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PubMed1997

Evaluation of the mutagenic, cytotoxic, and antitumor potential of triptolide, a highly oxygenated diterpene isolated from Tripterygium wilfordii.

Triptolide, a highly oxygenated diterpene isolated from Tripterygium wilfordii Hook f. (Celastraceae), has been shown to demonstrate potent antileukemic activity in rodent models at remarkably low treatment doses. A variety of other physiological responses are known to be mediated by this compound, including immunosuppressive and antifertility effects. We currently report that triptolide was not mutagenic toward Salmonella typhimurium strain TM677, either in the presence or absence of a metabolic activating system. Relatively potent but non-specific cytotoxicity was observed with a panel of cultured mammalian cell lines, and modest antitumor activity was observed when an i.p. dose of 25 microg was administered three times weekly to athymic mice carrying human breast tumors. Treatment regimens involving higher doses of triptolide (e.g. 50 microg/mouse three times weekly) were lethal.

Animals↗
PubMed1950

The sterilization of bacteriological media and other fluids with ethylene oxide.

Ethylene oxide is an effective sterilizing agent for bacteriological broths, milk, and serum. A short time after it has exerted its sterilizing effect, the treated fluids again become capable of supporting bacterial growth. Ethylene oxide has been shown to destroy a number of aerobic Gram-positive and Gram-negative organisms, aerobic and anaerobic spore-forming bacilli, fungi, and vaccinia virus. No organisms have been encountered which withstand its action. The quantity of ethylene oxide necessary for sterilization depends to some degree on the character of the medium sterilized. None of the materials tested required more than 1 volume per cent of liquid ethylene oxide. Ethylene oxide is highly reactive chemically, and its reactions with many of the components of complex biological fluids cannot be fully anticipated. Regardless of the chemical changes produced, ethylene oxide did not permanently alter the essential qualities of the growth factors in broth and milk which are required by fastidious organisms such as group A streptococci and others. However, its effect on the biological activity of any particular organic compound should be assayed before it can be assumed not to have a deleterious effect. The sterilization of media by ethylene oxide is accompanied by a rise in pH. Fluids which have a relatively high initial pH may require adjustment with sterile acid to return them to the optimal pH for bacterial growth. A mixture of ethylene oxide and broth was toxic to mice for 6 hours after admixture. Toxicity disappeared on incubating the mixture longer, and no residual toxicity could be demonstrated after 6 hours, even on repeated intraperitoneal inoculations. As a means of sterilizing bacteriological media and other biological fluids, ethylene oxide deserves consideration when heat and filtration cannot be used.

Animals↗
PubMed1978

Comparative aspects of pesticide metabolism in plants and animals.

Pesticide chemicals are an important component of modern agriculture. Through their use, plants and animals are exposed to pesticides directly and indirectly from transport through soil, water, and other environmental components. Pesticide chemicals which are absorbed by plants and animals undergo extensive biotransformation. Lipophilic compounds are converted to polar metabolites through a variety of microsomal and extramicrosomal reactions in plants and animals. Generally, biotransformations are qualitatively similar in both systems. However, there are important quantitative rate differences in metabolism which often determine the balance between activation and deactivation of a pesticide. Furthermore, there are qualitative differences in conjugative mechanisms in plants and animals. Animals through an efficient excretory system eliminate transformation products via the urine and feces. Since efficient excretory systems are absent in plants, terminal degradation products are stored as conjugates and/or derivatives which may be incorporated into the plants themselves. Metabolic transformations of selected pesticides illustrating various types of reactions in plants and animals are discussed.

Animals↗
PubMed1993

Bacterial and mammalian cell mutagenicity of four optically active bay-region 10,11-diol-8,9-epoxides of the nitrogen heterocycle dibenz[a,h]acridine.

The mutagenic activities of the enantiomers of the diastereomeric pair of bay-region 10,11-diol-8,9-epoxides of dibenz[a,h]acridine (DB[a,h]ACR) were evaluated in histidine-dependent strains of Salmonella typhimurium and in cultured Chinese hamster V79 cells. In strains TA98 and TA100 of S.typhimurium, the (-)-[8S,9R,10R,11S] diol-epoxide was the most mutagenic compound, inducing 1200 and 6900 His+ revertants/nmol respectively. The mutagenic activity of each of the remaining three isomers was essentially independent of the bacterial strain used and had 14-72% of the activity of the [S,R,R,S] isomer. However, in Chinese hamster V79 cells, the (+)-[8R,9S,10S,11R] diol-epoxide was the most mutagenic compound (68 8-azaguanine resistant variants/nmol/10(5) cells), inducing from 2 to 11 times as many mutations as the other three isomers. These results are analogous to previous studies with the bay-region diol-epoxides of other polycyclic hydrocarbons in that the isomer with [R,S,S,R] absolute configuration has had variable activity in the bacterial assays, but has generally been the most active in the mammalian cells. Furthermore, this isomer has almost always been highly tumorigenic in the mouse.

Acridines↗
PubMed2001

Chemical synthesis and biological evaluation of cis- and trans-12,13-cyclopropyl and 12,13-cyclobutyl epothilones and related pyridine side chain analogues.

The design, chemical synthesis, and biological evaluation of a series of cyclopropyl and cyclobutyl epothilone analogues (3-12, Figure 1) are described. The synthetic strategies toward these epothilones involved a Nozaki-Hiyama-Kishi coupling to form the C15-C16 carbon-carbon bond, an aldol reaction to construct the C6-C7 carbon-carbon bond, and a Yamaguchi macrolactonization to complete the required skeletal framework. Biological studies with the synthesized compounds led to the identification of epothilone analogues 3, 4, 7, 8, 9, and 11 as potent tubulin polymerization promoters and cytotoxic agents with (12R,13S,15S)-cyclopropyl 5-methylpyridine epothilone A (11) as the most powerful compound whose potencies (e.g. IC(50) = 0.6 nM against the 1A9 ovarian carcinoma cell line) approach those of epothilone B. These investigations led to a number of important structure-activity relationships, including the conclusion that neither the epoxide nor the stereochemistry at C12 are essential, while the stereochemistry at both C13 and C15 are crucial for biological activity. These studies also confirmed the importance of both the cyclopropyl and 5-methylpyridine moieties in conferring potent and potentially clinically useful biological properties to the epothilone scaffold.

Antineoplastic Agents↗
PubMed2006

Inhibitors of cysteine proteases.

The roles of cysteine proteases (CP) as protein degrading and protein processing enzymes both in physiological and pathological processes of mammals are well known. Furthermore, the key roles of CP;s in the life cycles of infectious agents like protozoa and viruses turn them into new important targets for anti-infective drugs. Thus, the effective inhibition of pathologically relevant cysteine proteases has raised increasing interest in drug development. One strategy to create CP inhibitors is the use of electrophilic moieties, which covalently bind to the cysteine residue of the active site of the target protease. In a previous approach we have selected the aziridine-2,3-dicarboxylic acid as weak electrophilic inhibitor fragment. In order to achieve effective enzyme inhibition this electrophile was incorporated into peptidic or peptidomimetic sequences addressing the substrate binding sites of the protease. High selectivity could be obtained with compounds, which bind into both the primed and non-primed substrate binding pockets. In a second approach the alpha,beta-unsaturated ketone of the well-known diuretic drug ethacrynic acid was found to be another appropriate electrophilic moiety. Derivatives thereof turned out to be new non-peptidic CP inhibitors. Results of inhibition assays obtained with these two inhibitor series on various proteases of human, protozoan, and viral origin, theoretical studies to investigate binding modes and inhibition mechanisms, and structure-activity relationships are presented. Furthermore, the results of in vitro assays on respective pathogens as well as the results of first toxicity studies are summarized.

Animals↗
PubMed1976

Binding of K- and non-K-region arene oxides and phenols of polycyclic hydrocarbons to polyguanylic acid.

Arene oxide derivatives of carcinogenic polycyclic hydrocarbons have been postulated as the reactive intermediates responsible for the in vivo binding of the parent hydrocarbon to cellular nucleic acids. In this study the reaction of 12 different K- and non-K-region arene oxides and 7 benzo(a)pyrene phenols with polyguanylic acid in aqueous acetone solutions has been investigated. The extent of binding of the polycyclic hydrocarbon was monitored by changes in the ultraviolet absorption and fluorescence spectra of the reisolated polyguanylic acid. The most reactive compound was the K-region arene oxide of 7,12-dimethylbenz(a)anthracene. A lower but significant level of binding was detected with the K-region arene oxides of benz(a)anthracene, benzo(a)pyrene, and 3-methylcholanthrene. Very low or negligible binding was detected with the K-region arene oxides of pyrene and phenanthrene; the non-K-region arene oxides of benzo(a)pyrene, phenanthrene, and naphthalene; and all of the benzo(a)pyrene phenols. Significant differences in the fluorescence spectra of polyguanylic acid modified with three different benzo(a)-pyrene arene oxides were observed.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1995

Inhibition of 2,3-oxidosqualene cyclase and sterol biosynthesis by 10- and 19-azasqualene derivatives.

The inhibition of 2,3-oxidosqualene-lanosterol cyclase (EC 5.4.99.7) (OSC) by new azasqualene derivatives, mimicking the proC-8 and proC-20 carbocationic high-energy intermediates of the cyclization of 2,3-oxidosqualene to lanosterol, was studied using pig liver microsomes, partially purified preparations of OSC, and yeast microsomes. The azasqualene derivatives tested were: 6E- and 6Z-10aza-10,11-dihydrosqualene-2,3-epoxide 17 and 18, 19-aza-18,19,22,23-tetrahydrosqualene-2,3-epoxide 19 and its corresponding N-oxide 20, and 19-aza-18,19,22,23-tetrahydrosqualene 21. The compounds 17 and 19 (i.e. the derivatives bearing the 2,3-epoxide ring and the same geometrical configuration as the OSC substrate) were effective inhibitors, as shown by the Ki obtained using partially purified OSC: 2.67 microM and 2.14 microM, respectively. Compound 18, having an incorrect configuration and the 19-aza derivative 21, lacking the 2,3-epoxide ring, were poor inhibitors, with IC50 of 44 microM and 70 microM, respectively. Compound 21 was a competitive inhibitor of OSC, whereas 17 and 19 were noncompetitive inhibitors, and showed a biphasic time-dependent inactivation of OSC, their apparent binding constants being 250 microM and 213 microM, respectively. The inhibition of sterol biosynthesis was studied using human hepatoma HepG2 cells. The incorporation of [14C] acetate in the C27 sterols was reduced by 50% by 0.55 microM 17, 0.22 microM 19, and 0.45 microM 21, whereas 2 microM 18 did not affect sterol biosynthesis. In the presence of 17, 19 and 21, only the intermediate metabolites 2,3-oxidosqualene and 2,3,22,23-dioxidosqualene accumulated, demonstrating a very specific inhibition of OSC.

Animals↗
PubMed2006

Enantioselective formation and ring-opening of epoxides catalysed by halohydrin dehalogenases.

Halohydrin dehalogenases catalyse the conversion of vicinal halohydrins into their corresponding epoxides, while releasing halide ions. They can be found in several bacteria that use halogenated alcohols or compounds that are degraded via halohydrins as a carbon source for growth. Biochemical and structural studies have shown that halohydrin dehalogenases are evolutionarily and mechanistically related to enzymes of the SDR (short-chain dehydrogenase/reductase) superfamily. In the reverse reaction, which is epoxide-ring opening, different nucleophiles can be accepted, including azide, nitrite and cyanide. This remarkable catalytic promiscuity allows the enzymatic production of a broad range of beta-substituted alcohols from epoxides. In these oxirane-ring-opening reactions, the halohydrin dehalogenase from Agrobacterium radiobacter displays high enantioselectivity, making it possible to use the enzyme for the preparation of enantiopure building blocks for fine chemicals.

Catalysis↗
PubMed1994

Assay of the antiangiogenic compound TNP-470, and one of its metabolites, AGM-1883, by reversed-phase high-performance liquid chromatography in plasma.

This paper describes a reversed-phase, high-performance liquid chromatographic (HPLC) method for the isolation, detection, and quantification of TNP-470 (I) and one of its active metabolites, AGM-1883 (II), from plasma. These compounds are initially extracted from plasma with an organic solvent and then separated from one another on a C18 column. Those fractions eluting from the C18 column and containing either I or II are then derivatized through their epoxide moieties with sodium 8-quinolinethiolate (SQT). This derivatization produces fluorescent species that are isolated and quantified by a second reversed-phase HPLC analysis. The assay yields a lower limit of reliable quantification of 2.5 ng/ml and is linear to a concentration at least as high as 160 ng/ml. The inter-assay percent coefficient of variation is less than 18%.

Acetamides↗
PubMedDate not supplied

Oxidative metabolites of 7,12-dimethylbenz[a]anthracene. Further investigation of the K-region epoxide.

Metabolism of 7,12-dimethylbenz[a]anthracene in rat liver 10,000 g supernatant fraction has been examined by combined gas chromatography-mass spectrometry subsequent to high-pressure liquid-chromatographic separation of the incubation mixture. In addition to the mono-, di-, and trihydroxylated oxidative metabolites usually associated with the biotransformation of polycyclic aromatic hydrocarbons, we observed the formation of a methanolysis product from the K-region epoxide intermediate during the workup procedure. The identification of this compound provides a direct evidence for the presence of the K-region epoxide in the metabolism mixture, and it serves as a convenient means to assay for this metabolite. Moreover, we detected the methanolysis derivative only from the K-region epoxide but none from the non-K-region counterparts. This finding suggests that the non-K-region epoxides undergo facile enzymatic and nonenzymatic hydrolysis and/or rearrangement reactions as soon as they are produced. On the other hand, the K-region epoxide possesses greater stability. It can remain longer in a metabolism mixture and react with methanol subsequently.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1981

Anticonvulsant toxicity in vitro: possible role of arene oxides.

Human lymphocytes incubated with a mouse hepatic microsomal drug metabolizing system were used to study the cytotoxicity of four anticonvulsants. In vitro toxicity assessed by trypan blue dye exclusion was significantly greater for compounds with relatively high clinical toxicity (mephenytoin and phenacemide) than those with only rare cytotoxic complications (phenytoin and phenobarbital). No toxicity occurred in the absence of microsomes and toxicity was enhanced by inhibitors of epoxide hydrolase suggesting that the cytotoxicity of the drugs may result from arene oxide metabolites. In vivo, the covalent binding of such metabolites to cell macromolecules could lead to cell death and, by acting as haptens, to secondary hypersensitivity reactions. The method may be useful in assessing the potential of a drug for toxicity, the mechanism of cell damage and individual differences in cell defenses within the human population.

Acetaminophen↗
PubMed1980

Pharmacokinetics of carbamazepine in the dog.

1. The pharmacokinetics of carbamazepine was studied in dogs after oral administration of two pharmaceutical preparations. Adsorption was rapid, however, the drug was much better absorbed from a liquid preparation than from tablets. Plasma concentrations declined with an elimination half-life of 1.5 hr. Carbamazepine-10,11-epoxide, which is equipotent with carbamazepine as an anticonvulsant, was rapidly formed and reached plasma concentrations higher than those of the mother compound. The concentrations of the epoxide remained high as long as plasma concentrations of carbamazepine were above 2--4 nmole/ml, then they fell with an average half-life of 2.2 hr. 2. During continued treatment with daily doses of 0.34--0.38 mmole/kg carbamazepine, plasma concentrations showed a pronounced and progressive decline from Day 2 which is considered as the result of induction of microsomal liver enzymes. 3. Carbamazepine and the epoxide pass into CSF at a rate comparable to that of phenobarbital or barbital and primidone, respectively. 4. Binding to serum proteins was about 70% for carbamazepine and 40% for the epoxide in dog serum; slightly higher values were found for human serum.

Animals↗
PubMed1976

External yeast beta-fructosidase. Affinity labeling of the active site.

Conduritol-B-epoxide, a compound structurally related to the substrates of external yeast beta-fructosidase (beta-D-fructofuranoside fructohydrolase, EC 3.2.1.26), is an active-site directed inhibitor of this enzyme. The inactivation is irreversible and first-order with respect to time and inhibitor concentration. From the kinetic data obtained, it is concluded that one molecule of inhibitor reacts with one molecule of the enzyme causing inactivation. The inactivation is prevented by the presence of substrates. The pH-dependence of inactivation shows two dissociating groups in the enzyme with pKa values 3.05 and 6.8 being involved in the inactivation process. A carboxylate at the active site with pKa 3.05 is suggested to be the reactive group with conduritol-B-epoxide.

Affinity Labels↗
PubMed1999

Methods for biological monitoring of propylene oxide exposure in Fischer 344 rats.

Propylene oxide (PO) is used as an intermediate in the chemical industry. Human exposure to PO may occur in the work place. Propylene, an important industrial chemical and a component of, for example, car exhausts and cigarette smoke, is another source of PO exposure. Once taken up in the organism, this epoxide alkylates macromolecules, such as haemoglobin and DNA. The aim of the present investigation was to compare two methods for determination of in vivo dose, the steady state concentration of PO in blood of exposed rats and the level of haemoglobin adducts. Male Fischer 344 rats were exposed for 4 weeks (6 h/day, 5 days/week) to PO at a mean atmospheric concentration of 500 ppm (19.9 micromol/l). Immediately after the last exposure blood was collected in order to determine the steady state concentration of PO. Free PO was measured in blood samples of three animals by means of a head space method to be 37 +/- 2 micromol/l blood (mean +/- S.D.). Blood samples were also harvested for the measurement of haemoglobin adducts. N-2-Hydroxypropyl adducts with N-terminal valine in haemoglobin were quantified using the N-alkyl Edman method with globin containing adducts of deuterium-substituted PO as an internal standard and N-D,L-2-hydroxypropyl-Val-Leu-anilide as a reference compound. Tandem mass spectrometry was used for adduct quantification. The adduct levels were < 0.02 and 77.7 +/- 4.7 nmol/g globin (mean +/- S.D.) in control animals (n = 7) and in exposed animals (n = 34), respectively. The adduct levels expected at the end of exposure were calculated to be 71.7 +/- 4.1 nmol/g globin (mean +/- S.D.) using the measured steady state concentration of PO in blood and taking into account the growth of animals, the life span of erythrocytes, the exposure conditions and the second order rate constant for adduct formation. The good agreement between the estimated and measured adduct levels indicates that both end-points investigated are suitable for biological monitoring.

Animals↗
PubMed2000

DNA binding and alkylation by the "left half" of azinomycin B.

Azinomycin B (also known as carzinophilin A) contains two electrophilic functional groups-an epoxide and an aziridine residue-that react with nucleophilic sites in duplex DNA to form cross-links at 5'-dGNT and 5'-dGNC sequences. Although the aziridine residue of azinomycin is undoubtedly required for cross-link formation, analogues containing an intact epoxide group but no aziridine residue retain significant biological activity. Azinomycin epoxide analogues (e.g., 5 and 6) are of interest due to their potent biological activity and because there is evidence that azinomycin may decompose in vivo to yield such compounds. To investigate the chemical events underlying the toxicity of azinomycin epoxides, DNA binding and alkylation by synthetic analogues of azinomycin B (6, 8, and 9) that comprise the naphthalene-containing "left half" of the antibiotic have been investigated. The epoxide-containing analogue of azinomycin (6) efficiently alkylates guanosine residues in duplex DNA. DNA alkylation by 6 is facilitated by noncovalent binding of the compound to the double helix. The results of UV-vis absorbance, fluorescence spectroscopy, DNA winding, viscometry, and equilibrium dialysis experiments indicate that the naphthalene group of azinomycin binds to DNA via intercalation. Equilibrium dialysis experiments provide an estimated binding constant of (1.3 +/- 0.3) x 10(3) M(-)(1) for the association of a nonalkylating azinomycin analogue (9) with duplex DNA. The DNA-binding and alkylating properties of the azinomycin epoxide 6 provide a basis for understanding the cytotoxicity of azinomycin analogues which contain an epoxide residue but no aziridine group and may provide insight into the mechanisms by which azinomycin forms interstrand DNA cross-links.

Alkylation↗
PubMed1986

Detection of sister chromatid exchanges induced by volatile genotoxicants.

To test the recently developed method of exposing cells to volatile compounds, phytohemagglutinin-stimulated human peripheral lymphocyte cultures were exposed to gaseous methyl bromide, ethylene oxide, and propylene oxide, as well as diesel exhaust. The cultures were placed in sterile dialysis tubing and inserted into enclosed flasks containing additional culture medium. The test compounds (in gaseous state) were diluted with air and bubbled through the flasks for various lengths of time. The cells were then washed and incubated for a total of 75 h. The harvest was performed according to established procedures, and second-division cells were scored for induction of sister chromatid exchanges (SCEs). The SCE frequency was more than doubled in the cultures treated with ethylene oxide and propylene oxide; methyl bromide also induced SCEs. Cultures treated with diesel exhaust showed an increase in the SCE frequency in cells from two of four donors tested. These results further substantiate the use of this method for detecting the induction of SCEs by airborne genotoxins.

Cells, Cultured↗
PubMed1998

Diepoxybutane cytotoxicity on mouse germ cells is enhanced by in vivo glutathione depletion: a flow cytometric approach.

Diepoxybutane is one of the key metabolites of butadiene, a compound of high environmental and occupational concern. The effects of diepoxybutane on mouse reproductive cells have been previously characterized by flow cytometry demonstrating a specific, dose-dependent cytotoxicity for differentiating spermatogonia. It is known that butadiene epoxides, deriving from butadiene bioactivation by cytochrome P450-monooxygenase systems, can be enzymatically conjugated to glutathione by glutathione S-transferases. In this paper, we tested the hypothesis whether a pretreatment with phorone, a well-known intracellular glutathione depleter, would enhance the germ cell cytotoxicity of diepoxybutane. Results were consistent with an active role played in vivo by the glutathione-detoxifying system, as diepoxybutane cytotoxicity was increased after chemically induced reduction of glutathione concentration.

Animals↗