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1.
J Med Chem ; 63(5): 2282-2291, 2020 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-31418565

RESUMO

Cancer immunotherapy has gained increasing attention due to its potential specificity and lack of adverse side effects when compared to more traditional modes of treatment. Toll-like receptor 2 (TLR2) agonists are lipopeptides possessing the S-[2,3-bis(palmitoyloxy)propyl]-l-cysteine (Pam2Cys) motif and exhibit potent immunostimulatory effects. These agonists offer a means of providing "danger signals" in order to activate the immune system toward tumor antigens. Thus, the development of TLR2 agonists is attractive in the search of potential immunostimulants for cancer. Existing SAR studies of Pam2Cys with TLR2 indicate that the structural requirements for activity are, for the most part, very intolerable. We have investigated the importance of stereochemistry, the effect of N-terminal acylation, and homologation between the two ester functionalities in Pam2Cys-conjugated lipopeptides on TLR2 activity. The R diastereomer is significantly more potent than the S diastereomer and N-terminal modification generally lowers TLR2 activity. Most notably, homologation gives rise to analogues which are comparatively active to the native Pam2Cys containing constructs.


Assuntos
Adjuvantes Imunológicos/química , Adjuvantes Imunológicos/farmacologia , Lipopeptídeos/química , Lipopeptídeos/farmacologia , Receptor 2 Toll-Like/agonistas , Adjuvantes Imunológicos/síntese química , Vacinas Anticâncer/farmacologia , Cisteína/análogos & derivados , Cisteína/síntese química , Cisteína/farmacologia , Humanos , Lipopeptídeos/síntese química , Neoplasias/prevenção & controle , Estereoisomerismo , Receptor 2 Toll-Like/metabolismo
2.
J Org Chem ; 84(18): 11441-11449, 2019 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-31432682

RESUMO

Persulfides have been considered as potential signaling compounds similar to the H2S in "S-persulfidation", a sulfur-mediated redox cycle. The research of this sulfur-mediated species is hindered because of the lack of efficient persulfide donors. In this current study, we have developed one- and two-photon-activated persulfide donors based on an o-nitrobenzyl (ONB) phototrigger, which releases the biologically active persulfide (N-acetyl l-cysteine persulfide, NAC-SSH) in a spatiotemporal manner. Next, we have demonstrated the detection of persulfide release both qualitatively and quantitatively using the well-known "turn on" fluorescence probe, that is, monobromobimane, and the trapping agent, that is, 2,4-dinitrofluorobenzene, respectively. Furthermore, we examined the cytotoxicity of synthesized persulfide donors on HeLa cells and the cytoprotective ability in the highly oxidizing cellular environment.


Assuntos
Antineoplásicos/síntese química , Antioxidantes/síntese química , Cisteína/análogos & derivados , Dissulfetos/síntese química , Descoberta de Drogas/métodos , Fótons , Antineoplásicos/química , Antineoplásicos/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cisteína/síntese química , Cisteína/química , Cisteína/farmacologia , Citoproteção/efeitos dos fármacos , Dissulfetos/química , Dissulfetos/farmacologia , Relação Dose-Resposta a Droga , Células HeLa , Humanos , Estrutura Molecular , Terapia de Alvo Molecular
3.
Methods Enzymol ; 624: 129-149, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31370927

RESUMO

The photo-control of protein activity can often be achieved via the photo-control of protein structure. Intramolecular cross-linkers that change length upon photoisomerization provide a means to photo-control protein structure by linking to pairs of Cys residues in a protein sequence. In this protocol, we describe general methods for introducing intramolecular cross-linkers, both UV light switchable and red-light switchable, under either denaturing or native conditions.


Assuntos
Compostos Azo/química , Reagentes para Ligações Cruzadas/química , Cisteína/química , Proteínas/química , Sequência de Aminoácidos , Compostos Azo/síntese química , Técnicas de Química Sintética/métodos , Cromatografia Líquida de Alta Pressão/métodos , Reagentes para Ligações Cruzadas/síntese química , Cisteína/síntese química , Luz , Modelos Moleculares , Processos Fotoquímicos , Conformação Proteica , Dobramento de Proteína , Proteínas/síntese química , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Espectrofotometria Ultravioleta/métodos , Raios Ultravioleta
4.
Molecules ; 24(13)2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31269651

RESUMO

This is the first report describing an analytical method for quantitative analysis of two naturally occurring sulphur compounds, S-methyl-l-cysteine (SMC) and S-methyl-l-cysteine sulfoxide (SMCSO), in human body fluids using isotope-labelled internal standards and liquid chromatography-mass spectrometry (LC-MS)/MS techniques. This method was validated according to the guideline of the Royal Society of Chemistry Analytical Methods Committee. It offers significant advantages including simple and fast preparation of human biological samples. The limits of detection of SMC were 0.08 µM for urine and 0.04 µM for plasma. The limits of detection of SMCSO were 0.03 µM for urine and 0.02 µM for plasma. The calibration curves of all matrices showed linearity with correlation coefficients r2 > 0.9987. The intra and inter day precisions in three levels of known concentrations were >10% and >20%, respectively. The quantification accuracy was 98.28 ± 5.66%. The proposed method would be beneficial for the rapid and accurate determination of the SMC and SMCSO in human plasma and urine samples using by isotope labelled internal standards.


Assuntos
Cromatografia Líquida/métodos , Cisteína/análogos & derivados , Espectrometria de Massas em Tandem/métodos , Adolescente , Adulto , Idoso , Cisteína/sangue , Cisteína/síntese química , Cisteína/química , Cisteína/urina , Feminino , Humanos , Marcação por Isótopo , Masculino , Pessoa de Meia-Idade , Padrões de Referência , Reprodutibilidade dos Testes , Adulto Jovem
5.
Bioconjug Chem ; 30(6): 1636-1641, 2019 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-31181891

RESUMO

Capsid of tomato bushy stunt virus consists of an outer coat protein shell decorated on an internal skeleton comprising a ß-annulus motif. We mimicked this capsid structure with our artificial viral capsid dressed up with protein. We synthesized the ß-annulus peptide bearing a Cys at the C-terminal side and linked it with Cys34 of the human serum albumin (HSA) via a bismaleimide linker. The ß-annulus peptide-HSA conjugate self-assembled into spherical structures of a 50-70 nm size range in the Tris-HCl buffer, with the ζ-potential of assemblies of such conjugate revealing that HSA proteins were displayed on the outer surface of the artificial viral capsid. Interestingly, the critical aggregation concentration (CAC) of the conjugate in the Tris-HCl buffer at 25 °C was approximately 0.01 µM, or 1/2500 lower than that of the unmodified ß-annulus peptides, suggesting that the artificial viral capsids were stabilized via HSA modification. The present strategy of constructing protein nanocapsule by self-assembly of a ß-annulus peptide-protein conjugate is simpler than that of previously reported protein nanocapsules.


Assuntos
Capsídeo/química , Cisteína/química , Nanocápsulas/química , Peptídeos/química , Albumina Sérica Humana/química , Reagentes para Ligações Cruzadas/síntese química , Reagentes para Ligações Cruzadas/química , Cisteína/síntese química , Humanos , Maleimidas/síntese química , Maleimidas/química , Modelos Moleculares , Peptídeos/síntese química , Albumina Sérica Humana/síntese química
6.
Molecules ; 24(13)2019 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-31252546

RESUMO

The mechanism by which cysteine-S-sulfate is formed from the reaction of sulfite with cystine in the absence of a dedicated oxidizing agent is investigated using high-resolution NMR. Changes to reactant ratio, pH, UV light exposure and temperature were evaluated to determine the most effective conditions to achieve the maximum yield of cysteine-S-sulfate without recourse to conventional oxidizing reagents. Herein evidence is provided for both nucleophilic and radical mechanisms, by which cysteine-S-sulfate can be generated with yields of up to 96%.


Assuntos
Cisteína/análogos & derivados , Cisteína/química , Sulfitos/química , Cisteína/síntese química , Concentração de Íons de Hidrogênio , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Processos Fotoquímicos , Temperatura
7.
Bioorg Med Chem ; 27(15): 3421-3439, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31204229

RESUMO

Compounds that react irreversibly with cysteines have reemerged as potent and selective tools for altering protein function, serving as chemical probes and even clinically approved drugs. The exquisite sensitivity of human immune cell signaling pathways to oxidative stress indicates the likely, yet still underexploited, general utility of covalent probes for selective chemical immunomodulation. Here, we provide an overview of immunomodulatory cysteines, including identification of electrophilic compounds available to label these residues. We focus our discussion on three protein classes essential for cell signaling, which span the 'druggability' spectrum from amenable to chemical probes (kinases), somewhat druggable (proteases), to inaccessible (phosphatases). Using existing inhibitors as a guide, we identify general strategies to guide the development of covalent probes for selected undruggable classes of proteins and propose the application of such compounds to alter immune cell functions.


Assuntos
Cisteína/farmacologia , Inibidores Enzimáticos/farmacologia , Fatores Imunológicos/farmacologia , Peptídeo Hidrolases/metabolismo , Monoéster Fosfórico Hidrolases/antagonistas & inibidores , Fosfotransferases/antagonistas & inibidores , Cisteína/síntese química , Cisteína/química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Fatores Imunológicos/síntese química , Fatores Imunológicos/química , Estrutura Molecular , Monoéster Fosfórico Hidrolases/metabolismo , Fosfotransferases/metabolismo , Transdução de Sinais/efeitos dos fármacos
8.
Mol Pharm ; 16(3): 1211-1219, 2019 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-30707584

RESUMO

The objective of the study was to compare poly(acrylic acid)- N-hydroxysulfosuccinimide reactive esters (PAA-Sulfo-NHS) and poly(acrylic acid)-cysteine conjugates (PAA-Cys) regarding their mucoadhesiveness. Polymer conjugates were synthesized in a water free environment and characterized by UV-vis spectroscopy and FTIR. Water uptake studies were performed, and the polymers were further examined for their mucoadhesive properties and cohesiveness using the rotating cylinder method. Tensile force measurements were conducted to define the strength of adhesion to porcine intestinal mucosa. Additionally, polymer-mucus mixtures were assessed for rheological synergism by measuring the increase in dynamic viscosity. Both modifications led to a prolonged adhesion time compared to unmodified PAA. Fast dissolution of PAA-Sulfo-NHS derivatives was monitored, whereas PAA-Cys tended to extensively swell while exhibiting high cohesive properties. Measurements of tensile force revealed up to 2.7-fold (PAA-Sulfo-NHS) and 2.3-fold (PAA-Cys) enhancement of the maximum detachment force and 7.6-fold (PAA-Sulfo-NHS) and 3.6-fold (PAA-Cys) increase in the total work of adhesion. Formation of a gel network between polymer and mucus was confirmed by a 10.8-fold (PAA-Sulfo-NHS) and 20.8-fold (PAA-Cys) increase in viscosity. Both types of polymers show high mucoadhesive properties due to the formation of covalent bonds with the mucus. As thiolated polymers are capable of forming stabilizing disulfide bonds within their polymeric network, they are advantageous over PAA-Sulfo-NHS.


Assuntos
Resinas Acrílicas/química , Cisteína/análogos & derivados , Ésteres/química , Mucosa Intestinal/química , Succinimidas/química , Adesividade , Animais , Células CACO-2 , Sobrevivência Celular/efeitos dos fármacos , Cisteína/síntese química , Cisteína/química , Sistemas de Liberação de Medicamentos , Estabilidade de Medicamentos , Sinergismo Farmacológico , Ésteres/síntese química , Hemólise/efeitos dos fármacos , Humanos , Hidrólise , Muco/fisiologia , Suínos , Resistência à Tração , Viscosidade
9.
Analyst ; 144(1): 180-185, 2018 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-30379147

RESUMO

S-nitrosothiols (RSNOs) are very important biomolecules that play crucial roles in many physiological and physiopathological processes. They act as NO-donors and are candidates for future medicines. Their identification and quantitation are therefore important for biomedical applications. One, two or more RSNOs can then be combined to design a drug and therefore, the quantification of each is important to establish an acceptable quality control process. Till date, miniaturized devices have been used to detect RSNOs based on their total quantitation without a preceding separation step. This study reports on an original and integrated microdevice allowing for the successive electrokinetic separation of low molecular weight RSNOs, their decomposition under metal catalysis, and their quantitation by amperometric detection of the produced nitrite in the end-channel arrangement, leading to their quantitation in a single run. For this purpose, a commercial SU-8/Pyrex microfluidic system was coupled to a portable and wireless potentiostat. Different operating and running parameters were optimized to achieve the best analytical data, allowing for an LOD equal to 20 µM. The simultaneous separation of S-nitrosoglutathione and S-nitrosocysteine was successfully obtained within 75 s. The proposed methodology using SU-8/Pyrex microfluidic devices opens new possibilities to investigate future drug candidates for NO-donors.


Assuntos
Cisteína/análogos & derivados , Dispositivos Lab-On-A-Chip , Técnicas Analíticas Microfluídicas/métodos , S-Nitrosoglutationa/análise , S-Nitrosotióis/análise , Catálise , Cobre/química , Cisteína/análise , Cisteína/síntese química , Cisteína/química , Técnicas Eletroquímicas/instrumentação , Técnicas Eletroquímicas/métodos , Limite de Detecção , Técnicas Analíticas Microfluídicas/instrumentação , S-Nitrosoglutationa/síntese química , S-Nitrosoglutationa/química , S-Nitrosotióis/síntese química , S-Nitrosotióis/química
10.
Angew Chem Int Ed Engl ; 57(50): 16533-16537, 2018 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-30346110

RESUMO

One-pot multiple peptide ligation is a key technology to improve the efficiency of chemical protein synthesis. One-pot repetitive peptide ligation requires a cycle of three steps: peptide ligation, removal of a protecting group, and inactivation of the deprotection reagent. However, previous strategies are not sufficient because of harsh deprotection conditions, slow deprotection rates, and difficulty in quenching the deprotection reagent. To address these issues, we developed a rapid, efficient deprotection and subsequent quenching strategy using an allyloxycarbonyl group to protect the N-terminal cysteine residue. 4-Mercaptophenylacetic acid (MPAA), a thiol additive for native chemical ligation, functioned not only as a scavenger for π-allyl palladium complexes, but also as a quencher of palladium(0) complexes. By utilizing the multifunctionality of MPAA, we carried out a one-pot five-segment ligation to afford histone H2AX (142 amino acids), which was isolated in 59 % yield.


Assuntos
Cisteína/química , Histonas/síntese química , Peptídeos/síntese química , Fenilacetatos/química , Técnicas de Química Sintética , Cisteína/síntese química , Histonas/química , Humanos , Modelos Moleculares , Paládio/química , Peptídeos/química
11.
Angew Chem Int Ed Engl ; 57(36): 11640-11643, 2018 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-29978532

RESUMO

We report a new method herein coined SP-CLipPA (solid-phase cysteine lipidation of a peptide or amino acid) for the synthesis of mono-S-lipidated peptides. This technique utilizes thiol-ene chemistry for conjugation of a vinyl ester to a free thiol of a semiprotected, resin-bound peptide. Advantages of SP-CLipPA include: ease of handling, conversions of up to 91 %, by-product removal by simple filtration, and a single purification step. Additionally, the desired lipidated products show high chromatographic separation from impurities, thus facilitating RP-HPLC purification. To showcase the utility of SP-CLipPA, we synthesized a potent calcitonin gene-related peptide (CGRP) receptor antagonist peptide in excellent yield and purity. This peptide, selected from a series of lipidated analogues of CGRP8-37 and CGRP7-37 , has potential for the treatment of migraine.


Assuntos
Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/síntese química , Cisteína/química , Lipídeos/química , Peptídeos/síntese química , Técnicas de Síntese em Fase Sólida/métodos , Sequência de Aminoácidos , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/química , Cisteína/síntese química , Lipídeos/síntese química , Peptídeos/química , Estereoisomerismo
12.
J Am Chem Soc ; 140(23): 7065-7069, 2018 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-29790740

RESUMO

An efficient method for chemoselective cysteine arylation of unprotected peptides and proteins using Au(III) organometallic complexes is reported. The bioconjugation reactions proceed rapidly (<5 min) at ambient temperature in various buffers and within a wide pH range (0.5-14). This approach provides access to a diverse array of S-aryl bioconjugates including fluorescent dye, complex drug molecule, affinity label, poly(ethylene glycol) tags, and a stapled peptide. A library of Au(III) arylation reagents can be prepared as air-stable, crystalline solids in one step from commercial reagents. The selective and efficient arylation procedures presented in this work broaden the synthetic scope of cysteine bioconjugation and serve as promising routes for the modification of complex biomolecules.


Assuntos
Complexos de Coordenação/química , Cisteína/análogos & derivados , Ouro/química , Compostos Organoáuricos/química , Complexos de Coordenação/síntese química , Cisteína/síntese química , Glutationa/química , Concentração de Íons de Hidrogênio , Fenômenos de Química Orgânica , Compostos Organoáuricos/síntese química , Oxirredução
13.
Bioconjug Chem ; 29(2): 225-233, 2018 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-29341592

RESUMO

Considerable attention has been devoted to fluorinated compounds due to their unique and interesting properties. Many modern pharmaceuticals contain fluorinated substituents, which are commonly synthesized using selective fluorinating reagents. Decafluorobiphenyl (DFBP) as a fluorinated linker is susceptible to nucleophilic attack. This nucleophilic reaction has been widely studied using various nucleophiles. Sulfur and nitrogen containing nucleophiles have been of particular interest, especially in bioconjugated reactions. This review focuses on the SNAr reactivity of DFBP in formation of C-X (X = S, N) bonds, to be applied in bioconjugation in organic chemistry. The review aims to highlight the crucial factors that govern the chemistry behind the activation of F-CAr-CAr-F bonds as a linker in the synthesis of novel peptides, proteins, and biologics.


Assuntos
Compostos de Bifenilo/química , Flúor/química , Peptídeos/química , Compostos de Bifenilo/síntese química , Técnicas de Química Sintética/métodos , Cisteína/síntese química , Cisteína/química , Halogenação , Modelos Moleculares , Nitrogênio/química , Peptídeos/síntese química , Compostos de Sulfidrila/química , Enxofre/química
14.
Naunyn Schmiedebergs Arch Pharmacol ; 391(2): 123-130, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29147738

RESUMO

In this study, the protocol of a single-step L-cysteine functionalized silver nanoparticle synthesis was described. Particle size distribution was determined. The crystallinity and chemical properties were investigated using XRD, HR-TEM, and XPS methods. Acute toxicity and irritant properties of obtained nanoparticles were studied using mice and rats as an animal model. The results showed that thanks to the applied protocol, it was possible to synthesize silver nanoparticles with narrow particle size distribution. Moreover, the concentration of final product was extremely high in comparison to other known methods. These nanoparticles showed neither irritant properties nor acute toxicity.


Assuntos
Cisteína/administração & dosagem , Cisteína/síntese química , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/síntese química , Nanopartículas Metálicas/química , Prata/química , Animais , Feminino , Masculino , Camundongos , Ratos , Ratos Wistar , Pele/efeitos dos fármacos , Pele/metabolismo , Testes de Toxicidade Aguda/métodos , Difração de Raios X/métodos
15.
Chemistry ; 24(4): 818-821, 2018 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-29181870

RESUMO

3-Sulfanyl-oxetanes are presented as promising novel bioisosteric replacements for thioesters or benzyl sulfides. From oxetan-3-ols, a mild and inexpensive Li catalyst enables chemoselective C-OH activation and thiol alkylation. Oxetane sulfides are formed from various thiols providing novel motifs in new chemical space and specifically as bioisosteres for thioesters due to their similar shape and electronic properties. Under the same conditions, various π-activated secondary and tertiary alcohols are also successful. Derivatization of the oxetane sulfide linker provides further novel oxetane classes and building blocks. Comparisons of key physicochemical properties of the oxetane compounds to selected carbonyl and methylene analogues indicate that these motifs are suitable for incorporation into drug discovery efforts.


Assuntos
Álcoois/química , Compostos de Sulfidrila/química , Alquilação , Cisteína/análogos & derivados , Cisteína/síntese química , Cisteína/química , Compostos de Sulfidrila/síntese química , Sulfetos/síntese química , Sulfetos/química , Sulfonas/síntese química , Sulfonas/química
16.
Bioconjug Chem ; 29(1): 29-34, 2018 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-29231709

RESUMO

The attachment of two different functionalities in a site-selective fashion represents a great challenge in protein chemistry. We report site specific dual functionalizations of peptides and proteins capitalizing on reactivity differences of cysteines in their free (thiol) and protected, oxidized (disulfide) forms. The dual functionalization of interleukin 2 and EYFP proceeded with no loss of bioactivity in a stepwise fashion applying maleimide and disulfide rebridging allyl-sulfone groups. In order to ensure broader applicability of the functionalization strategy, a novel, short peptide sequence that introduces a disulfide bridge was designed and site-selective dual labeling in the presence of biogenic groups was successfully demonstrated.


Assuntos
Compostos Alílicos/química , Cisteína/química , Maleimidas/química , Peptídeos/química , Proteínas/química , Compostos de Sulfidrila/química , Sulfonas/química , Compostos Alílicos/síntese química , Animais , Proteínas de Bactérias/síntese química , Proteínas de Bactérias/química , Linhagem Celular , Cisteína/síntese química , Humanos , Interleucina-2/síntese química , Interleucina-2/química , Proteínas Luminescentes/síntese química , Proteínas Luminescentes/química , Maleimidas/síntese química , Camundongos , Modelos Moleculares , Peptídeos/síntese química , Proteínas/síntese química , Proteínas Recombinantes/síntese química , Proteínas Recombinantes/química , Coloração e Rotulagem/métodos , Compostos de Sulfidrila/síntese química , Sulfonas/síntese química
17.
Bioorg Med Chem Lett ; 27(11): 2410-2414, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28416133

RESUMO

The sulfinic acid analog of aspartic acid, cysteine sulfinic acid, introduces a sulfur atom that perturbs the acidity and oxidation properties of aspartic acid. Cysteine sulfinic acids are often introduced in peptides and proteins by oxidation of cysteine, but this method is limited as all cysteine residues are oxidized and cysteine residues are often oxidized to sulfonic acids. To provide the foundation for the specific incorporation of cysteine sulfinic acids in peptides and proteins, we synthesized a 9-fluorenylmethyloxycarbonyl (Fmoc) benzothiazole sulfone analog. Oxidation conditions to generate the sulfone were examined and oxidation of the Fmoc-protected sulfide (3) with NbC in hydrogen peroxide provided the corresponding sulfone (4) in the highest yield and purity. Reduction with sodium borohydride generated the cysteine sulfinic acid (5) suggesting this approach may be an efficient method to incorporate a cysteine sulfinic acid in biomolecules. A model tripeptide bearing a cysteine sulfinic acid was synthesized using this approach. Future studies are aimed at using this method to incorporate cysteine sulfinic acids in peptide hormones and proteins for use in the study of biological function.


Assuntos
Cisteína/análogos & derivados , Cisteína/síntese química , Peptídeos/síntese química , Ácidos Sulfínicos/síntese química , Benzotiazóis/síntese química , Oxirredução , Técnicas de Síntese em Fase Sólida , Solubilidade , Estereoisomerismo
18.
Biochimie ; 138: 70-81, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28454919

RESUMO

In spite of the tremendous stride in modern medicine, conventional drugs used in the hepatotoxic management are mostly inadequate. The present study aims in the synthesis of novel Schiff base compound derived using s-allyl cystiene and methionine. The newly synthesized compound, 2-((2-((2-(allylthio)-1-carboxyethyl)imino)ethylidene)amino)-4-(methylthio)butanoic acid (ACEMB) was characterized using UV-visible spectrophotometer, FTIR, 1HNMR, and GC-MS. ACEMB showed potent in vitro antioxidant property. Chronic administration of ACEMB prior to CCl4 intoxication: i) attenuated the leakage of liver injury markers, such as, enzymes (AST, ALT, GGT, ALP and LDH) and biomolecules (bilirubin) into the blood circulation; ii) normalized the concentration of total proteins, albumin and globulin to control level; and iii) protected the liver against dyslipidemia. These effects of ACEMB show the preservation of endoplasmic reticulum function against CCl4 toxicity in the liver. The protective effect of ACEMB was due to its antioxidant property, which was revealed by reduced oxidative stress (TBARS and HP) and enhanced functions of the endogenous antioxidative system (SOD, catalase, GPx, GST, GSH, vitamin E and C) against CCl4 intoxication. Also, ACEMB protected the functional activities of the various mitochondrial tricarboxylic acid cycle and oxidative phosphorylation enzymes. The biochemical alterations are in concurrence with the histological observations, wherein ACEMB pretreatment prevented the vacuolation, degeneration of nuclei and necrosis of hepatocytes. In addition, in silico analysis reveals the interaction of ACEMB in the active site of cytochrome P450. ACEMB mediates hepatoprotective effect by substituting itself as an antioxidant and decreasing oxidative stress, thereby diminishing the intracellular organelle dysfunction against CCl4 toxicity in the liver.


Assuntos
Antioxidantes/uso terapêutico , Intoxicação por Tetracloreto de Carbono/complicações , Cisteína/análogos & derivados , Iminas/uso terapêutico , Hepatopatias/tratamento farmacológico , Animais , Antioxidantes/síntese química , Sítios de Ligação , Domínio Catalítico , Cisteína/síntese química , Cisteína/uso terapêutico , Citocromo P-450 CYP2E1/metabolismo , Citocromo P-450 CYP3A/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Iminas/síntese química , Hepatopatias/etiologia , Hepatopatias/metabolismo , Masculino , Simulação de Acoplamento Molecular , Estresse Oxidativo/efeitos dos fármacos , Ratos
19.
Molecules ; 22(4)2017 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-28362335

RESUMO

S-1-Propenyl-l-cysteine (S1PC) is a stereoisomer of S-1-Propenyl-l-cysteine (SAC), an important sulfur-containing amino acid that plays a role for the beneficial pharmacological effects of aged garlic extract (AGE). The existence of S1PC in garlic preparations has been known since the 1960's. However, there was no report regarding the biological and/or pharmacological activity of S1PC until 2016. Recently, we performed a series of studies to examine the chemical, biological, pharmacological and pharmacokinetic properties of S1PC, and obtained some interesting results. S1PC existed only in trace amounts in raw garlic, but its concentration increased almost up to the level similar of SAC through aging process of AGE. S1PC showed immunomodulatory effects in vitro and in vivo, and reduced blood pressure in a hypertensive animal model. A pharmacokinetic study revealed that S1PC was readily absorbed after oral administration in rats and dogs with bioavailability of 88-100%. Additionally, S1PC had little inhibitory influence on human cytochrome P450 activities, even at a concentration of 1 mM. Based on these findings, S1PC was suggested to be another important, pharmacologically active and safe component of AGE similar to SAC. In this review, we highlight some results from recent studies on S1PC and discuss the potential medicinal value of S1PC.


Assuntos
Cisteína/química , Cisteína/farmacologia , Alho/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Vias Biossintéticas , Cisteína/análogos & derivados , Cisteína/síntese química , Cisteína/farmacocinética , Extratos Vegetais/farmacocinética , Enxofre/química , Fatores de Tempo
20.
Chemistry ; 23(2): 224-233, 2017 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-27538566

RESUMO

Synthetic methodologies to chemically modify peptide molecules have long been investigated for their impact in the field of chemical biology. They allow the introduction of biochemical probes useful for studying protein functions, for manipulating peptides with therapeutic potential, and for structure-activity relationship investigations. The commonly used approach was the derivatization of an amino acid side chain. In this regard, the cysteine, for its unique reactivity, has been widely employed as the substrate for such modifications. Herein, we report on methodologies developed to modify the cysteine thiol group through the S-alkylation reaction. Some procedures perform the alkylation of cysteine derivatives, in order to prepare building blocks to be used during the peptide synthesis, whilst some others selectively modify peptide sequences containing a cysteine residue with a free thiol group, both in solution and in the solid phase.


Assuntos
Cisteína/análogos & derivados , Peptídeos/síntese química , Técnicas de Síntese em Fase Sólida/métodos , Compostos de Sulfidrila/química , Alquilação , Sequência de Aminoácidos , Amônia/química , Aziridinas/química , Catálise , Cisteína/síntese química , Peptídeos/química , Sódio/química , Compostos de Sulfidrila/síntese química , Acetato de Zinco/química
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