A4 Methyl Ester Research Articles

Mechanism-based inactivation of leukotriene A4 hydrolase during leukotriene B4 formation by human erythrocytes.

Evidence is presented in support of a mechanism-based (suicide) inactivation of leukotriene A4 hydrolyase in intact human erythrocytes by leukotriene A4 and leukotriene A4 methyl ester. Loss of enzymatic activity, accompanying leukotriene B4 formation, was proportional to the substrate concentration. Inactivation was directly related to the amount of leukotriene B4 formation: for several, different experimental protocols 50% loss of hydrolase activity corresponded with formation of 10.3 +/- 2.1 microM leukotriene B4. The time course of inactivation was pseudo-first order and obeyed saturation kinetics. Apparent inactivation (KI) and first-order rate (ki) constants for leukotriene A4 were 28 microM and 0.35 min-1, respectively. Leukotriene A4 methyl ester was also a site-directed inactivator with a similar KI = 25 microM and a ki = 0.1 min-1. For single incubations substrate instability limited the extent of inactivation to 50% of the initial enzyme activity. Following multiple, consecutive incubations with leukotriene A4 this increased and approached 80-90%; however, a residual activity of 10-20% suggested that a pool of enzyme was not susceptible to inactivation. Recovery of enzymatic activity, following inactivation, was negligible in intact erythrocytes and isolated enzyme. A single radiolabeled protein, corresponding to leukotriene A4 hydrolase, was detected by electrophoretic analysis of the incubation between [3H]leukotriene A4 and erythrocytes, or partially purified enzyme. Incorporation of [3H]leukotriene A4 methyl ester into enzyme was linearly related to its inactivation: 191 +/- 5 pmol incorporated corresponded to 10% loss of activity. Results conform to criteria for a mechanism-based inactivation, in which leukotriene A4 participates in two parallel processes, one leading to leukotriene B4 formation, the other to "suicide" inactivation of leukotriene A4 hydrolase in intact erythrocytes. The specific, rather than indiscriminate nature of this process has implications for the regulation of cellular leukotriene B4 formation. It may also afford a basis to monitor transcellular biosynthesis of leukotriene B4 in vivo.

Stereoselective synthesis of optically active α-methyl esters

Trifluoromethanesulfonic esters of α-hydroxyesters which are easily available from the corresponding esters and triflic anhydride react with lithium dimethylcuprate in ether or magnesiocuprates in THF to provide α-methyl esters in high enantiomerical purity.

Determination of the enantiomeric composition of cycloprofen by proton nuclear magnetic resonance spectroscopy with a europium(III) shift reagent

The enantiomeric composition of cycloprofen was determined in a simple and reliable manner by proton nuclear magnetic resonance spectroscopy with a chiral Europium(III) shift reagent. Effective complexation with the shift reagent took place in CCl4 after conversion of the enantiomeric sample into a mixture of the methyl ester derivatives. Optimisation of the experimental conditions in terms of substrate concentration and shift reagent to substrate molar ratio led to two sets of enantiomeric resonance signals of utility for quantitative purposes. Analysis of synthetic enantiomeric mixtures by the proposed method demonstrated an excellent agreement between the assay results and the known masses of each enantiomer present in the mixture samples. The average ± standard deviation recovery values were 100.1 ± 0.4%(n= 6) and 99.9 ± 0.6%(n= 6) of (–)-cycloprofen depending on whether the quantification is based on the α-methyl protons or ester methyl protons, respectively.

Synthesis of 19,19,20,20,20-pentadeuteriolipoxin A4 methyl ester and 19,19,20,20,20-pentadeuteriarachidonic acid. Agents for use in the quantitative detection of naturally occurring eicosanoids

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTSynthesis of 19,19,20,20,20-pentadeuteriolipoxin A4 methyl ester and 19,19,20,20,20-pentadeuteriarachidonic acid. Agents for use in the quantitative detection of naturally occurring eicosanoidsB. E. Marron, R. A. Spanevello, M. E. Elisseou, C. N. Serhan, and K. C. NicolaouCite this: J. Org. Chem. 1989, 54, 23, 5522–5527Publication Date (Print):November 1, 1989Publication History Published online1 May 2002Published inissue 1 November 1989https://doi.org/10.1021/jo00284a025RIGHTS & PERMISSIONSArticle Views889Altmetric-Citations32LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (742 KB) Get e-AlertsSupporting Info (1)»Supporting Information Supporting Information Get e-Alerts

A convenient synthesis of deuterated leukotriene A4 methyl ester

Abstract2,2,3,3‐[2H4]‐1‐Iodopentane (8b) was prepared in four steps from propargyl alcohol and used in the C‐alkylation of the THP‐protected 3‐butyne‐1‐ol (10). Subsequent protective group removal of 11b, semi‐deuteration of the acetylenic alcohol 12b, and further transformation by known methods afforded the labelled key reagent 3,4,6,6,7,7‐[2H6]‐(Z)‐(3‐nonen‐1‐yl)triphenylphosphonium iodide (3b). Wittig olefination of epoxy dienal 2 with the ylide generated from 3b completed the convenient synthesis of hexadeuterated leukotriene A4 methyl ester (1b).

Synthesis of leukotrienes labelled with deuterium: [11,12,14,15‐2H4]‐LTA4 ‐LTC4, ‐LTD4 and ‐LTE4

AbstractSemi‐hydrogenation by D2 gas on Lindlar catalyst of an acetylenic precursor led to [11,12,14,15‐2H4]‐LTA4 methyl ester 1a. Nucleophilic opening of the epoxide ring by amino thioacids afforded after saponification the corresponding deuterated peptidoleukotrienes LTC4, LTD4 and LTE4.

ChemInform Abstract: Stereoselective Synthesis of Conjugated Unsaturated Compounds from sec‐Propargylic Alcohols

Stereoselective routes to conjugated unsaturated compounds from sec-propargylic alcohols (1) are described. Thermal treatments of β-allenic esters, prepared by the reaction of 1 with trialkyl orthoacetates, with alumina gave (2 E, 4 Z) -alkadienoic esters with high stereoselectivity. β-Allenic amides also rearranged with alumina to give (2 E, 4 Z) -alkadienoic amides. Direct oxidation of 2, 4-alkadienoates with SeO2 afforded furans and selenophenes. Iodolactonization of, β-allenic acids gave γ-alkylidene butenolide in one step. Stereoselective rearrangements of 2, 4-alkadienoates to 3, 5-alkadienoates with lithium diisopropylamide are described. Application of (2 E 4Z) -dienoates to the synthesis of natural products such as insect pheromones, flavors, octadecapolyenoic acids and leukotriene A4 methyl ester are described. Base-catalyzed condensation of sec-pro-pargylic alcohols with 1-cyanopyrrolidine gave imidates, which undergo thermal rearrangement to give pyridones or dienyl-ureas. Reaction of 1-alkyn-3-ol with benzonitrile gave 4-methylene-4, 5-dihydrooxazoles, which serve as useful intermediates for the synthesis of highly functionalized oxazoles.

Leukotriene C4 Synthesis Catalyzed by Dirofilaria Immitis Glutathione S-Transferase

The biologically active sulfidopeptide leukotriene, leukotriene C4, is formed by the enzymatic action of leukotriene C4 synthase, which conjugates glutathione with leukotriene A4. We have found that a filarial glutathione S-transferase can function as a leukotriene C4 synthase. Glutathione S-transferase was purified from the cytosol of adult Dirofilaria immitis by glutathione-agarose affinity chromatography and was reacted with 25 microM leukotriene A4 methyl ester and 10 mM glutathione. The filarial enzyme catalyzed the formation of leukotriene C4 methyl ester, as shown by reverse phase high pressure liquid chromatographic analyses. The finding that filarial glutathione S-transferase can function as leukotriene C4 synthase provides a mechanism whereby filarial parasites could form lipoxygenase pathway derived sulfidopeptide leukotrienes.

Dimethylisopropylsilyl ether derivatives in gas chromatography-mass spectrometry of some prostanoids : Application to the microdetermination of 15-ketoprostaglandin F 2α formed by enzymatic conversion of PGF 2α in vitro

Treatment of 15-ketoprostaglandin F 2α (15-keto-PGF 2α) with ethereal diazomethane at −78°C provided only the expected methyl ester (ME), without the formation of the pyrazoline adduct. The electron-ionization mass spectrum of the dimethylisopropylsilyl (DMiPS) ether derivative of 15-keto-PGF 2α ME showed the molecular ion, and the characteristic fragment ion of [M−43] + was of high abundance. The appearance of these ions in the high-mass region made it possible to determine trace amounts of 15-keto-PGF 2α in biological specimens without any interference from endogenous substances. The detection limit for the DMiPS ether derivatives of 15-keto-PGF 2α ME was 12 pg (signal-to-noise ratio = 10). The method was applied to the analysis of 15-keto-PGF 2α obtained by the enzymatic conversion of PGF 2α with 15-hydroxyprostaglandin dehydrogenase in vitro.

ｓｅｃ‐プロパギルアルコール誘導体を用いる共役不飽和化合物の立体選択的合成

Stereoselective routes to conjugated unsaturated compounds from sec-propargylic alcohols (1) are described. Thermal treatments of β-allenic esters, prepared by the reaction of 1 with trialkyl orthoacetates, with alumina gave (2 E, 4 Z) -alkadienoic esters with high stereoselectivity. β-Allenic amides also rearranged with alumina to give (2 E, 4 Z) -alkadienoic amides. Direct oxidation of 2, 4-alkadienoates with SeO2 afforded furans and selenophenes. Iodolactonization of, β-allenic acids gave γ-alkylidene butenolide in one step. Stereoselective rearrangements of 2, 4-alkadienoates to 3, 5-alkadienoates with lithium diisopropylamide are described. Application of (2 E 4Z) -dienoates to the synthesis of natural products such as insect pheromones, flavors, octadecapolyenoic acids and leukotriene A4 methyl ester are described. Base-catalyzed condensation of sec-pro-pargylic alcohols with 1-cyanopyrrolidine gave imidates, which undergo thermal rearrangement to give pyridones or dienyl-ureas. Reaction of 1-alkyn-3-ol with benzonitrile gave 4-methylene-4, 5-dihydrooxazoles, which serve as useful intermediates for the synthesis of highly functionalized oxazoles.

ChemInform Abstract: Synthesis of the Methyl Ester of (2R,4R,6R,8R)‐2,4,6,8‐Tetramethylundecanoic Acid, an Acid Component of the Preen‐Gland Wax of the Graylag Goose, Anser anser.

The methyl ester 1a of (2R,4R,6R,8R)-2,4,6,8-tetramethylundecanoic acid found in the feather wax of the graylag goose was synthesized from optically pure lardolure.

Conformation and structure of a blocked Gla residue: N-benzyloxycarbonyl-(γ,γ-di-tert-butyl)-L-carboxyglutamic acid α-methyl ester

Conformation and structure of a blocked Gla residue: N-benzyloxycarbonyl-(γ,γ-di-tert-butyl)-L-carboxyglutamic acid α-methyl ester

Leukotriene A4 hydrolase in the human lung. Inactivation of the enzyme with leukotriene A4 isomers.

Leukotriene A4 hydrolase from the human lung was purified to apparent homogeneity. The molecular weight (68,000-71,000), the amino acid composition, and the N-terminal amino acid sequence were similar to those of the human neutrophil enzyme but different from those of human erythrocyte enzyme. The lung enzyme was inactivated by its substrate, leukotriene A4. To elucidate the substrate and the inactivator specificity of this enzyme, we synthesized various geometric and positional isomers of leukotriene A4. 14,15-Leukotriene A4, leukotriene A4 methyl ester, and geometric isomers of leukotriene A4 could not serve as substrates, but they inactivated the enzyme. On the other hand, styrene oxide and (5S)-trans-5,6-oxide-8,10,14-cis-12-trans-eicosatetraenoic acid neither served as substrates nor inactivated the enzyme. These results indicate that whereas allylic epoxide structures of arachidonic acids are responsible for inactivation of the enzyme, the free carboxylic acid, 5,6-oxide, and the tetraene structure with the 7,9-trans-11,14-cis configuration are required as a substrate for leukotriene A4 hydrolase.

Synthesis of the Methyl Ester of (2R,4R,6R,8R)‐2,4,6,8‐Tetramethylundecanoic Acid, an Acid Component of the Preen‐Gland Wax of the Graylag Goose, Anser anser

AbstractThe methyl ester 1a of (2R,4R,6R,8R)‐2,4,6,8‐tetramethylundecanoic acid found in the feather wax of the graylag goose was synthesized from optically pure lardolure.

The crystal and molecular structure of a dioxan photoadduct of 3‐dehydro‐gibberellin A1 methyl ester

AbstractThe three‐dimensional structure of a dioxan photoadduct of 3‐dehydro‐gibberellin A1 methyl ester has been established as (2′S)‐3‐[dioxanyl‐(2′)]‐3‐epi‐gibberellin A1 methyl ester (1) by X‐ray analysis. The compound crystallizes in the orthorhombic space group P212121 with four molecules in the unit cell of dimensions a = 9.751, b = 22.189, c = = 10.064 Å. The final R‐value is 0.103 for 1151 reflections.

ChemInform Abstract: A Facile Stereoselective Synthesis of Leukotriene A4 (LTA4) Methyl Ester.

AbstractD‐Glyceraldehyde acetonide (I) is transformed into the leucotriene A4 methyl ester (IX) as shown in the reaction scheme.

Diethylhydrogensilyl-cyclic diethylsilylene derivatives in gas chromatography-mass spectrometry of prostanoids : III. F α-prostaglandins and thromboxane B 2 derivatives

The gas chromatographic (GC) and GC-mass spectrometric properties of the diethylhydrogensilyl-cyclic diethylsilylene (DEHS-DES) derivatives of prostaglandin (PG) F 1α methyl ester, PGF 2α methyl ester, 6-keto-PGF 1α methyl ester-alkyloxime and thromboxane (TX) B 2 methyl ester-alkyloxime and the DES derivative of 13,14-dihydro-15-keto-PGF 2α methyl ester-alkyloxime were studied. When the ketonic PGs and TXB 2 were converted into their methyloxime derivatives, the methylene unit values of these five prostanoid derivatives were slightly greater than those of the corresponding dimethylethylsilyl ether derivatives. When the ketonic PGs were converted into their corresponding ethyloxime derivatives, baseline separation was achieved in 20 min by use of a methylsilicone cross-linked fuse-silica capillary column. The mass spectra of these derivatives were characterized by the ion at m/z 157 for F α prostaglandins and m/z 269 for TXB 2. The major fragmentations were directed by the DES group, and other fragmentations common to the prostanoid derivatives were losses of an ethyl radical at the silicon atom, C 5H 11 hydrocarbon fragment, diethylhydrogensilanol and C 15–C 20 hydrocarbon fragment. The mass fragmentations of these prostanoid derivatives are briefly discussed. GC with high-resolution selected-ion monitoring was carried out for the TXB 2 derivative at a resolution of 8000 by monitoring the ion at m/z 269.1573. A 25-pg amount of this derivative showed a well shaped doublet with a signal-to-noise ratio of more than 300:1.

Chiral zinc homoenolate of methyl isobutyrate. A new building block for the synthesis of chiral α-methylesters

Chiral homoenolate of methyl isobutyrate prepared in a few steps from optically active methyl β-hydroxy isobutyrate reacts with carbon electrophiles to give chiral α-methyl esters.

Design criteria for controlled release delivery systems of carboprost methyl

Permeabilities of carboprost methyl (15(s)-15 methyl prostaglandin F 2α methyl ester) were determined for a series of synthetic polymeric membranes. Membrane compositions consisted of a polyurethane ether and a series of poly(co-ethylene) vinyl acetate copolymers with vinyl acetate concentrations varying from 9% w/w to 60% w/w. Permeability increased as a function of the percent vinyl acetate in the copolymer. The increase in permeability was mainly due to an increase in the solubility of carboprost methyl in the polymer. Diffusion coefficients were independent of vinyl acetate concentrations above 9% w/w. The highest permeability and solubility value was associated with the polyurethane polymer. Membranes of identical composition yielded different transport rates depending upon the method of preparation (casted versus blown) and transport rates were inversely related to the thickness of the membrane. Permeability was shown to be a key parameter in determining the sequencing of polymeric membranes in the design of laminated controlled release delivery systems for carboprost methyl.

A facile stereoselective synthesis of leukotriene A4(LTA4) methyl ester

A facile synthesis of LTA41 methyl ester was achieved according to Scheme 1, in which the key intermediates 6 and 7 were prepared with the new procedures conveniently, stereoselectively and in good yields.