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PubMed1992

Mutagenicity of 2-methylpropene (isobutene) and its epoxide in a modified Salmonella assay for volatile compounds.

The mutagenic properties of 2-methylpropene (MP) and 2-methyl-1,2- epoxypropane (MEP) were investigated in the Salmonella assay. A simple exposure system, consisting of gastight tissue culture flasks, was used. This method has the advantage that the volatile test chemical is present during the entire incubation period and that several concentrations of the investigated compound can be tested on a single day. MP is not mutagenic in strains TA100, TA102 and TA1535, and in the latter strain not even in the presence of metabolizing S9 mix. MEP is mutagenic in all the strains tested, as demonstrated by a clear dose-response relationship. Strain TA1535 seems to be most sensitive to MEP compared with the other bacterial strains studied. For this strain, the mutagenic activity of MEP decreased significantly in the presence of S9 mix, compatible with the epoxide being inactivated by epoxide hydrolase and by glutathione S-transferase, as reported previously. From the present study it can be concluded that the parent compound MP is not mutagenic, but that its primary metabolite MEP is a mutagenic substance. However, very high concentrations are necessary to induce a mutagenic effect and the epoxide is efficiently detoxified by different liver enzymes.

Alkenes↗
PubMed2003

Medical management of secondary hyperparathyroidism in chronic renal failure.

Abnormalities in calcium and phosphorus metabolism are common, and metabolic bone disease develops often in patients with chronic renal failure (CRF). Effective clinical management includes measures to control phosphorus retention and prevent hyperphosphataemia, to maintain serum calcium concentrations within the normal range and to prevent excess parathyroid hormone (PTH) secretion by the judicious use of vitamin D sterols. Certain of these interventions appear to increase the risk of soft tissue and vascular calcification in patients with end-stage renal disease (ESRD), changes that may contribute to the development of cardiovascular disease. Current therapeutic approaches are thus being re-evaluated in an effort to limit these risks. Despite the importance of controlling phosphorus retention and preventing hyperphosphataemia in patients with CRF, current management strategies often are inadequate, particularly in those ingesting diets containing adequate amounts of protein. Results from clinical trials using daily haemodialysis strongly suggest that thrice-weekly haemodialysis regimens are only marginally adequate for achieving weekly phosphorus balance in many patients with ESRD. The safety of large oral doses of calcium as a phosphate-binding agent in patients with ESRD has also been questioned because excess amounts of calcium that are absorbed from the gastrointestinal tract may lead to ongoing calcium retention in those with little or no residual renal function. Arterial calcification and cardiac valve calcification are two serious complications that adversely affect cardiovascular haemodynamics. The use of large, often supraphysiological, doses of calcitriol or other vitamin D sterols to treat secondary hyperparathyroidism may aggravate hypercalcaemia and hyperphosphataemia, further increasing the risk of soft tissue and vascular calcification. Phosphate-binding agents that do not contain calcium, new vitamin D analogues and calcimimetic compounds offer new therapeutic alternatives for managing renal osteodystrophy. The integration of these novel agents into existing treatment regimens may provide safer and more effective methods for controlling secondary hyperparathyroidism and renal bone disease, while limiting the risks of soft tissue and vascular calcification in patients with CRF.

Administration, Oral↗
PubMed1994

Stereostructure of plagiochiline A and conversion of plagiochiline A and stearoylvelutinal into hot-tasting compounds by human saliva.

The stereostructure of plagiochiline A (1) isolated from the liverwort Plagiochila fruticosa has been established by X-ray crystallographic analysis. Plagiochiline A was converted into plagiochilal B (2) and furanoplagiochilal (3) by human saliva, and stearoylvelutinal (4) isolated from the fungus Lactarius vellerus was converted into velleral (5), also by human saliva.

Benzofurans↗
PubMed1985

Teratogenicity and embryolethality of acrolein and structurally related compounds in rats.

Acrolein, a metabolite of the anticancer agent cyclophosphamide, is teratogenic to rats after intraamniotic administration. It is not known whether acrolein or a metabolite of acrolein is responsible for the teratogenicity of this compound. We assessed the teratogenicity and embryolethality of acrolein and five structurally related compounds: acrylic acid, allyl alcohol, glycidol, glyceraldehyde, and propionaldehyde by intraamniotic injections in Sprague-Dawley rats on day 13 of gestation. All compounds tested were significantly embryolethal with at least one concentration of the drug. Acrolein was the most embryolethal of the drugs, causing a significant increase in resorptions with as little as 0.1 micrograms/fetus; the other drugs were embryolethal at doses 100-10,000 times that of acrolein. Acrolein was also the most teratogenic of the drugs tested; a dose as low as 5 micrograms/fetus caused a significant increase in the incidence of fetal malformations. Of the other compounds tested, only glycidol at a dose of 1,000 micrograms/fetus induced a significant number of malformed fetuses compared to control. These results suggest that it is acrolein itself that is responsible for its teratogenicity.

1-Propanol↗
PubMed1979

Inhibition of hepatic lipogenesis by 2-tetradecylglycidic acid.

2-Tetradecylglycidic acid (TDGA), a hypoglycemic agent, has been found to be a very effective inhibitor of de novo fatty acid synthesis by isolated hepatocytes. A comparison was made between the effectiveness of TDGA and 5-(tetradecyloxy)-2-furoic acid (TOFA), a hypolipidemic agent, on the metabolic processes of isolated hepatocytes. These compounds are structurally related and both inhibit fatty acid synthesis; however, they have opposite effects from each other on the oxidation and esterification of fatty acids. TDGA inhibits whereas TOFA stimulates fatty acid oxidation. TDGA stimulates whereas TOFA inhibits fatty acid esterification.

Animals↗
PubMedDate not supplied

Solid-phase synthesis of oxazolidinones by cycloaddition of resin-bound epoxides with isocyanates.

The first solid-phase synthesis of oxazolidinones by cycloaddition of resin-bound epoxides with isocyanates is described. Synthesis of the title compounds was achieved by alkylation of resin-bound carbamates with glycidyl tosylate, followed by cycloaddition of the resulting epoxides with isocyanates at elevated temperature in high yields and purity. Because N-aryloxazolidinones have been known to possess various biological activities, this method is useful from the viewpoint of drug discovery.

Epoxy Compounds↗
PubMed2002

Searching for the second oxidant in the catalytic cycle of cytochrome P450: a theoretical investigation of the iron(III)-hydroperoxo species and its epoxidation pathways.

Iron(III)-hydroperoxo, [Por(CysS)Fe(III)-OOH](-), a key species in the catalytic cycle of cytochrome P450, was recently identified by EPR/ENDOR spectroscopies (Davydov, R.; Makris, T. M.; Kofman, V.; Werst, D. E.; Sligar, S. G.; Hoffman, B. M. J. Am. Chem. Soc. 2001, 123, 1403-1415). It constitutes the last station of the preparative steps of the enzyme before oxidation of an organic compound and is implicated as the second oxidant capable of olefin epoxidation (Vaz, A. D. N.; McGinnity, D. F.; Coon, M. J. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 3555-3560), in addition to the penultimate active species, Compound I (Groves, J. T.; Han, Y.-Z. In Cytochrome P450: Structure, Mechanism and Biochemistry, 2nd ed.; Ortiz de Montellano, P. R., Ed.; Plenum Press: New York, 1995; pp 3-48). In response, we present a density functional study of a model species and its ethylene epoxidation pathways. The study characterizes a variety of properties of iron(III)-hydroperoxo, such as the O-O bonding, the Fe-S bonding, Fe-O and Fe-S stretching frequencies, its electron attachment, and ionization energies. Wherever possible these properties are compared with those of Compound I. The proton affinities for protonation on the proximal and distal oxygen atoms of iron(III)-hydroperoxo, and the effect of the thiolate ligand thereof, are determined. In accordance with previous results (Harris, D. L.; Loew, G. H. J. Am. Chem. Soc. 1998, 120, 8941-8948), iron(III)-hydroperoxo is a strong base (as compared with water), and its distal protonation leads to a barrier-free formation of Compound I. The origins of this barrier-free process are discussed using a valence bond approach. It is shown that the presence of the thiolate is essential for this process, in line with the "push effect" deduced by experimentalists (Sono, M.; Roach, M. P.; Coulter, E. D.; Dawson, J. H. Chem. Rev. 1996, 96, 2841-2887). Finally, four epoxidation pathways of iron(III)-hydroxperoxo are located, in which the species transfers oxygen to ethylene either from the proximal or from the distal sites, in both concerted and stepwise manners. The barriers for the four mechanisms are 37-53 kcal/mol, in comparison with 14 kcal/mol for epoxidation by Compound I. It is therefore concluded that iron(III)-hydroperoxo, as such, cannot be a second oxidant, in line with its significant basicity and poor electron-accepting capability. Possible versions of a second oxidant are discussed.

Catalysis↗
PubMed2002

Electron transfer initiated heterogenerative cascade cyclizations: polyether synthesis under nonacidic conditions.

[reaction: see text] Single-electron oxidation has been employed to initiate heterogenerative cascade cyclization reactions that form polyether compounds under essentially neutral conditions. The reactions proceed through mesolytic benzylic carbon-carbon bond cleavages of homobenzylic ether-derived radical cations followed by intramolecular epoxonium ion formation, leading to further cyclizations. Both oligotetrahydrofuran and tetrahydropyran structures can be prepared by altering substrate topography.

Cyclization↗
PubMedDate not supplied

Ovarian toxicity of 4-vinylcyclohexene and related olefins in B6C3F1 mice: role of diepoxides.

4-Vinylcyclohexene (VCH) is an ovarian toxicant in mice. Studies have established that bioactivation of VCH to epoxides is required for its ovotoxicity, with vinylcyclohexene diepoxide being the most potent epoxide of VCH in terms of follicular depletion. To determine the role of the diepoxide in the ovarian toxicity of VCH and related compounds, a structure-activity study was conducted. Following administration (ip) of VCH for 30 days, a significant depletion of ovarian follicles was observed. No alteration of small ovarian follicle counts occurred following treatment with structural analogues of VCH (vinylcyclohexane, ethylcyclohexene, and cyclohexene) that contain only a single unsaturated site. These VCH analogues were converted to monoepoxides both in vitro and in vivo. In addition, when the monoepoxide forms of the VCH analogues were administered to mice, they were not ovotoxic. These results indicate that vinylcyclohexene diepoxide may be the ultimate ovotoxic metabolite of VCH. A diepoxide was also shown to be critical for butadiene- and isoprene-induced follicular loss. Butadiene monoepoxide, butadiene diepoxide, and isoprene were ovotoxic. In contrast, the monoepoxide, epoxybutane, was not ovotoxic. The ovotoxicity of these compounds correlated with their chemical reactivity as assessed by alkylation of nicotinamide. Vinylcyclohexene diepoxide and butadiene diepoxide had a 3.5- to 10-fold higher chemical reactivity as compared to their monoepoxide precursors and structurally related monoepoxides. Thus, a relationship exists between chemical reactivity and ovotoxicity. Only those compounds which are metabolized to a diepoxide or are a diepoxide were ovotoxic. The formation of these diepoxide metabolites may in turn be linked to the ovarian toxicity and carcinogenicity of these olefins.

Alkenes↗
PubMed2007

Cantharimide dimers from the Chinese blister beetle, Mylabris phalerate PALLAS.

Five cantharidin-related compounds were isolated from the Chinese blister beetle, Mylabris phalerate PALLAS (Meloidae). Their structures were determined based on spectroscopic and chemical evidence. Three of them were identified as cantharimide dimers, which consist of two units of cantharimide combined with a tri-, tetra-, or penta-methylene group.

Animals↗
PubMed1987

A QSAR study of the acute toxicity of some industrial organic chemicals to goldfish. Narcosis, electrophile and proelectrophile mechanisms.

1. A baseline toxicity QSAR model was derived for the 24-h LC50 to the goldfish, Carassius auratus. 2. The QSAR-predicted LC50 values for six epoxide derivatives were 2.8-985 times greater than measured. The excess toxicity of these epoxides and other compounds was ascribed to an electrophile molecular mechanism involving SN2 reaction with sulphydryl and other neucleophile groups present in enzymes and other biological macromolecules. 3. The excess toxicities of allyl alcohol and pentaerythritol triallyl ether were interpreted in terms of proelectrophile mechanisms. For the latter compound, this involves a monooxygenase-mediated free radical proton abstraction to a stable allyl radical. The allyl-free radical can undergo enzymic free radical hydroxylation to afford the corresponding acetal, which on decomposition yields the Michael acceptor electrophile acrolein.

Animals↗
PubMedDate not supplied

Modulation of different stress pathways after styrene and styrene-7,8-oxide exposure in HepG2 cell line and normal human hepatocytes.

Styrene is one of the most important monomers produced worldwide. IARC classified styrene as a possible carcinogen to humans (group 2B). Styrene-7,8-oxide (SO) is the main reactive metabolite of styrene, and it is found to be genotoxic in several in vitro test systems. Styrene and styrene-7,8-oxide (SO) toxicity to HepG2 cells was investigated by evaluating end-points such as heat shock proteins (Hsps), metallothioneins (MT), apoptosis-related proteins, accumulation of styrene within the cells and expression of two isoforms of cytochrome P450. The potential activity of styrene and styrene-7,8-oxide in modulating gene expression was also investigated. The results showed induction of Hsp70, metallothioneins, BclX(S/L) and c-myc expression and a decrease in Bax expression in HepG2 after treatments, confirming that these compounds activated protective mechanisms. Moreover, up-regulation of TGFbeta2 and TGFbetaRIII in HepG2 cells was found after exposure to styrene, while in human primary hepatocytes these genes were down-regulated after both treatments. Finally, it was found that styrene and SO treatments did not induce CYP1A2 and CYP2E1 protein expression. In conclusion, both compounds caused toxic stress in HepG2 cells, with SO being more toxic; in the meantime, a different effect of the two compounds in HepG2 cells and primary human hepatocytes was observed regarding their activity in gene modulation.

Carcinogens↗
PubMed1982

Non-mutagenicity of 2-methyl-2,3-epoxybutane and factors influencing the mutagenicity of 2,3-epoxybutane.

The compound 2,3-epoxybutane (2,3-EB) is a direct mutagen for the base-pair-substitution-sensitive strains TA 1530, TA 1535 and TA 100, in the absence and in the presence of metabolic activation by liver S9-mix. Under the same experimental conditions, the 2-methyl derivative of 2,3-EB was not mutagenic, up to 10 mg per plate. The parent compound (2,3-EB) was more active on strain TA 1530 in the presence of liver S9-mix. This was observed at every epoxide concentration tested. The increase of mutagenicity depended on the S9 concentration, the mix composition and to a small extent on the method utilized.

Animals↗
PubMed1986

The lipoxins: determination of their biosynthesis.

The stereochemistry and double bond geometry of a novel series of leukocyte derived arachidonic acid metabolites, the lipoxins, was determined by comparison to pure unambiguous synthetic standards. The lipoxins were found to be a mixture of four lipoxin A isomers and two lipoxin B isomers. In determining the biosynthesis of these compounds, they were shown to be formed via a tetraene epoxide. In addition, it was shown that all of the lipoxin isomers formed by the incubation of 15-HPETE with human leukocytes were also formed by non enzymatic hydrolysis of this tetraene epoxide.

Arachidonic Acids↗
PubMed1986

Alkylglycidic acids: potential new hypoglycemic agents.

A series of alkylglycidic acid analogues and derivatives were synthesized and tested for their ability to inhibit long-chain fatty acid oxidation in vitro and to lower blood sugar in rats. The extent of inhibition of carnitine acyl transferase, the enzyme at the mitochondrial membrane necessary to transport long-chain fatty acids into the mitochondria for subsequent beta-oxidation, was determined for the series. Structure-activity relationships using in vitro inhibition of [1-14C]palmitic acid oxidation in rat hemidiaphragm muscle indicate that potent activity resides mainly in 2-alkyl (C12-C16) glycidates. Replacement of the oxirane ring with cyclopropyl, thiirane, or other rings diminishes activity, as does substitution of the glycidate ring at the 3-position. In vivo potency in the rat glucose tolerance test roughly parallels the hemidiaphragm results. The lead compound, methyl 2-tetradecylglycidate (8), is a potent hypoglycemic agent following oral administration to several animal species. The hypoglycemic analogues interfere with fatty acid oxidation by specific and irreversible inhibition of mitochondrial carnitine palmitoyl transferase-A.

Animals↗
PubMed2000

Inactivation of cysteine proteases by peptidyl epoxides: characterization of the alkylation sites on the enzyme and the inactivator.

Erythro peptidyl epoxides are selective inactivators of cysteine proteases. The alkylation site, both on the enzyme papain and on the epoxide itself, was characterized. The inactivation of papain with the peptidyl epoxide erythro benzyloxycarbonyl-Phe-Ala-epoxide was followed by total hydrolysis by acid. Mass spectral analysis of the hydrolysate revealed, in addition to the expected amino acids, a unique signal of m/z 209 (MH(+)). Its high-resolution mass spectrum and daughter peak analysis correspond to the product of alkylation on cysteine and the expected fragmentation. A similar MS pattern was obtained for a synthetic model compound corresponding to the expected hydrolysis product. A (13)C NMR analysis of papain inactivated by a specifically (13)C-labelled peptidyl epoxide indicated that the alkylation of the enzyme's cysteine residue occurs on the primary carbon of the epoxide moiety.

Acids↗
PubMed1993

Genotoxic effects of ethylene oxide and propylene oxide in mouse bone marrow cells.

Ethylene oxide and propylene oxide are high-volume reactive alkylating agents used primarily as intermediates in the chemical industry. Studies were undertaken to investigate the ability of these alkylating agents to induce chromosomal aberrations, micronuclei and sister-chromatid exchanges in mouse bone marrow cells. The mice were exposed to these chemicals by intraperitoneal injection. The data show that both compounds are effective in inducing chromosomal alterations. Our studies confirm the findings reported by different investigators that ethylene oxide is more cytotoxic than propylene oxide. This difference is to a large extent due to a faster detoxification of propylene oxide than of ethylene oxide.

Animals↗