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1.
Bioorg Med Chem ; 27(1): 36-42, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30473360

RESUMO

Design and synthesis of LuxS enzyme inhibitors otherwise known as S-ribosylhomocysteine analogues, to target quorum sensing in bacteria, has been considerably developed within the last decade. This review presents which molecules have been synthesized to target LuxS enzyme in other words inhibitors of S-ribosylhomocysteinase. It reports their tested biological activity as LuxS inhibitors when available. A systematic overview has been conducted by searching PubMed, Medline, and The Cochrane Library and data extraction of all synthesized S-ribosylhomocysteine analogues has been collected. This mini-review shows limited data to date on this area and should continue to be studied.


Assuntos
Antibacterianos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Liases de Carbono-Enxofre/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Homocisteína/análogos & derivados , Antibacterianos/síntese química , Antibacterianos/química , Proteínas de Bactérias/química , Liases de Carbono-Enxofre/química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Homocisteína/síntese química , Homocisteína/farmacologia , Percepção de Quorum/efeitos dos fármacos
2.
Bioorg Med Chem Lett ; 27(8): 1681-1685, 2017 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-28302398

RESUMO

LuxS (S-ribosylhomocysteinase; EC 4.4.1.21) is an enzyme that catalyzes the cleavage of the thioether linkage in the catalytic pathway of S-ribosylhomocysteine (SRH) which produces homocysteine and 4,5-dihydroxy-2,3-pentanedione (DPD). DPD is the precursor of the signaling molecules known as autoinducer 2 (AI-2) responsible for the bacterial quorum sensing (QS) identified as cell to cell communication. Inhibitors of LuxS should be able to interfere with its catalytic pathway thus preventing the formation of the autoinducer molecules. In this work, the synthesis of 2-deoxy-2-bromo-SRH analogues was attempted by the coupling of the corresponding 2-bromo-2-deoxypentafuranosyl sugars with the homocysteinate anion. The displacement of the bromide from C2 rather than the expected substitution of the mesylate group from C5 was observed leading to a novel isomeric analogue of SRH in which Hcy moiety is attached to a ribose ring via C2-sulfur bond.


Assuntos
Bacillus subtilis/enzimologia , Proteínas de Bactérias/antagonistas & inibidores , Liases de Carbono-Enxofre/antagonistas & inibidores , Inibidores Enzimáticos/química , Homocisteína/análogos & derivados , Ribose/análogos & derivados , Proteínas de Bactérias/metabolismo , Liases de Carbono-Enxofre/metabolismo , Cristalografia por Raios X , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Homocisteína/síntese química , Homocisteína/farmacologia , Isomerismo , Modelos Moleculares , Ribose/síntese química , Ribose/farmacologia
3.
Chem Commun (Camb) ; 52(30): 5336-9, 2016 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-27004992

RESUMO

A methodology was developed for efficient, chemoselective transformation of methionine residues into stable, functional homocysteine derivatives. Methionine residues can undergo highly chemoselective alkylation reactions at low pH to yield stable sulfonium ions, which could then be selectively demethylated to give stable alkyl homocysteine residues. This mild, two-step process is chemoselective, efficient, tolerates many functional groups, and provides a means for creation of new functional biopolymers, site-specific peptide tagging, and synthesis of biomimetic and structural analogs of peptides.


Assuntos
Homocisteína/análogos & derivados , Metionina/química , Peptídeos/química , Alquilação , Materiais Biomiméticos/química , Homocisteína/síntese química , Concentração de Íons de Hidrogênio , Metilação , Compostos de Sulfônio/química
4.
Chembiochem ; 15(12): 1793-9, 2014 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-24976145

RESUMO

We report the genetic incorporation of caged cysteine and caged homocysteine into proteins in bacterial and mammalian cells. The genetic code of these cells was expanded with an engineered pyrrolysine tRNA/tRNA synthetase pair that accepts both light-activatable amino acids as substrates. Incorporation was validated by reporter assays, western blots, and mass spectrometry, and differences in incorporation efficiency were explained by molecular modeling of synthetase-amino acid interactions. As a proof-of-principle application, the genetic replacement of an active-site cysteine residue with a caged cysteine residue in Renilla luciferase led to a complete loss of enzyme activity; however, upon brief exposure to UV light, a >150-fold increase in enzymatic activity was observed, thus showcasing the applicability of the caged cysteine in live human cells. A simultaneously conducted genetic replacement with homocysteine yielded an enzyme with greatly reduced activity, thereby demonstrating the precise probing of a protein active site. These discoveries provide a new tool for the optochemical control of protein function in mammalian cells and expand the set of genetically encoded unnatural amino acids.


Assuntos
Cisteína/química , Cisteína/genética , Escherichia coli/genética , Código Genético/genética , Homocisteína/química , Homocisteína/genética , Células Cultivadas , Cisteína/síntese química , Escherichia coli/citologia , Células HEK293 , Homocisteína/síntese química , Humanos , Luciferases de Renilla/química , Luciferases de Renilla/metabolismo , Modelos Moleculares , Estrutura Molecular
5.
Carbohydr Polym ; 111: 125-32, 2014 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-25037337

RESUMO

We report a new "green" approach to synthesize a novel thiolated chitosan conjugate, chitosan-N-acetyl-homocysteine thiolactone (chitosan-AcHcys) using a "Good's buffers", 2-(N-morpholino)ethanesulfonic acid (MES). After that, the crosslinked Xr-chitosan-AcHcys was obtained only in the presence of air, without other reactants. The chitosan-AcHcys spectrum shows a partial incorporation of the thiolactone onto the polymer backbone. The derivative thermogravimetric analysis confirmed that chitosan-AcHcys is slightly less stable than starting chitosan; however, the peak profile is broadened which is indicative of deeper changes in the thermal degradation process. Also, aqueous dispersions with different concentrations of the crosslinked material (Xr-chitosan-AcHcys) were prepared and rheologically characterized. All aqueous dispersions are viscoelastic fluid with shear-thinning behavior. The viscosity of the dispersions (1-7% of chitosan-AcHcys) increases as a function of polymer concentration. So, we have achieved to disperse a high concentration of thiolated-chitosan derivative in water with different rheological characteristics, which could affect the drug release.


Assuntos
Ácidos Alcanossulfônicos/química , Quitosana/análogos & derivados , Homocisteína/análogos & derivados , Morfolinas/química , Substâncias Viscoelásticas/química , Tampões (Química) , Quitosana/síntese química , Química Verde , Homocisteína/síntese química , Homocisteína/química , Substâncias Viscoelásticas/síntese química , Viscosidade
6.
Carbohydr Res ; 394: 32-8, 2014 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-24967680

RESUMO

Cleavage of the thioether bond of S-D-ribosyl-L-homocysteine (SRH) by the enzyme S-ribosylhomocysteinase (LuxS) serves as the final biosynthetic step in the generation of the quorum sensing autoinducer AI-2 by bacteria. Herein, a revised chemical synthesis of SRH is presented at convenient scale and purity for in vitro studies of LuxS. Potassium bis(trimethylsilyl)amide (KHMDS) is identified as a judicious base for the formation of the thioether of the target compound from readily-accessible precursors: a thiol nucleophile derived from l-homocystine and a sulfonate-activated d-ribosyl electrophile. The exclusive use of acid-labile protecting groups allows for facile deprotection to the final product, producing the TFA salt of SRH in five synthetic steps and 26% overall yield. The chemically-synthesized material is isolated at high purity and demonstrated to serve as the LuxS substrate by an in vitro assay.


Assuntos
Homocisteína/análogos & derivados , Percepção de Quorum , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Liases de Carbono-Enxofre/química , Liases de Carbono-Enxofre/metabolismo , Técnicas de Química Sintética , Homocisteína/síntese química
7.
Amino Acids ; 44(2): 443-8, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22782216

RESUMO

Natural L-homocysteine and L,L-cystathionine, along with a series of unnatural analogues, have been prepared from L-aspartic and L-glutamic acid. Manipulation of the protected derivatives provided ω-iodoamino acids, which were used in thioalkylation reactions of sulfur nucleophiles, such as the ester of L-cysteine and potassium thioacetate.


Assuntos
Cistationina/síntese química , Homocisteína/síntese química , Ácido Aspártico/química , Cistationina/química , Ácido Glutâmico/química , Homocisteína/química , Estrutura Molecular
8.
J Med Chem ; 55(15): 6822-31, 2012 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-22775318

RESUMO

Betaine-homocysteine S-methyltransferase 2 (BHMT-2) catalyzes the transfer of a methyl group from S-methylmethionine to l-homocysteine, yielding two molecules of l-methionine. It is one of three homocysteine methyltransferases in mammals, but its overall contribution to homocysteine remethylation and sulfur amino acid homeostasis is not known. Moreover, recombinant BHMT-2 is highly unstable, which has slowed research on its structural and catalytic properties. In this study, we have prepared the first series of BHMT-2 inhibitors to be described, and we have tested them with human recombinant BHMT-2 that has been stabilized by copurification with human recombinant BHMT. Among the compounds synthesized, (2S,8RS,11RS)-5-thia-2,11-diamino-8-methyldodecanedioic acid (11) was the most potent (K(i)(app) ∼77 nM) and selective inhibitor of BHMT-2. Compound 11 only weakly inhibited human BHMT (IC(50) about 77 µM). This compound (11) may be useful in future in vivo studies to probe the physiological significance of BHMT-2 in sulfur amino acid metabolism.


Assuntos
Betaína-Homocisteína S-Metiltransferase/antagonistas & inibidores , Homocisteína/análogos & derivados , Sulfetos/síntese química , Betaína-Homocisteína S-Metiltransferase/química , Ensaios Enzimáticos , Homocisteína/síntese química , Homocisteína/química , Humanos , Cinética , Proteínas Recombinantes/antagonistas & inibidores , Estereoisomerismo , Relação Estrutura-Atividade , Sulfetos/química
9.
Bioorg Med Chem ; 19(18): 5507-19, 2011 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-21855358

RESUMO

LuxS (S-ribosylhomocysteinase) catalyzes the cleavage of the thioether linkage of S-ribosylhomocysteine (SRH) to produce homocysteine and 4,5-dihydroxy-2,3-pentanedione (DPD), the precursor to a small signaling molecule that mediates interspecies bacterial communication called autoinducer 2 (AI-2). Inhibitors of LuxS should interfere with bacterial interspecies communication and potentially provide a novel class of antibacterial agents. In this work, SRH analogues containing substitution of a nitrogen atom for the endocyclic oxygen as well as various deoxyriboses were synthesized and evaluated for LuxS inhibition. Two of the [4-aza]SRH analogues showed modest competitive inhibition (K(I) ∼40 µM), while most of the others were inactive. One compound that contains a hemiaminal moiety exhibited time-dependent inhibition, consistent with enzyme-catalyzed ring opening and conversion into a more potent species (K(I)(∗)=3.5 µM). The structure-activity relationship of the designed inhibitors highlights the importance of both the homocysteine and ribose moieties for high-affinity binding to LuxS active site.


Assuntos
Bacillus subtilis/enzimologia , Proteínas de Bactérias/antagonistas & inibidores , Liases de Carbono-Enxofre/antagonistas & inibidores , Homocisteína/análogos & derivados , Ribose/química , Proteínas de Bactérias/metabolismo , Liases de Carbono-Enxofre/metabolismo , Relação Dose-Resposta a Droga , Homocisteína/síntese química , Homocisteína/química , Homocisteína/farmacologia , Estrutura Molecular , Ribose/análogos & derivados , Estereoisomerismo , Relação Estrutura-Atividade
10.
Bioorg Khim ; 37(2): 216-22, 2011.
Artigo em Russo | MEDLINE | ID: mdl-21721254

RESUMO

L-[methyl-(11C)]-methionine ([11C]MET), labelled with carbon-11 (T1/2 = 20 min), is the most commonly used amino acid radiotracer for PET diagnostics of brain tumors. The production of [11C]MET via on-line 11C-methylation of L-homocysteine thiolactone hydrochloride (lactone) on C18 solid-phase extraction cartridge creates a problem of insufficient enantiomeric purity (content of L-isomer) of the product. The results of a systematic study of the influence of reaction parameters (lactone/base and the EtOH/H20 ratios, time of 11C-methylation) on the content of L-isomer in the preparation are presented. The developed method of on-line [11C]MET synthesis allows to obtain a product with a sufficiently high radiochemical yield (75 +/- 3%, n = 100, based on [11C]CH3I) and reliably high content of L-isomer (93.7 +/- 0.5%) satisfying the requirements of clinical applications. [11C] MET synthesis was performed on a fully automated module designed by the Institute of Human Brain (IHB RAS).


Assuntos
Neoplasias Encefálicas/diagnóstico , Homocisteína/análogos & derivados , Metionina/síntese química , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Animais , Automação Laboratorial , Neoplasias Encefálicas/patologia , Radioisótopos de Carbono/química , Fenômenos Químicos , Homocisteína/síntese química , Humanos , Metionina/análogos & derivados , Metilação , Estereoisomerismo
11.
Bioorg Med Chem Lett ; 21(13): 4050-3, 2011 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-21632244

RESUMO

A N-trifluoroacetyl-protected amino acid containing a thioester function, 2,2,2-trifluoro-N-(2-oxo-tetrahydrothiophen-3-yl)acetamide (TFA-tHcy), has been synthesized and characterized. It was then used to prepare a fluorine-labeled N-homocysteinylated protein, (19)F-Hcy-εN-Lys-albumin, that was characterized by SDS-PAGE, MALDI-TOF-MS, UV-vis and (19)F NMR spectroscopy. On average, four N-trifluoroacetylhomocysteine residues were covalently conjugated to human serum albumin through the N-substituted homocysteine thiolactone. The in situ homocysteinylation of human plasma proteins with TFA-tHcy has also been performed and has led to the formation of N-homocysteinylated proteins, with albumin modification accounting for ca. 75% of all fluorine-labeled human plasma proteins. The synthesized fluorinated molecular probes can be potentially used as informative molecular probes for in vivo (19)F magnetic resonance spectroscopy and imaging.


Assuntos
Corantes Fluorescentes/síntese química , Homocisteína/síntese química , Espectroscopia de Ressonância Magnética , Eletroforese em Gel de Poliacrilamida , Corantes Fluorescentes/química , Homocisteína/química , Humanos , Estrutura Molecular , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
12.
J Med Chem ; 54(6): 1860-70, 2011 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-21351733

RESUMO

Interest in radiolabeled amino acids for metabolic imaging of cancer and limitations with [(11)C]methionine has prompted the development of a new (18)F-labeled methionine derivative S-(3-[(18)F]fluoropropyl)homocysteine ([(18)F]FPHCys). The L and D enantiomers of [(18)F]FPHCys were prepared from their respective protected S-(3-tosyloxypropyl)homocysteine precursors 1 by [(18)F]fluoride substitution using K(2.2.2) and potassium oxalate, followed by acid hydrolysis on a Tracerlab FX(FN) synthesis module. [(18)F]-L-FPHCys and [(18)F]-D-FPHCys were isolated in 20 ± 5% radiochemical yield and >98% radiochemical and enantiomeric purity in 65 min. Competitive uptake studies in A375 and HT29 tumor cells suggest that L- and D-[(18)F]FPHCys are taken up by the L-transporter system. [(18)F]-L-FPHCys and [(18)F]-D-FPHCys displayed good stability In Vivo without incorporation into protein at least 2 h postinjection. Biodistribution studies demonstrate good uptake in A375 tumor-bearing rodents with tumor to blood ratios of 3.5 and 5.0 for [(18)F]-L-FPHCys and [(18)F]-D-FPHCys, respectively, at 2 h postinjection.


Assuntos
Homocisteína/análogos & derivados , Neoplasias Experimentais/diagnóstico por imagem , Compostos Radiofarmacêuticos/síntese química , Sistema A de Transporte de Aminoácidos/antagonistas & inibidores , Sistema A de Transporte de Aminoácidos/metabolismo , Sistema L de Transporte de Aminoácidos/antagonistas & inibidores , Sistema L de Transporte de Aminoácidos/metabolismo , Animais , Linhagem Celular Tumoral , Radioisótopos de Flúor , Homocisteína/síntese química , Homocisteína/química , Homocisteína/farmacocinética , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Experimentais/metabolismo , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacocinética , Estereoisomerismo , Relação Estrutura-Atividade , Distribuição Tecidual
13.
Orig Life Evol Biosph ; 41(3): 201-12, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21063908

RESUMO

Original extracts from an unpublished 1958 experiment conducted by the late Stanley L. Miller were recently found and analyzed using modern state-of-the-art analytical methods. The extracts were produced by the action of an electric discharge on a mixture of methane (CH(4)), hydrogen sulfide (H(2)S), ammonia (NH(3)), and carbon dioxide (CO(2)). Racemic methionine was formed in significant yields, together with other sulfur-bearing organic compounds. The formation of methionine and other compounds from a model prebiotic atmosphere that contained H(2)S suggests that this type of synthesis is robust under reducing conditions, which may have existed either in the global primitive atmosphere or in localized volcanic environments on the early Earth. The presence of a wide array of sulfur-containing organic compounds produced by the decomposition of methionine and cysteine indicates that in addition to abiotic synthetic processes, degradation of organic compounds on the primordial Earth could have been important in diversifying the inventory of molecules of biochemical significance not readily formed from other abiotic reactions, or derived from extraterrestrial delivery.


Assuntos
Metionina/síntese química , Compostos de Enxofre/síntese química , Amônia/química , Dióxido de Carbono/química , Cromatografia Líquida de Alta Pressão , Cisteamina/síntese química , Cisteína/análogos & derivados , Cisteína/síntese química , Eletricidade , História do Século XX , Homocisteína/análogos & derivados , Homocisteína/síntese química , Sulfeto de Hidrogênio/química , Metano/química , Metionina/análogos & derivados , Raios Ultravioleta
14.
J Med Chem ; 52(12): 3652-65, 2009 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-19534555

RESUMO

Betaine-homocysteine S-methyltransferase (BHMT) catalyzes the transfer of a methyl group from betaine to l-homocysteine, yielding dimethylglycine and l-methionine. In this study, we prepared a new series of BHMT inhibitors. The inhibitors were designed to mimic the hypothetical transition state of BHMT substrates and consisted of analogues with NH, N(CH(3)), or N(CH(3))(2) groups separated from the homocysteine sulfur atom by a methylene, ethylene, or a propylene spacer. Only the inhibitor with the N(CH(3)) moiety and ethylene spacer gave moderate inhibition. This result led us to prepare two inhibitors lacking a nitrogen atom in the S-linked alkyl chain: (RS,RS)-5-(3-amino-3-carboxypropylthio)-3-methylpentanoic acid and (RS)-5-(3-amino-3-carboxypropylthio)-3,3-dimethylpentanoic acid. Both of these compounds were highly potent inhibitors of BHMT. The finding that BHMT does not tolerate a true betaine mimic within these inhibitors, especially the nitrogen atom, is surprising and evokes questions about putative conformational changes of BHMT upon the binding of the substrates/products and inhibitors.


Assuntos
Betaína-Homocisteína S-Metiltransferase/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Homocisteína/análogos & derivados , Ácidos Pentanoicos/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Homocisteína/síntese química , Homocisteína/química , Homocisteína/farmacologia , Humanos , Estrutura Molecular , Ácidos Pentanoicos/síntese química , Ácidos Pentanoicos/química , Estereoisomerismo , Relação Estrutura-Atividade
15.
Bioorg Med Chem Lett ; 19(10): 2742-6, 2009 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-19364644

RESUMO

Potent SAH analogues with constrained homocysteine units have been designed and synthesized as inhibitors of human DNMT enzymes. The five membered (2S,4S)-4-mercaptopyrrolidine-2-carboxylic acid, in 1a, was a good replacement for homocysteine, while the corresponding six-member counterpart was less active. Further optimization of 1a, changed the selectivity profile of these inhibitors. A Chloro substituent at the 2-position of 1a, compound 1d, retained potency against DNMT1, while N(6) alkylation, compound 7a, conserved DNMT3b2 activity. The concomitant substitutions of 1a at both 2- and N(6) positions reduced activity against both enzymes.


Assuntos
DNA (Citosina-5-)-Metiltransferases/antagonistas & inibidores , Inibidores Enzimáticos/química , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Homocisteína/análogos & derivados , Pirrolidinas/síntese química , DNA (Citosina-5-)-Metiltransferase 1 , DNA (Citosina-5-)-Metiltransferases/metabolismo , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/química , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Homocisteína/síntese química , Homocisteína/farmacologia , Humanos , Pirrolidinas/química , Pirrolidinas/farmacologia , Relação Estrutura-Atividade
16.
Bioorg Med Chem ; 16(9): 5090-102, 2008 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-18375129

RESUMO

Treatment of the protected ribose or xylose 5-aldehyde with sulfonyl-stabilized fluorophosphonate gave (fluoro)vinyl sulfones. Stannyldesulfonylation followed by iododestannylation afforded 5,6-dideoxy-6-fluoro-6-iodo-d-ribo or xylo-hex-5-enofuranoses. Coupling of the hexenofuranoses with alkylzinc bromides gave 10-carbon ribosyl- and xylosylhomocysteine analogues incorporating a fluoroalkene. The fluoroalkenyl and alkenyl analogues were evaluated for inhibition of Bacillus subtilis S-ribosylhomocysteinase (LuxS). One of the compounds, 3,5,6-trideoxy-6-fluoro-d-erythro-hex-5-enofuranose, acted as a competitive inhibitor of moderate potency (K(I)=96microM).


Assuntos
Carbono/química , Inibidores Enzimáticos/química , Homocisteína/análogos & derivados , Sulfonas/química , Enxofre/química , Compostos de Vinila/química , Bacillus subtilis/enzimologia , Proteínas de Bactérias/antagonistas & inibidores , Liases de Carbono-Enxofre/antagonistas & inibidores , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Homocisteína/síntese química , Homocisteína/química , Homocisteína/farmacologia , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-Atividade
17.
Rev. lab. clín ; 1(1): 13-16, mar. 2008. tab, ilus
Artigo em Espanhol | IBECS | ID: ibc-84419

RESUMO

Introducción y objetivos. La homocisteína se relaciona con enfermedad vascular, alteraciones del estado nutricional y detección de homocistinuria en neonatos, entre otras enfermedades. Debido a la importancia de su determinación, han aparecido diferentes métodos de cuantificación; el objeto de este trabajo es evaluar el método inmunonefelométrico del aparato BN II (Dade Behring). Material y método. Se realizó una comparación entre 2 métodos de cuantificación: el inmunoanálisis competitivo (IMMULITE 2000, DPC) y el análisis nefelométrico (BN II, Dade Behring), para lo cual se compararon los resultados de 74 muestras, además de determinar la imprecisión intraserial, imprecisión interdiaria, el límite de detección, el límite de cuantificación y el valor crítico del método inmunonefelométrico del BN II de Dade Behring. Resultados. La comparación entre ambos métodos mostró una buena correlación entre el inmunoanálisis competitivo, IMMULITE 2000 de DPC y el análisis nefelométrico, BN II de Dade Behring (Y = 1,4825 + 0,8342X). El valor crítico obtenido fue de 5,46 mmol/l y el límite de detección, de 5,77 mmol/l. La imprecisión intraserial fue inferior al 5% (3,65-4,66%). Conclusiones. El análisis nefelométrico (BN II, Dade Behring) ha demostrado cumplir todos los requisitos técnicos necesarios para su validación como método para la determinación de la homocisteína(AU)


Introduction. The homocysteine is associated with vascular diseases, alterations in the nutritional states, homocystinuria detection in neonates, as well as other diseases. Due to the importance of its determination, different measurement methods have been developed. The aim of this work is to evaluate the imunonephelometric method used in the Dade Behring BN II Nephelometer system. Material and method. We present a comparison between 2 methods: a competitive inmunoassay (IMMULITE 2000, DPC) and the nephelometric test (BN II, Dade Behring). For the determination of within batch and between-day imprecision, 74 samples were analysed and compared. Results. The detection and quantification limits, and the critical value of the inmunonephelometric method, were also determined. Both methods showed good correlations (Y = 1.4825 + 0.8342X). We also obtained a critical value of 5.46 mmol/L and the detection limit was 5.77 mmol/L. Within batch imprecision was below 5 % (3.65-4.66%). Conclusions. The nephelometric test (Dade Behring BN II System) has demonstrated to fulfill all the technical requirements needed for its validation as a method for the determination of homocysteine(AU)


Assuntos
Humanos , Masculino , Feminino , Homocisteína/análise , Homocisteína/biossíntese , Homocisteína/síntese química , Nefelometria e Turbidimetria/instrumentação , Nefelometria e Turbidimetria , Doenças Vasculares/diagnóstico , Doenças Vasculares/patologia , Imunoensaio/métodos , Técnicas de Laboratório Clínico , Técnicas de Laboratório Clínico , Nefelometria e Turbidimetria/tendências , Técnicas de Laboratório Clínico/instrumentação , Técnicas de Laboratório Clínico/tendências
18.
Artigo em Inglês | MEDLINE | ID: mdl-18058535

RESUMO

Selective cross-coupling of the protected 6-fluoro-6-iodo-alpha-D-ribo-hex-5-enofuranose with 2 equivalents of 4-ethoxy-4-oxobutylzinc bromide in the presence of Pd[P(Ph)(3)](4) followed by deprotections gave methyl 5,6,7,8,9-pentadeoxy-6-fluoro-alpha/beta-D-ribo-dec-5(Z)-enofuranuronate; a S-ribosylhomocysteine analogue with the sulfur and carbon-5 atoms replaced by the fluoro(vinyl) unit.


Assuntos
Proteínas de Bactérias/antagonistas & inibidores , Liases de Carbono-Enxofre/antagonistas & inibidores , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Homocisteína/análogos & derivados , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Homocisteína/síntese química , Homocisteína/química , Homocisteína/farmacologia
19.
J Med Chem ; 50(19): 4630-41, 2007 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-17725337

RESUMO

Bioisosteric replacements of the distal acidic group of L-glutamic acid (L-Glu, 1) and conformational constraining of its carbon skeleton, have been widely exploited to discover competitive modulators of glutamate receptors. Noteworthy, L-homocysteic acid (L-HCA, 18), a neurotransmitter belonging to the class of excitatory sulfur-containing amino acids, may be considered an endogenous occurring bioisoster of L-Glu (1). L-HCA (18) has been reported to mediate signaling between glial cells and postsynaptic neurons through the activation of glutamate receptors and others hitherto not well-characterized receptors. As a continuation of our work in the preparation of conformationally constrained glutamate analogs, we report the synthesis and the preliminary pharmacological characterization at iGluRs and mGluRs of all eight stereoisomers of 2-(2'-sulfonocyclopropyl)glycine (SCGs, 8-15). Among the reported compounds, S-SCG-4 (15) showed to be a potent and relatively selective AMPA ligand. Docking experiments coupled to molecular electrostatic potential calculations allowed insight into the molecular basis of the activity of this compound to be gained. The library of SCGs (8-15), while providing a novel source of modulators of the glutamate receptors, represents a valuable chemical tool to better characterize L-HCA pathways in the CNS.


Assuntos
Ciclopropanos/síntese química , Glicina/análogos & derivados , Glicina/síntese química , Homocisteína/análogos & derivados , Modelos Moleculares , Sulfonas/síntese química , Animais , Encéfalo/metabolismo , Linhagem Celular , Cricetinae , Cristalografia por Raios X , Ciclopropanos/química , Ciclopropanos/farmacologia , Glicina/química , Glicina/farmacologia , Homocisteína/síntese química , Homocisteína/química , Homocisteína/farmacologia , Técnicas In Vitro , Conformação Molecular , Análise de Componente Principal , Ratos , Receptores de AMPA/metabolismo , Receptores de Ácido Caínico/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonas/química , Sulfonas/farmacologia , Termodinâmica
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