively catabolised by an inducible diol dehydrase to propionaldehyde and subsequently reduced to n-propanol as an end product of metabolism.     

Synthesis of 1,2-dipalmitoyloxypropyl-3-(2-trimethylammoniumethyl)phosphinate

The total synthesis of 1,2-dipalmitoyloxypropyl-3-(2-trimethylammoniumethyl)phosphinate, the phosphinate analog of phosphatidylcholine, is described. The phosphinate analog has been essentially prepared by an Arbusov type reaction between 1,2-dipalmitoyl-sn-glycerolbromohydrin and 2-bromoethyl phosphonic acid dimethyl ester for 48 h at 170°C, followed by removal of the methyl ester with sodium iodide and reaction with aqueous trimethylamine to yield the final product. The phosphinate analog of phosphatidylcholine was characterized by elemental analysis, thin-layer chromatography (TLC), IR spectroscopy and phosphonophosphorus determinations.     

Bacterial metabolism of propane-1,2-diol

The pathway of propane-1,2-diol metabolism by a species of Flavobacterium able to grow on the diol as the sole source of carbon was influenced by the degree of aeration of the growth medium. Under strongly aerobic conditions the diol was exclusively catabolised to lactaldehyde by an initial diol oxidase, subsequently metabolised to pyruvate and then oxidised to CO2 by the tricarboxylic acid cycle. Under microaerophilic conditions some propane-1,2-diol was catabolised by the oxidase-initiated pathway, but some diol was alternatively catabolised by an inducible diol dehydrase to propionaldehyde and subsequently reduced to n-propanol as an end product of metabolism.     

Isolation of a bacterium assimilating (R)-3-chloro-1,2-propanediol and production of (S)-3-chloro-1,2-propanediol using microbial resolution

A bacterium capable of assimilating 3-chloro-1,2-propanediol was isolated from soil by enrichment culture. The strain was identified as Alcaligenes sp. by taxonomic studies. The crude extracts of the cells had dehalogenating activities and converted various halohydrins to the corresponding epoxides. 3-Chloro-1,2-propanediol was degraded stereospecifically by the strain, liberating chloride ion. The residual isomer was found to be the (S)-form (99.4% enantiomeric excess). (S)-3-Chloro-1,2-propanediol was obtained from the racemate by use of this strain in 38% yield, and (S)-glycidol (99.4% enantiomeric excess) was subsequently synthesized from the obtained (S)-3-chloro-1,2-propanediol by alkaline treatment.     

Comparative toxicity of (+)-(R)- and (−)-(S)-1,2-dibromo-3-chloropropane

The haloalkane 1,2-dibromo-3-chloropropane (DBCP), an environmental pollutant that was widely used as a soil fumigant, is a carcinogen and a mutagen and displays target-organ toxicity to the testes and the kidneys. Because little is known about effects of stereochemistry on the metabolism and toxicity of halogenated alkyl compounds and because DBCP, which has a chiral center at C-2, may show enantioselectivity in its metabolism and/or toxicities, the optically pure enantiomers of DBCP were tested in vivo in rats for organ toxicity as well as for bacterial mutagenicity. Organ toxicity studies showed that (S)-DBCP was slightly more renal toxic than (R)-DBCP but was not significantly more toxic than the racemate, and that no significant differences were observed in the extents of testicular necrosis and atrophy caused by either enantiomer or the racemate. In contrast, (R)-DBCP was more mutagenic than either (S)-DBCP or the racemate to Salmonella typhimurium (S. typhimurium) strains TA 100 and TA104. However, there was little or no enantioselectivity in glutathione S-transferase (GST)-catalyzed conjugation reactions of glutathione with DBCP based on the lack of selectivity in the rates of disappearance of the enantiomers of DBCP in the presence of glutathione (GSH) and GSTs as monitored by chiral gas chromatography (GC). © 1995 Wiley-Liss, Inc.     

Antiparkinsonian activity of some 9-N-, O-, S- and C-derivatives of 3-methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-1,2-diol

Earlier it was found, that (1R,2R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-1,2-diol (1) possess high antiparkinsonian activity. The N-, O-, S- and C-derivatives at the C-9 position of diol 1 were synthesized in this work. The antiparkinsonian activity of these compounds was studied in MPTP mice models. As a rule, the introduction of substituents containing nitrogen atoms at the C-9 position led to a considerable decrease or loss of antiparkinsonian activity. A derivative of 2-aminoadamantane 8 significantly decreased the locomotor activity time, thus enhancing the symptoms of the parkinsonian syndrome. However the introduction of butyl or propylthio substituents at the C-9 position of diol 1 did not diminish the antiparkinsonian activity comparing to parent compound. This information is important when choosing a route for immobilization of compound 1 to find possible targets.     

Lipase-catalyzed enantioselective acylation of 3-benzyloxypropane-1,2-diol in supercritical carbon dioxide

Lipase-catalyzed acylation of 3-benzyloxypropane-1,2-diol with vinyl acetate as acyl donor using different lipases [porcine pancreas lipase (PPL), Lipase AK “Amano”, Lipase PS “Amano”, and crude enzymes from Trichoderma reesei RUT-C30, Thermoascus thermophilus (NRRL5208), Talaromyces emersonii (NRLL3221)] was studied in supercritical carbon dioxide (scCO₂). In the reactions catalyzed by different lipases different amounts of monoacetate and diacetate products along with minor amounts of cyclic acetals forming from the diol and acetaldehyde were obtained.Application of Lipase AK led to the highest conversion (84.7%) and the highest enantiomeric excess values (ee_monoacetates = 38%, ee_diacetate = 85%). Effect of water content of scCO₂ on the productivity and the enantiomer selectivity of the reactions with Lipase AK was also investigated.     

The importance of 3,4-epoxy-1,2-butanediol and hydroxymethylvinyl ketone in 3-butene-1,2-diol associated mutagenicity

1,2:3,4-Diepoxybutane is hypothesized to be the main intermediate involved in mutagenicity following exposure to low levels of 1,3-butadiene (BD) in mice, while metabolites of 3-butene-1,2-diol (BD-diol) are thought to become involved in both rats and mice at higher exposures. BD-diol is biotransformed to hydroxymethylvinyl ketone (HMVK), a potentially mutagenic metabolite, and 3,4-epoxy-1,2-butanediol (EB-diol), a known mutagen. To determine the relative importance of HMVK and EB-diol in BD-diol associated mutagenesis, we have examined the dosimetry of a HMVK derived DNA adduct, as well as EB-diol derived DNA and hemoglobin adducts, in rodents exposed to BD-diol. We previously demonstrated similarities in the shapes of the dose-response curves for EB-diol derived DNA adducts, hemoglobin adducts, and Hprt mutant frequencies in BD-diol exposed rodents, indicating that EB-diol was involved in the mutagenic response associated with BD-diol exposure. To examine the role of HMVK in BD-diol mutagenicity, a method to quantify the alpha-regioisomer of HMVK derived 1,N(2)-propanodeoxyguanosine (alpha-HMVK-dGuo) was developed. The method involved enzymatic hydrolysis of DNA, HPLC purification, and adduct measurement by liquid chromatography - tandem mass spectrometry. Intra- and inter-experimental variabilities were determined to be 2.3-18.2 and 4.1%, respectively. The limit of detection was approximately 5 fmol of analyte standard injected onto the column or 5 fmol/200 microg DNA. The method was used to analyze liver DNA from control female F344 rats and female F344 rats exposed to 36 ppm BD-diol. In addition, liver samples from female Sprague-Dawley rats exposed to 1000 ppm BD were analyzed. alpha-HMVK-dGuo was not detected in any of the samples analyzed. Several possible explanations exist for the negative results including the possibility that alpha-HMVK-dGuo may be a minor adduct or may be efficiently repaired. Alternatively, HMVK itself may be readily detoxified by glutathione (GSH) conjugation. While experiments must be conducted to understand the exact mechanism(s), these results, in addition to published EB-diol derived adduct dosimetry and existing HMVK derived mercapturic acid data, suggest that EB-diol is primarily responsible for BD-diol induced mutagenicity in rodents.     

Synthesis of novel 3-(alkylcarbamoyl)-2-aryl-1,2-dihydro-6,7-(methylenedioxy)-3H-quinazolin-4-ones as anticonvulsant agents

A series of 3-(alkylcarbamoyl)-2-aryl-1,2-dihydro-6,7-(methylenedioxy)-3H-quinazolin-4-ones, compounds 3-6, were synthesized, and screened as anticonvulsant agents in DBA/2 mice against sound-induced seizure (Table). The new compounds were found to display anticonvulsant properties inferior to those of the known dehydro congeners 1 and 2. The binding affinities of 1-6 at the AMPA and NMDA receptors were also evaluated.     

Anthranilic acid and 3-indolyl-propan-1,2-diol as precursors of photorubin in Saccharomyces

Summary The formation of photorubin, the orange-red pigment produced by Saccharomyces, is due to a photochemical reaction between anthranilic acid and an indole derivative identified with 3-indolyl-propan-1,2-diol. These two compounds are excreted into the medium by strains partly or completely requiring pyridoxine which are grown in the presence of a suboptimal amount of this vitamin. If pyridoxine is added to the growth medium in amounts either sufficient or exceeding the needs of the cells (over 50 g per liter), or if the strain is auxo-autotrophic, a secretion of hypoxanthine occurs.     

Microsomal ring-fission of cis- and trans-acenaphthene-1,2-diol

1. The ring-fission of cis- and trans-acenaphthene-1,2-diol by rat liver microsomes was studied. 2. 1,8-Naphthalic acid was detected and isolated after microsomal incubations of the diols. 3. The accompanying reduction of NAD(+) was followed spectrophotometrically. 4. The optimum pH for the microsomal reaction was 9.4 for the oxidation of the cis-diol and 9.8 for that of the trans-diol. 5. p-Chloromercuribenzoate and 2,4-dichlorophenol inhibited the reaction. 6. Possible mechanisms for the microsomal ring-fission, involving 1,8-naphthalic aldehyde, are discussed.     

Cryopreservation of human platelets with propane-1,2-diol

The preceding papers in this series have described techniques that permit the introduction and removal of propane-1,2-diol (propylene glycol, PG) with human platelets, in concentrations up to 2 M, without producing serious damage. These methods have now been used in attempts to cryopreserve platelets, with assessment of survival by the hypotonic stress response and ADP-induced aggregation. PG concentrations of 0.5, 1.0, 2.0, and 2.5 M and cooling rates between 0.4 and 100 degrees C/min were studied. The maximum response in the hypotonic stress test was no better than 17% and the greatest ADP-induced aggregation was only 6%; these results were obtained with 0.5 M PG, a cooling rate of 14 degrees C/min, and rapid warming (approximately 150 degrees C/min). The failure of PG concentrations greater than 0.5 M to improve survival was unexpected. When cooling was interrupted at progressively lower temperatures and function assessed, it was possible to relate the extent of damage to temperature and then, with the aid of phase diagrams, it was possible to show that, irrespective of the initial concentration of PG, the extent of damage was closely correlated with the concentration of PG produced at the minimum temperature used. It is concluded that the toxicity of PG increases so steeply with the increasing concentration produced by the separation of ice during freezing that this effect is sufficient to counteract the cryoprotective action of this solute for platelets.     

The metabolism of cis- and trans-indane-1,2-diol

1. The metabolism of cis-indane-1,2-diol, trans-indane-1,2-diol, indene epoxide and 2-hydroxyindan-1-one in rats has been studied. The substances were administered to the animals by subcutaneous injection. 2. The urine of the dosed animals was examined for the presence of free and conjugated cis- and trans-dihydrodiols, and for each compound it was possible to isolate both cis and trans forms of indane-1,2-diol from the urine. 3. The urines were also examined by paper chromatography for ketones and two ketonic metabolites were detected in the urine of rats dosed separately with cis-indane-1,2-diol, trans-indane-1,2-diol, 2-hydroxyindan-1-one and indene epoxide. The ketones were provisionally identified as (1-oxoindan-2-yl glucosid)uronic acid and 1-oxoindan-2-yl sulphuric acid. 4. (1-Oxoindan-2-yl glucosid)uronic acid was isolated as the 2,4-dinitrophenylhydrazone from the urine of rats dosed separately with cis-indane-1,2-diol and trans-indane-1,2-diol. 5. Possible mechanisms for the interconversion of cis- and trans-indane-1,2-diol are discussed.