The synthesis of diastereomeric epoxy-(beta-D-glucopyranosyl)ethanes and 1,2-epoxy-3-(beta-D-glucopyranosyl)propanes, as irreversible inhibitors of beta-D-glucosidase.
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The synthesis and structure-activity relationship study of a series of 1-indol-1-yl-3-phenoxypropan-2-one inhibitors of cytosolic phospholipase A(2)alpha (cPLA(2)alpha) are described. The compounds were evaluated in a vesicle assay with isolated cPLA(2)alpha and in cellular assays with intact human platelets. Systematic variation led to 3-methylhydrogen 1-[3-(4-decyloxyphenoxy)-2-oxopropyl]indole-3,5-dicarboxylate (57), which revealed the highest activity against the isolated enzyme. With an IC(50) value of 4.3 nM in this assay, it is one of the most potent in vitro cPLA(2)alpha inhibitors known today.
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Repeated inhalation exposure and 1-generation reproduction studies have been conducted in the rat to address the adequacy of the 10 ppm occupational exposure limit established for 1,2,3-trichloropropane (TriCP). Groups of 5 rats per sex were exposed for 6 h/d, 5 d/wk up to 4 wk to target TriCP concentrations of 0-900 ppm. Nine of 10 rats died after a single exposure at 900 ppm. Additional deaths were seen in the 300 (1 death) and 600 (3 deaths) ppm test groups. Mean body weights for all TriCP-treated groups were lower than control values. Liver weights were increased in animals of both sexes at 600 ppm and lower. For females ovary weights for the 300 and 600 ppm groups and spleen weights for the 300 ppm group were lower than those of controls. Males exhibited decreased testes weights only at the 600 ppm TriCP level (not evaluated at 900 ppm). Results of a 13-wk exposure, 6 h/d, 5 d/wk of 15 rats/sex.group to TriCP target vapor concentrations of 5, 15, or 50 ppm also resulted in liver weight increases at all test levels. Histopathologic examination showed hepatocellular hypertrophy in male rats at all TriCP levels. Other microscopic findings related to treatment in rats exposed to 15 ppm and to 5 ppm TriCP included lung hyperplasia (both sexes) and splenic extramedullary hematopoiesis (females only) and parallel observed organ weight increases. No treatment-related deaths were observed in this study, nor were there apparent effects on the hematology or clinical chemistries. Group mean body weights at 50 ppm (both sexes) and 15 ppm (females only) TriCP were reduced when compared to controls. In a 13-wk follow-up study in rats at 0, 0.5, and 1.5 ppm TriCP, no gross or microscopic findings related to treatment were found. Groups of 10 male and 20 female rats were exposed 6 h/d, 5 d/wk to 0, 5, or 15 ppm TriCP vapor during premating and mating. Females also were exposed during gestation. Low mating performance was observed in all groups of female rats including the controls, although fewer females in the 15-ppm group mated than in other study groups. Mating and fertility indices of male rats in both treated and control groups were generally low. All measured progeny indices appeared unaffected by treatment. A follow-up study of the same design was conducted at levels of 0, 0.5, and 1.5 ppm TriCP.(ABSTRACT TRUNCATED AT 250 WORDS)
Comparative subchronic and reproductive toxicity studies by inhalation exposure were conducted with 1,2,2,3-tetrachloropropane (TECP) and 1,1,2,2,3-pentachloropropane (PCP). Groups of 5 male and 5 female CD rats were exposed 6 h/d, 5 d/wk for 4 wk to either TECP or PCP at target concentrations of 0, 100, 300, 600, or 900 ppm (single exposure only). Deaths occurred at and above 300 ppm PCP and 600 ppm TECP. Significant irritation of mucosal tissue was attributed to vapors of TECP and PCP. Lower group mean body weights of surviving male rats of all groups were observed after 4 wk of exposure to TECP. Liver, kidney, and ovary weights were affected by PCP treatment. Groups of 15 male and 15 female CD rats were exposed to target vapors of 0-50 ppm TECP or PCP for 6 h/d, 5 d/wk for 13 wk. Irritation about the nose and eyes was observed at all TECP, but not with PCP, test levels. Liver weights were increased at and above 5 ppm in all groups of TECP-treated males. Kidney weights were also elevated in male rats at 15 and 50 ppm PCP and females from the 50 ppm PCP group. Degenerative changes in these two corresponding tissues were seen at and above 5 ppm TECP and PCP. A treatment level of 1.5 ppm TECP or PCP was without systemic effect clinically or pathologically. Groups of 10 male and 20 female CD rats were exposed 6 h/d, 5 d/wk for a premating, mating, or gestation (F only) period to target levels of 0, 5, or 15 ppm TECP or PCP. No treatment-related effects were seen in the PCP study. While mating performance overall was poor in the TECP study, female mating performance of the 15 ppm TECP-exposed group appeared lower than control. In a follow-up study with TECP using the same study design, no effects on female or male fertility or fecundity or on offspring were seen up to 1.5 ppm TECP.
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We have developed a temperature controlled specimen stage on the existing jet-freezing apparatus, in order to quench samples from elevated temperatures up to 330 K. We have shown that the phase transition both from the liquid-crystalline to solid phase for pure phosphatidylcholines and from hexagonal II to lamellar phase for phosphatidylethanolamine/4% egg phosphatidic acid is prevented. Moreover, cooling rates exceeding 10,000 K s-1 were recorded indicative of ultra-rapid freezing capacity. Cryoprotectants can be omitted, since phase separation due to ice crystal growth does not occur.
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