Oxidative metabolism of foreign compounds by higher plants.
Explore the source record for details and available documents.
Dealkylation↗
SEARCH · Search PubMed
Results for “Epoxy Compounds”
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
Lessons learned from macrolide synthesis.
The highlights of three macrolide syntheses recently completed in our laboratory are described. In the epothilone B synthesis we developed the "early epoxide approach," which resulted in the first completely stereocontrolled synthesis of this natural product. In the laulimalide synthesis our contribution was the auxiliary controlled ene-macrocyclization and Sharpless' kinetic resolution for achieving a regioselective epoxidation of two pseudo-enantiomorphic allylic alcohol subunits. The tartrolon B synthesis was the first to be completed. In this case, a substrate controlled aldol addition was used to assemble the entire carbon skeleton of the compound.
Borates↗
Differential catalytic efficiency and enantioselectivity of murine glutathione S-transferase isoenzymes in the glutathione conjugation of carcinogenic anti-diol epoxides of chrysene and benzo(g)chrysene.
The kinetics of the conjugation of carcinogenic anti-diol epoxides of chrysene (anti-CDE) and benzo(g)chrysene [anti-B(g)CDE] with glutathione (GSH) catalyzed by GSH S-transferase (GST) isoenzymes mGSTP1-1, mGSTM1-1, mGSTA3-3, mGSTA4-4, and GST 9.5 of female A/J mouse tissues has been investigated. When GST activity was measured as a function of varying anti-CDE or anti-B(g)-CDE concentrations at a fixed concentration of GSH, each isoenzyme obeyed Michaelis-Menten kinetics. The catalytic efficiencies (k(cat)/Km) of murine GSTs in the GSH conjugation of anti-CDE were in the order of GST 9.5 > mGSTP1-1 > mGSTM1-1 > mGSTA3-3 > mGSTA4-4. While each GST isoenzyme examined in the present study exhibited preference for the GSH conjugation of (+)-anti-CDE with the (R,S)-diol (S,R)-epoxide absolute configuration, which is a far more potent carcinogen than the (-)-anti-CDE [(S,R)-diol (R,S)-epoxide absolute configuration], the enantioselectivity was relatively more pronounced for mGSTP1-1 compared with other murine GSTs. Anti-B(g)CDE was a relatively poor substrate for each GST isoenzyme examined compared with anti-CDE. The catalytic efficiencies of murine GSTs in the GSH conjugation of anti-B(g)CDE were in the order of GST 9.5 > mGSTP1-1 > mGSTM1-1 > mGSTA3-3. With the exception of mGSTM1-1, all other murine GSTs exhibited preference for the GSH conjugation of anti-B(g)CDE enantiomer with the (R,S)-diol (S,R)-epoxide absolute configuration. In summary, the results of the present study indicate that the murine GSTs significantly differ in their catalytic efficiency and enantioselectivity in the GSH conjugation of both anti-CDE and anti-B(g)CDE, and that anti-B(g)CDE is a relatively poor substrate for murine GSTs compared with anti-CDE, which may partially account for the observed relatively higher carcinogenic potency of the former compound.
Animals↗
The garlic ingredient diallyl sulfide inhibits cytochrome P450 2E1 dependent bioactivation of acrylamide to glycidamide.
Genotoxic effects of acrylamide are supposed to result from oxidative biotransformation to glycidamide. After incubation of rat liver slices with acrylamide we detected free glycidamide using a liquid chromatography tandem mass spectrometric method. Glycidamide formation was diminished in the presence of the cytochrome P450 2E1 inhibitor diallyl sulfide (DAS), which is a specific ingredient of garlic. This may be relevant to human health since the suggested carcinogenic risk of dietary acrylamide may be reduced by concomitant intake of garlic.
Acrylamide↗
Ryanodine action at calcium release channels. 1. importance of hydroxyl substituents.
Ryanodine (1) and dehydroryanodine (2) have a polar face formed by cis-hydroxyls at C-2, C-4, C-6, and C-12. The importance of the hydroxyls to the action of 1 and 2 at the ryanodine receptor (ryr) of calcium release channels is examined at [3H]-1 binding sites in brain and skeletal muscle and in heart membranes relative to cardiac contractility, a pharmacologic response which appears to be mediated by the ryr. Five types of changes are considered: blocking the 4- and 6-hydroxyls as cyclic borates and boronates; blocking the 10- and 12-hydroxyls as cyclic phosphates, phosphonates, and phosphoramidates; methylation at nitrogen or hydroxyls at C-4 and C-10; dehydration of the C-2 hydroxyl; additional data for a 4,12-oxygen-bridged series. The first change has little effect on potency possibly due to the lability of the boron protective groups whereas the cyclic phosphorus compounds have reduced activity. Methylation reduces potency the least at nitrogen and the C-4 hydroxyl. Dehydration of 1 to 2-deoxy-2(13)-dehydro-1 allows the restoration of oxygen at C-2 by conversion to epoxides or a diol. One of the epoxides and 2-deoxy-2(13)-dehydro-2 retain 8-31% of ryanodine's potency in the ryr assays and 81% in the cardiac contractility system. In the 4,12-oxygen-bridged series, high potency at the receptor and cardiac muscle is retained in the 4-hydroxy ketal.
Animals↗
Oxiranyl anion-mediated synthesis of highly enantiomerically enriched styrene oxide derivatives.
[reaction: see text] The stereospecific alpha-lithiation of optically active styrene oxides and the trapping reaction of the corresponding highly reactive intermediates with electrophiles to produce optically active styrene oxide derivatives are described. This methodology has been applied to the synthesis of an optically active oral antifungal agent of industrial interest.
Aluminum Compounds↗
Pd-catalyzed asymmetric allylic alkylation. A short route to the cyclopentyl core of viridenomycin.
A palladium-catalyzed asymmetric allylic alkylation effects a dynamic kinetic asymmetric transformation of racemic isoprene monoepoxide and a surrogate for Nazarov's reagent in which a quaternary center is created with exellent ee. The resultant adduct allows easy access to a substrate for ring-closing metathesis to form a cyclopentenone and sets the stage for an 11-step synthesis of the cyclopentyl core of the antibiotic antitumor agent viridenomycin. [reaction: see text]
Alkylation↗
Bisphenol A diglycidyl ether (BADGE) is a PPARgamma agonist in an ECV304 cell line.
Peroxisome proliferator activated receptors (PPAR)s are nuclear transcription factors of the steroid receptor super-family. One member, PPARgamma, a critical transcription factor in adipogenesis, is expressed in ECV304 cells, and when activated participates in the induction of cell death by apoptosis. Here we describe a clone of ECV304 cells, ECV-ACO.Luc, which stably expresses a reporter gene for PPAR activation. ECV-ACO.Luc respond to the PPARgamma agonists, 15-deoxy-Delta(12,14) PGJ(2), and ciglitizone, by inducing luciferase expression. Furthermore, using ECV-ACO.Luc, we demonstrate that a newly described PPARgamma antagonist, bisphenol A diglycidyl ether (BADGE) has agonist activities. Similar to 15-deoxy-Delta(12,14) PGJ(2), BADGE induces PPARgamma activation, nuclear localization of the receptor, and induces cell death.
Benzhydryl Compounds↗
Bisphenol A diglycidyl ether-induced apoptosis involves Bax/Bid-dependent mitochondrial release of apoptosis-inducing factor (AIF), cytochrome c and Smac/DIABLO.
(1) Bisphenol A diglycidyl ether (BADGE) is a peroxisome proliferator-activated receptor-gamma (PPAR-gamma) antagonist, which is able to induce apoptosis in tumor cells independently of PPAR-gamma in caspase-dependent and -independent manners. Additionally, BADGE promotes TRAIL-induced apoptosis. (2) We report that BADGE activates via Bax and caspases-2 and -8 both the intrinsic and extrinsic apoptotic pathways using Bid as a shunt. (3) BADGE stimulates the mitochondrial release of apoptosis-inducing factor (AIF), cytochrome c and second mitochondria-derived activator of caspase/direct IAP-binding protein with low pl (Smac/DIABLO). The release of cytochrome c could not be blocked by inhibitors of caspases-3, -8 and -9 indicating that BADGE acts upstream of caspases-3 and -9 and does not involve caspase-8 to release cytochrome c. (4) While the caspase-independent apoptotic effect might be mediated by AIF, the sensitizing effect of BADGE against other apoptotic substances is most likely mediated by the X-linked inhibitor of apoptosis inhibitor Smac/DIABLO. (5) Our data suggest that BADGE or BADGE derivatives could represent promising substances for the treatment of neoplasms improving the antitumoral activity of TRAIL.
Apoptosis↗
A common pharmacophore for epothilone and taxanes: molecular basis for drug resistance conferred by tubulin mutations in human cancer cells.
The epothilones are naturally occurring antimitotic drugs that share with the taxanes a similar mechanism of action without apparent structural similarity. Although photoaffinity labeling and electron crystallographic studies have identified the taxane-binding site on beta-tubulin, similar data are not available for epothilones. To identify tubulin residues important for epothilone binding, we have isolated two epothilone-resistant human ovarian carcinoma sublines derived in a single-step selection with epothilone A or B. These epothilone-resistant sublines exhibit impaired epothilone- and taxane-driven tubulin polymerization caused by acquired beta-tubulin mutations (beta274(Thr-->Ile) and beta282(Arg-->Gln)) located in the atomic model of alphabeta-tubulin near the taxane-binding site. Using molecular modeling, we investigated the conformational behavior of epothilone, which led to the identification of a common pharmacophore shared by taxanes and epothilones. Although two binding modes for the epothilones were predicted, one mode was identified as the preferred epothilone conformation as indicated by the activity of a potent pyridine-epothilone analogue. In addition, the structure-activity relationships of multiple taxanes and epothilones in the tubulin mutant cells can be fully explained by the model presented here, verifying its predictive value. Finally, these pharmacophore and activity data from mutant cells were used to model the tubulin binding of sarcodictyins, a distinct class of microtubule stabilizers, which in contrast to taxanes and the epothilones interact preferentially with the mutant tubulins. The unification of taxane, epothilone, and sarcodictyin chemistries in a single pharmacophore provides a framework to study drug-tubulin interactions that should assist in the rational design of agents targeting tubulin.
Alkaloids↗
Ferric chloride-catalyzed activation of hydrogen peroxide for the demethylation of N,N-dimethylaniline, the epoxidation of olefins, and the oxidative cleavage of vicinal diols in acetonitrile: a reaction mimic for cytochrome P-450.
In dry acetonitrile, anhydrous Fe(III)Cl3 catalyzes the demethylation of N,N-dimethylaniline, the epoxidation of olefins, and the oxidative cleavage of 1-phenyl-1,2-ethanediol (and other 1,2-diols) by hydrogen peroxide. For each class of substrate the products closely parallel those that result from their enzymatic oxidation by cytochrome P-450. Because of the close congruence of products, the catalytic nature of the Fe(III)Cl3/H2O2 reaction mimic, and the similarity of the dipolar aprotic solvent (acetonitrile) to the proteinaceous lipid matrix of the biomembrane, the form of the reactive intermediate may be the same in each case. A mechanism is proposed in which an initial Lewis acid-base interaction of Fe(III)Cl3 with H2O2 generates a highly electrophilic Fe(III)-oxene species as the reactive intermediate. This is in contrast to the prevailing view that cytochrome P-450 acts as a redox catalyst to generate an Fe(V)-oxo species or an Fe(IV)-oxo cation radical as the reactive intermediate.
Acetonitriles↗
Nitric oxide production and regulation of endothelial nitric-oxide synthase phosphorylation by prolonged treatment with troglitazone: evidence for involvement of peroxisome proliferator-activated receptor (PPAR) gamma-dependent and PPARgamma-independent signaling pathways.
Recently, peroxisome proliferator-activated receptor gamma (PPARgamma) ligands have been reported to increase endothelial NO, but the signaling mechanisms involved are unknown. Using troglitazone, a PPARgamma ligand known as an antidiabetic compound, we investigated the molecular mechanism of its effect on NO production in bovine aortic endothelial cells. Troglitazone increased endothelial NO production in a dose- and time-dependent manner with no alteration in endothelial nitric-oxide synthase (eNOS) expression. The maximal increase ( approximately 3.1-fold) was achieved with 20 microm troglitazone treatment for 12 h, and this increase was accompanied by increases in the expression of vascular endothelial growth factor (VEGF) and its receptor, KDR/Flk-1, and in Akt phosphorylation. Analysis with antibodies specific for each phosphorylated site demonstrated that troglitazone (20 microm treatment for 12 h) significantly increased both the phosphorylation of Ser(1179) of eNOS (eNOS-Ser(1179)) and the dephosphorylation of eNOS-Ser(116) but did not alter eNOS-Thr(497) phosphorylation. Treatment with anti-VEGF antibody to scavenge the increased VEGF induced by troglitazone partially inhibited troglitazone-stimulated NO production. This was accompanied by the attenuation of troglitazone-stimulated increases in the phosphorylation of Akt and eNOS-Ser(1179) with no alteration in eNOS-Ser(116) dephosphorylation. We also found that bisphenol A diglycidyl ether, a PPARgamma antagonist, partially inhibited troglitazone-stimulated NO production with a concomitant reduction in VEGF-KDR/Flk-1-Akt-mediated eNOS-Ser(1179) phosphorylation but with no alteration in eNOS-Ser(116) dephosphorylation induced by troglitazone. Taken together, our results demonstrate that prolonged treatment with troglitazone increases endothelial NO production by at least two independent signaling pathways: PPARgamma-dependent, VEGF-KDR/Flk-1-Akt-mediated eNOS-Ser(1179) phosphorylation and PPARgamma-independent, eNOS-Ser(116) dephosphorylation.
Animals↗
Molecular dosimetry of DNA adducts in C3H mice treated with bisphenol A diglycidylether.
The formation of a glycidaldehyde-DNA adduct in skin of C3H mice treated with [14C]bisphenol A diglycidylether has been previously reported and it was assumed that the modification occurred on guanine residues. We were interested in elucidating the structure of this glycidaldehyde-DNA adduct by using a non-radioactive approach. Male C3H mice were treated with a single topical dose of 2 mg bisphenol A diglycidylether in acetone for 48, 96 or 192 h. An additional two mice were treated with 2 mg glycidaldehyde in acetone for 24 h. Epidermal DNA was isolated and enzymatically digested to nucleoside-3'-monophosphates. Aliquots of the DNA hydrolysates were separated on HPLC using a reverse-phase column with a potassium dihydrogen phosphate/methanol gradient. Fluorescence analysis of the eluent indicated the presence of a fluorescent DNA adduct, which was identified as hydroxymethylethenodeoxyadenosine-3'-monophosphate by comparison with a synthetic reference standard. Amounts of adducts were determined by fluorescence measurements using a calibration curve obtained with the authentic adduct standard. Irrespective of duration of exposure, all DNA hydrolysates of treated mice contained similar amounts of the deoxyadenosine adduct. The alkylation frequency was 0.1-0.8 and 166 adducts/10(6) normal nucleotides for the treatment with bisphenol A diglycidylether and glycidaldehyde respectively. The limit of detection using 500 micrograms DNA samples for analysis was approximately 0.03 adducts/10(6) normal nucleotides.
Aldehydes↗
EPA and DHA reduce LPS-induced inflammation responses in HK-2 cells: evidence for a PPAR-gamma-dependent mechanism.
BACKGROUND: Recent studies have shown that fish oil, containing omega-3 polyunsaturated fatty acids (omega-3 PUFAs) eicosapentaenoic acid (EPA) (C20:5 omega 3), and docosahexaenoic acid (DHA) (C22:6 omega 3) retard the progression of renal disease, especially in IgA nephropathy (IgAN). Despite increasing knowledge of the beneficial effects of fish oils, little is known about the mechanisms of action of omega-3 PUFAs. It has been reported that activation of peroxisome proliferator-activated receptors (PPARs) inhibits production of proinflammatory cytokines. Both EPA and DHA have been shown to activate PPARs. The aim of this study was to examine if omega-3 PUFAs have anti-inflammatory effects via activation of PPARs in human renal tubular cells. METHODS: An immortalized human proximal tubular cell line [human kidney-2 (HK-2) cells] was used in all experiments. Conditioned media was collected from omega-3 PUFAs- treated cells and subjected to enzyme-linked immunosorbent assay (ELISA). Total cellular RNA was isolated from the above cells for real-time quantitative polymerase chain reaction (PCR). Nuclear Extracts were prepared from the HK-2 cells for transcription factor activation assay. RESULTS: Both EPA and DHA at 10 micromol/L and 100 micromol/L concentrations effectively decreased lipopolysaccharide (LPS)-induced nuclear factor-kappaB (NF-kappaB) activation and monocyte chemoattractant protein-1 (MCP-1) expression. EPA and DHA also increased both PPAR-gamma mRNA and protein activity (two- to threefold) in HK-2 cells. A dose of 100 micromol/L bisphenol A diglycidyl ether (BADGE) abolished the PPAR-gamma activation induced by both EPA and DHA and removed the inhibitory effect of EPA and DHA on LPS-induced NF-kappaB activation in HK-2 cells. Overexpression of PPAR-gamma further inhibited NF-kappaB activation compared to the control cells in the presence of EPA and DHA. CONCLUSION: Our data demonstrate that both EPA and DHA down-regulate LPS-induced activation of NF-kappaB via a PPAR-gamma-dependent pathway in HK-2 cells. These results suggest that PPAR-gamma activation by EPA and DHA may be one of the underlying mechanisms for the beneficial effects of fish oil.
Benzhydryl Compounds↗
Effect of phosphate binders on supplemental iron absorption in healthy subjects.
A single-dose, prospective, randomized, four-treatment, four-period crossover study was conducted to determine the acute effect of therapeutically equivalent doses of three commonly used phosphate binders on oral iron absorption. Twenty-three healthy subjects received 65 mg of elemental iron alone and with each phosphate binder (calcium carbonate 3000 mg, calcium acetate 2668 mg, or sevelamer HCl 2821 mg). Area under the change in plasma iron concentration-time curve over 6 hours postdosing was measured. ANOVA was used to assess the statistical significance of differences in iron absorption among the treatments. The relative bioavailability of iron administered with each phosphate binder compared to iron administered alone was estimated. The relative iron bioavailabilities (95% confidence intervals) for the calcium carbonate, calcium acetate, and sevelamer HCI treatments were 0.81 (0.70, 0.94), 0.73 (0.63, 0.85), and 0.90 (0.78, 1.05), respectively. Thus, single doses of both calcium-based phosphate binders significantly reduced single-dose iron absorption, while sevelamer HCl did not.
Acetates↗
Aza-peptide epoxides: potent and selective inhibitors of Schistosoma mansoni and pig kidney legumains (asparaginyl endopeptidases).
Aza-peptide epoxides are a new class of irreversible cysteine protease inhibitors. Derivatives containing a P1 aza-asparagine residue are specific for Schistosoma mansoni and pig kidney legumains, which are clan CD cysteine proteases. The inhibitors have second-order rate constants of up to 10(4) M(-1) s(-1) with pig kidney legumain and IC50 values as low as 45 nM with S. mansoni legumain. The most potent epoxides contain an ester moiety with S,S stereochemistry attached to the epoxide. Interestingly, amide and amino acid derivatives of the epoxysuccinate moiety were not inhibitors of legumain, while disubstituted amide derivatives are quite potent. The inhibitors have little or no inhibitory activity with other proteases such as caspases, chymotrypsin, papain, cathepsin B, granzyme B, and various aspartyl proteases.
Animals↗
[Correlation between clinical and laboratory data in depression. Therapeutic orientation by means of vitamins and amino acids].
This work is based upon the study of 472 cases from author's private practice. We considered the three following starting points: a) Catecholaminic hypothesis of depressive disorders such as formulated by late Prof. E. Fischer. b) Biochemical analysis of neuro transmitters according to H. Spatz and Mattock to study clinical and laboratory correlation and guide therapy. c) Biological psychiatry's practice and experience in our empirical definition of a final metabolic response to the patients situation. We would like to stress the following conclusions resulting from this investigation: first, the efficacy without unwanted side effects of the formula described as treatment B in the special paragraph; second, a stronger response to tricyclics or Maois when the formula is also administered; third, the confirmation of previous reports pointing out low PEA urinary elimination in those patients with clinical diagnoses different from endogenous depression.
Adjustment Disorders↗
[Cathepsin D from chicken liver: irreversible inhibition and localization of catalytically active groups in the heavy chain of the enzyme].
Explore the source record for details and available documents.
Animals↗