RESUMO
N-Azidoacetyl-d-glucosamine (GlcNAz) is a particularly useful tool in chemical biology as the azide is a metabolically stable yet accessible handle within biological systems. Herein, we report a practical synthesis of FmocAsn(N-Ac3GlcNAz)OH, a building block for solid phase peptide synthesis (SPPS). Protecting group manipulations are minimised by taking advantage of the inherent chemoselectivity of phosphine-mediated azide reduction, and the resulting glycosyl amine is employed directly in the opening of Fmoc protected aspartic anhydride. We show potential application of the building block by establishing it as a substrate for enzymatic glycan extension using sugar oxazolines of varying size and biological significance with several endo-ß-N-acetylglucosaminidases (ENGases). The added steric bulk resulting from incorporation of the azide is shown to have no or a minor impact on the yield of enzymatic glycan extension.
Assuntos
Asparagina/síntese química , Asparagina/metabolismo , Glucosamina/síntese química , Polissacarídeos/química , Acetilglucosaminidase/metabolismo , Sequência de Aminoácidos , Aminoácidos/química , Azidas/química , Glucosamina/metabolismo , Estrutura Molecular , Oxirredução , Técnicas de Síntese em Fase Sólida/métodos , Relação Estrutura-AtividadeRESUMO
The development of a convenient and rapid method to synthesize radiolabeled, enantiomerically pure amino acids (AAs) as potential positron emission tomography (PET) imaging agents for mapping various biochemical transformations in living organisms remains a challenge. This is especially true for the synthesis of carbon-11-labeled AAs given the short half-life of carbon-11 (11 C, t1/2 =20.4â min). A facile synthetic pathway to prepare enantiomerically pure 11 C-labeled l-asparagine was developed using a partially protected serine as a starting material with a four-step transformation providing a chiral five-membered cyclic sulfamidate as the radiolabeling precursor. Its structure and absolute configuration were confirmed by X-ray crystallography. Utilizing a [11 C]cyanide nucleophilic ring opening reaction followed by selective acidic hydrolysis and deprotection, enantiomerically pure l-[4-11 C]asparagine was synthesized. Further optimization of reaction parameters, including base, metal ion source, solvent, acid component, reaction temperature and reaction time, a reliable two-step method for synthesizing l-[4-11 C]asparagine was presented: within a 45±3â min (n=5, from end-of-bombardment), the desired enantiomerically pure product was synthesized with the initial nucleophilic cyanation yield of 69±4 % (n=5) and overall two-step radiochemical yield of 53±2 % (n=5) based on starting [11 C]HCN, and with radiochemical purity of 96±2 % (n=5).
Assuntos
Asparagina/química , Compostos Radiofarmacêuticos/química , Ácidos Sulfônicos/química , Asparagina/síntese química , Radioisótopos de Carbono/química , Cristalografia por Raios X , Conformação Molecular , Nitrilas/química , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/síntese química , EstereoisomerismoRESUMO
The cystobactamids are a family of antibacterial natural products with unprecedented chemical scaffolds that are active against both Gram-positive and Gram-negative pathogens. Herein, we describe the first total synthesis of cystobactamid 919-2 from three fragments. Our convergent synthesis enabled both the confirmation of the correct structure and the determination of the absolute configuration of cystobactamid 919-2.
Assuntos
Antibacterianos/síntese química , Asparagina/análogos & derivados , Produtos Biológicos/síntese química , Nitrocompostos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Asparagina/síntese química , Asparagina/química , Asparagina/farmacologia , Bactérias/efeitos dos fármacos , Infecções Bacterianas/tratamento farmacológico , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Técnicas de Química Sintética , Humanos , Modelos Moleculares , Conformação Molecular , Nitrocompostos/química , Nitrocompostos/farmacologia , EstereoisomerismoRESUMO
Salmonella can utilize fructose-asparagine (F-Asn), a naturally occurring Amadori product, as its sole carbon and nitrogen source. Conversion of F-Asn to the common intermediates glucose-6-phosphate, aspartate, and ammonia was predicted to involve the sequential action of an asparaginase, a kinase, and a deglycase. Mutants lacking the deglycase are highly attenuated in mouse models of intestinal inflammation owing to the toxic build-up of the deglycase substrate. The limited distribution of this metabolic pathway in the animal gut microbiome raises the prospects for antibacterial discovery. We report the biochemical characterization of the kinase that was expected to transform fructose-aspartate to 6-phosphofructose-aspartate during F-Asn utilization. In addition to confirming its anticipated function, we determined through studies of fructose-aspartate analogues that this kinase exhibits a substrate-specificity with greater tolerance to changes to the amino acid (including the d-isomer of aspartate) than to the sugar.
Assuntos
Asparagina/análogos & derivados , Ácido Aspártico/análogos & derivados , Proteínas de Bactérias/química , Frutose/análogos & derivados , Regulação Bacteriana da Expressão Gênica , Fosfotransferases/química , Salmonella enterica/enzimologia , Asparagina/síntese química , Asparagina/metabolismo , Ácido Aspártico/síntese química , Ácido Aspártico/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Escherichia coli/enzimologia , Escherichia coli/genética , Frutose/síntese química , Frutose/metabolismo , Concentração de Íons de Hidrogênio , Cinética , Óperon , Fosfotransferases/genética , Fosfotransferases/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Salmonella enterica/genética , Estereoisomerismo , Especificidade por Substrato , TemperaturaRESUMO
The development of new antibiotics faces a severe crisis interâ alia owing to a lack of innovative chemical scaffolds with activities against Gram-negative and multiresistant pathogens. Herein, we report highly potent novel antibacterial compounds, the myxobacteria-derived cystobactamids 1-3, which were isolated from Cystobacter sp. and show minimum inhibitory concentrations in the low µg mL(-1) range. We describe the isolation and structure elucidation of three congeners as well as the identification and annotation of their biosynthetic gene cluster. By studying the self-resistance mechanism in the natural producer organism, the molecular targets were identified as bacterial typeâ IIa topoisomerases. As quinolones are largely exhausted as a template for new type II topoisomerase inhibitors, the cystobactamids offer exciting alternatives to generate novel antibiotics using medicinal chemistry and biosynthetic engineering.
Assuntos
Antibacterianos/química , Asparagina/análogos & derivados , Proteínas de Bactérias/antagonistas & inibidores , DNA Topoisomerases Tipo I/química , Myxococcales/enzimologia , Nitrocompostos/química , Inibidores da Topoisomerase/química , Antibacterianos/biossíntese , Antibacterianos/farmacologia , Asparagina/síntese química , Asparagina/química , Asparagina/farmacologia , Proteínas de Bactérias/metabolismo , DNA Topoisomerases Tipo I/metabolismo , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Nitrocompostos/síntese química , Nitrocompostos/farmacologia , Peptídeo Sintases/metabolismo , Inibidores da Topoisomerase/metabolismo , Inibidores da Topoisomerase/farmacologiaRESUMO
Several N-linked glycoproteins have been identified in archaea and there is growing evidence that the N-glycan is involved in survival and functioning of archaea in extreme conditions. Chemical synthesis of the archaeal N-glycans represents a crucial step towards understanding the putative function of protein glycosylation in archaea. Herein the first total synthesis of the archaeal L-asparagine linked hexasaccharide from Methanothermus fervidus is reported using a highly convergent [3+3] glycosylation approach in high overall yields. The synthesis relies on efficient preparation of regioselectively protected thioglycoside building blocks for orthogonal glycosylations and late stage N-aspartylation.
Assuntos
Archaea/química , Asparagina/síntese química , Polissacarídeos/síntese química , Asparagina/química , Glicoproteínas/metabolismo , Glicosilação , Estrutura Molecular , Polissacarídeos/químicaRESUMO
Here we present a synthetic route for solid phase synthesis of N-linked glycoconjugates containing high mannose oligosaccharides which allows the incorporation of useful functional handles on the N-terminus of asparagine. In this strategy, the C-terminus of an Fmoc protected aspartic acid residue is first attached to a solid phase support. The side chain of aspartic acid is protected by a 2-phenylisopropyl protecting group, which allows selective deprotection for the introduction of glycosylation. By using a convergent on-resin glycosylamine coupling strategy, an N-glycosidic linkage is successfully formed on the free side chain of the resin bound aspartic acid with a large high mannose oligosaccharide, Man8GlcNAc2, to yield N-linked high mannose glycosylated asparagine. The use of on-resin glycosylamine coupling provides excellent glycosylation yield, can be applied to couple other types of oligosaccharides, and also makes it possible to recover excess oligosaccharides conveniently after the on-resin coupling reaction. Useful functional handles including an alkene (p-vinylbenzoic acid), an alkyne (4-pentynoic acid), biotin, and 5-carboxyfluorescein are then conjugated onto the N-terminal amine of asparagine on-resin after the removal of the Fmoc protecting group. In this way, useful functional handles are introduced onto the glycosylated asparagine while maintaining the structural integrity of the reducing end of the oligosaccharide. The asparagine side chain also serves as a linker between the glycan and the functional group and preserves the native presentation of N-linked glycan which may aid in biochemical and structural studies. As an example of a biochemical study using functionalized high mannose glycosylated asparagine, a fluorescence polarization assay has been utilized to study the binding of the lectin Concanavalin A (ConA) using 5-carboxyfluorescein labeled high mannose glycosylated asparagine.
Assuntos
Asparagina/síntese química , Manose/síntese química , Oligossacarídeos/síntese química , Asparagina/química , Ácido Aspártico/química , Concanavalina A/química , Fluorescência , Glicosilação , Manose/química , Oligossacarídeos/química , Resinas Sintéticas/química , Técnicas de Síntese em Fase SólidaRESUMO
Adenosine diphosphate ribosylation (ADP-ribosylation) is a widely occurring post-translational modification of proteins at nucleophilic side chain of amino acid residues. Elucidation of ADP-ribosylation events would benefit greatly from the availability of well-defined ADP-ribosylated peptides and analogues thereof. In this paper we present a novel approach to the chemical synthesis of ribosylated amino acid building blocks using traceless Staudinger ligation. We describe an efficient and stereoselective synthesis of α-N-ribosyl-asparagine (α-N-ribosyl-Asn) and α-N-ribosyl-glutamine (α-N-ribosyl-Gln) building blocks starting from 5-tert-butyldiphenylsilyl-ß-D-ribofuranosyl azide. The N-glycosyl aminoacids are produced in good yields as pure α-anomers, suitably protected for peptide synthesis.
Assuntos
Aminoácidos/síntese química , Asparagina/síntese química , Glutamina/síntese química , Difosfato de Adenosina/química , Difosfato de Adenosina/metabolismo , Aminoácidos/química , Asparagina/análogos & derivados , Asparagina/química , Técnicas de Química Sintética , Glutamina/análogos & derivados , Glutamina/química , Glicosilação , Processamento de Proteína Pós-TraducionalRESUMO
Certain spiders contain large pools of polyamine toxins, which are putative pharmacological tools awaiting further discovery. Here we present a general synthesis strategy for this class of toxins and prepare five structurally varied polyamine toxins. Electrophysiological testing at three ionotropic glutamate receptor subtypes reveals that two of these, Nephila polyamine toxins 1 (NPTX-1) and 8 (NPTX-8), comprise intriguing pharmacological activities by having subnanomolar IC(50) values at kainate receptors.
Assuntos
Asparagina/análogos & derivados , Ácidos Indolacéticos/síntese química , Poliaminas/síntese química , Receptores Ionotrópicos de Glutamato/antagonistas & inibidores , Venenos de Aranha/química , Aranhas/química , Toxinas Biológicas/síntese química , beta-Alanina/química , Animais , Asparagina/síntese química , Asparagina/farmacologia , Ácidos Indolacéticos/farmacologia , Estrutura Molecular , Poliaminas/farmacologia , Receptores Ionotrópicos de Glutamato/metabolismo , Receptores de Ácido Caínico/antagonistas & inibidores , Receptores de Ácido Caínico/metabolismo , Relação Estrutura-Atividade , Toxinas Biológicas/farmacologiaRESUMO
Biodegradable stimulus-responsive polymers have attracted more attention in biomedical fields. Here, a series of pH-responsive polyaspartamide derivatives are successfully synthesized from poly(N-substituted α/ß-asparagines) by a facile, solvent-free and catalyst-free microwave-assisted method. The polymer structure is confirmed by (1)H NMR, IR and UV-Vis spectra. With much shorter reaction time (13-18 min), the degree of substitution (DS) of the anhydride-modified polyaspartamide derivatives obtained by microwave heating is two to three times higher as that obtained by conventional heating in DMF (24h). In addition, pH-induced phase transition behavior of polyaspartamide derivatives is investigated by dynamic light scattering (DLS). The critical pH transition (pHtr) of the resulted polymers increases with increasing DS of the polymers. The hydrophile-lipophile balance (HLB) of the obtained polymers is evaluated to study the relationship between pHtr and polymer structure.
Assuntos
Asparagina/síntese química , Concentração de Íons de Hidrogênio , Micro-Ondas , Polimerização , Espectroscopia de Prótons por Ressonância MagnéticaRESUMO
Suplementos nutricionales orales a base de nuevos complejos de cobre, magnesio, manganeso y zinc Los oligoelementos cobre, magnesio, manganeso y zinc intervienen en numerosos procesos metabólicos, enzimáticos, inmunológicos y tisulares, forman parte estructural de proteínas y pueden participar en la regulación de la expresión genética. La deficiencia de estos elementos esenciales dificulta el apropiado funcionamiento del organismo e induce el desarrollo de diversas enfermedades. Se debe garantizar la incorporación de oligoelementos a través de la dieta; sin embargo, la cantidad suministrada no siempre es suficiente y el uso de suplementos nutricionales convencionales presenta dos problemas; el primero se atribuye a la asociación de los metales a sales inorgánicas que generan una baja absorción e intolerancias a nivel gástrico y el segundo corresponde a las interacciones antagonistas entre diversos metales componentes de la formulación. Como una alternativa a los problemas mencionados, en este trabajo se propone la elaboración de tabletas para la administración oral de nuevos complejos de cobre, zinc, magnesio y manganeso ligados a los aminoácidos glicina y asparagina. En la síntesis de estos complejos, cada ligando se unió a duplas de cationes no antagonistas, se verificó la formación de los complejos por espectroscopía infrarroja, calorimetría de barrido diferencial, análisis termogravimétrico y difracción de rayos X de polvos, y se determinaron los tiempos de desintegración y de disolución in-vitro a las formas farmacéuticas finales.
Oral dietary supplements with copper, magnesium, manganese and zinc-based new complexes Oligoelements such as copper, magnesium, manganese and zinc are involved in several metabolic, enzymatic and immunological processes. They are also important for the integral tissue proteins and could be involved in gene expression regulation. The deficiency of these essential elements hampers the appropriate function of the body and may cause various diseases. Therefore, it is important to guarantee the incorporation of these trace elements in the diet, but the quantity provided is not always adequate for the optimum body performance. Currently, conventional nutritional supplements have two major problems. The first one is attributed to the association of inorganic salts with metals which might cause low absorption and gastric intolerance. The second problem is caused when several metals are present in a formulation which could lead to possible antagonistic interactions. For this reason, this study explores the development of cations (i.e., copper, zinc, magnesium and manganese) and amino acids (i.e., glycine and asparagine) new complexes formulated into compacts for oral administration. In each reaction, ligands were linked to non-antagonistic cation pairs. The complex formation was characterized by infrared spectroscopy, differential scanning calorimetry, thermogravimetric analysis and powder X-ray diffraction analyses. Compact disintegration and in-vitro dissolution tests for these complexes were also determined.
Assuntos
Asparagina/síntese química , Glicina/síntese química , Oligoelementos/síntese química , Calorimetria , Cobre/química , Suplementos Nutricionais , Magnésio/química , Manganês/química , Espectrofotometria Infravermelho , Termogravimetria , Difração de Raios X , Zinco/químicaRESUMO
Reduced amide pseudopeptides have been proposed as structural probes that could be useful as potential malarial vaccine components. However, designing determined pseudopeptide sequences containing isoster peptide bonds, either on an asparagine (Asn) or on a glutamine (Gln) residues, can become difficult because these precursor amino acid aldehydes are obtained in yields lower than 0.5%. This work presents a new strategy for obtaining both Asn and Gln aldehydes based on a controlled side-chain protection approach as well as a suitable solvent partition procedure. FT-IR, (1) H-NMR and (13) C-NMR were used for molecule characterization and identification. Amino acid aldehydes were successfully incorporated into a 20-mer peptide from a malarial-relevant sequence, and their impact on the molecule's conformational properties was assessed.
Assuntos
Aldeídos/síntese química , Asparagina/síntese química , Glutamina/síntese química , Técnicas de Síntese em Fase Sólida/métodos , Aldeídos/química , Amidas/síntese química , Amidas/química , Asparagina/química , Glutamina/química , OxirreduçãoRESUMO
Oligoelements such as copper, magnesium, manganese and zinc are involved in several metabolic, enzymatic and immunological processes. They are also important for the integral tissue proteins and could be involved in gene expression regulation. The deficiency of these essential elements hampers the appropriate function of the body and may cause various diseases. Therefore, it is important to guarantee the incorporation of these trace elements in the diet, but the quantity provided is not always adequate for the optimum body performance. Currently, conventional nutritional supplements have two major problems. The first one is attributed to the association of inorganic salts with metals which might cause low absorption and gastric intolerance. The second problem is caused when several metals are present in a formulation which could lead to possible antagonistic interactions. For this reason, this study explores the development of cations (i.e., copper, zinc, magnesium and manganese) and amino acids (i.e., glycine and asparagine) new complexes formulated into compacts for oral administration. In each reaction, ligands were linked to non-antagonistic cation pairs. The complex formation was characterized by infrared spectroscopy, differential scanning calorimetry, thermogravimetric analysis and powder X-ray diffraction analyses. Compact disintegration and in-vitro dissolution tests for these complexes were also determined.
Assuntos
Asparagina/síntese química , Glicina/síntese química , Oligoelementos/síntese química , Calorimetria , Cobre/química , Suplementos Nutricionais , Magnésio/química , Manganês/química , Espectrofotometria Infravermelho , Termogravimetria , Difração de Raios X , Zinco/químicaRESUMO
The Fmoc-protected heptasaccharide asparagine building block beta-GlcNAc-(1-->2)-alpha-Man-(1-->3)-[beta-GlcNAc-(1-->2)-alpha-Man-(1-->6)]beta-Man-(1-->4)-beta-GlcNAc-(1-->4)-beta-GlcNAc-(Fmoc)Asn was obtained by chemical synthesis. Two flexible strategies were developed with optimized conditions for the simultaneous debenzylation of the sugar and the amino acid part. The heptasaccharide asparagine building block is a partial structure of many glycoproteins and can be used for glycopeptide synthesis in solution and on the solid phase. In this work the heptasaccharide asparagine was elongated in solution to an Fmoc-glycopentapeptide methylester. After chemical cleavage of the Fmoc group the methylester was removed enzymatically by chymotrypsin. The use of beta-(1-->4)-galactosyltransferase and alpha-(2-->6)-sialyltransferase in the presence of alkaline phosphatase allowed the efficient transfer of four sugar units to the acceptor resulting in an undecasaccharide glycopentapeptide.
Assuntos
Asparagina/análogos & derivados , Enzimas/metabolismo , Glicopeptídeos/química , Glicopeptídeos/síntese química , Oligossacarídeos/química , Oligossacarídeos/síntese química , Animais , Asparagina/síntese química , Asparagina/química , Sequência de Carboidratos , Bovinos , Dados de Sequência MolecularRESUMO
A series of new thienyl ring containing analogues of nelfinavir and saquinavir with different substitution patterns were synthesized from suitable enantiopure diols. Their inhibitory activity against wild type recombinant HIV-1 protease was evaluated. In general thienyl groups spaced from the core by a methylene group gave products showing IC(50) in the nanomolar range, irrespective of the type and the substitution pattern of the heterocycle. The range of activity of the two most active compounds is substantially maintained or even increased against two commonly selected mutants, under drug pressure, such as V32I and V82A.
Assuntos
Asparagina/análogos & derivados , Inibidores da Protease de HIV/síntese química , Protease de HIV/química , Nelfinavir/análogos & derivados , Nelfinavir/síntese química , Quinolinas/síntese química , Saquinavir/análogos & derivados , Saquinavir/síntese química , Asparagina/síntese química , Asparagina/química , Protease de HIV/genética , Inibidores da Protease de HIV/química , Mutação , Nelfinavir/química , Quinolinas/química , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/química , Saquinavir/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Orthogonally protected L-threo-beta-ethoxyasparagine (Fmoc-EtOAsn(Trt)-OH, 1) was synthesized from diethyl (2S,3S)-2-azido-3-hydroxysuccinate 2 in eight steps as a building block for solid-phase peptide synthesis. The starting material is easily available in multi-gram scale from D-diethyltartrate. The transformation steps reported here are robust and scalable. Thus, a significant amount of 1 (1.8 g) was obtained in 21% overall yield. The synthesis reported is also expected to be useful for the preparation of other O-substituted L-threo-beta-hydroxyasparagine derivatives.
Assuntos
Asparagina/análogos & derivados , Fluorenos/síntese química , Glicopeptídeos/síntese química , Asparagina/síntese química , Asparagina/química , Ciclização , Fluorenos/química , Glicopeptídeos/química , Estrutura Molecular , EstereoisomerismoRESUMO
Asparaginyl endopeptidase, or legumain, is a lysosomal cysteine protease that was originally identified in plants and later found to be involved in antigen presentation in higher eukaryotes. Legumain is also up-regulated in a number of human cancers, and recent studies suggest that it may play important functional roles in the process of tumorigenesis. However, detailed functional studies in relevant animal models of human disease have been hindered by the lack of suitably selective small molecule inhibitors and imaging reagents. Here we present the design, optimization, and in vivo application of fluorescently labeled activity-based probes (ABPs) for legumain. We demonstrate that optimized aza-peptidyl Asn epoxides are highly selective and potent inhibitors that can be readily converted into near-infrared fluorophore-labeled ABPs for whole body, noninvasive imaging applications. We show that these probes specifically label legumain in various normal tissues as well as in solid tumors when applied in vivo. Interestingly, addition of cell-penetrating peptides to the probes enhanced cellular uptake but resulted in increased cross-reactivity toward other lysosomal proteases as the result of their accumulation in lysosomes. Overall, we find that aza-peptidyl Asn ABPs are valuable new tools for the future study of legumain function in more complex models of human disease.
Assuntos
Asparagina/análogos & derivados , Cisteína Endopeptidases/análise , Compostos de Epóxi/química , Corantes Fluorescentes/química , Neoplasias/enzimologia , Animais , Asparagina/síntese química , Asparagina/química , Carbocianinas/química , Inibidores de Cisteína Proteinase/química , Compostos de Epóxi/síntese química , Corantes Fluorescentes/síntese química , Humanos , Camundongos , Camundongos Endogâmicos , Células NIH 3T3 , Espectroscopia de Luz Próxima ao Infravermelho , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Thermolysis of isonitriles with carboxylic acids provides, in one step, N-formyl imides (see, for example, 8 + 19 --> 21). The resultant N-formyl group can be converted to N-H, NCH2OH, or NCH3. This chemistry allows for a new route for synthesizing beta-N (asparagine)-linked glycosyl amino acids.
Assuntos
Amidas/síntese química , Asparagina/síntese química , Ácidos Carboxílicos/química , Glicopeptídeos/síntese química , Nitrilas/química , Asparagina/análogos & derivados , Imidas/química , Modelos QuímicosRESUMO
Reaction of cyclic thioanhydrides with amines affords amides functionalized with thioacids, which can be trapped in situ with electron-deficient azides or, preferably, 2,4-dinitrobenzenesulfonamides. In this manner the cyclic thioanhydride serves as a linchpin in a three-component coupling sequence. The use of thiomaleic anhydride and a bifunctional nucleophile extends the process to heterocycle synthesis, while a cyclic thioanhydride prepared from aspartic acid directly provides N-functionalized asparagine derivatives.
Assuntos
Ácidos/química , Anidridos/síntese química , Azidas/química , Elétrons , Compostos Macrocíclicos/síntese química , Compostos de Sulfidrila/química , Sulfonamidas/química , Aminas/química , Anidridos/química , Asparagina/síntese química , Asparagina/química , Compostos Macrocíclicos/química , Estrutura Molecular , Nitrobenzenos/químicaRESUMO
Endomorphin-2 (1; H-Tyr-Pro-Phe-Phe-NH2; EM2) and its novel cyclic asparagine (cycloAsn) analogues, H-Tyr-cAsn(CHPh)-Phe-Phe-NH2 (2) and H-Tyr-cAsn(CHMe2)-Phe-Phe-NH2 (3), were synthesized via liquid-phase synthesis. The structures of the products and intermediates were characterized by IR, 1H-NMR, MS, and HR-MS analyses. The antinociceptive activity of EM2 and its cyclic asparagine analogues were assessed in AcOH-induced abdominal constriction tests in mice with i.p. injection. The results show that the antinociceptive activities of EM2 and its cyclic asparagine analogue 2 were higher than those of aspirine and meperidine. Analogue 2 was observed to be a stronger analgesic with dose-dependence than EM2. The test mice did not show any tendency to be addicted while administrated of analogue 2 repeatedly and regularly.