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1.
Nat Commun ; 11(1): 5340, 2020 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-33087708

RESUMO

Thiols are important precursors for the synthesis of a variety of pharmaceutically important sulfur-containing compounds. In view of the versatile reactivity of free thiols, here we report the development of a visible light-mediated direct decarboxylative thiolation reaction of alkyl redox-active esters to free thiols based on the abundant carboxylic acid feedstock. This transformation is applicable to various carboxylic acids, including primary, secondary, and tertiary acids as well as natural products and drugs, forging a general and facile access to free thiols with diverse structures. Moreover, the direct access to free thiols affords an advantage of rapid in situ diversification with high efficiency to other important thiol derivatives such as sulfide, disulfide, thiocyanide, thioselenide, etc.


Assuntos
Compostos de Sulfidrila/química , Compostos de Sulfidrila/síntese química , Descoberta de Drogas , Ésteres/síntese química , Ésteres/química , Modelos Químicos , Estrutura Molecular , Oxirredução , Processamento de Proteína Pós-Traducional , Bibliotecas de Moléculas Pequenas
2.
J Chromatogr A ; 1622: 461133, 2020 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-32354557

RESUMO

This work reports procedures for the immobilization of vinyl ligands on silica particles by UV-initiated thiol-ene radical addition reaction (photo-click immobilization). tert­Butylcarbamoyl quinine was the functional ligand (ene component) for the synthesis of chiral stationary phases. Two distinct surface chemistries were evaluated. In one approach, the ligand was directly attached to 3-mercaptopropyl-silica triggered by radicals generated by UV irradiation from a photoinitiator. In another approach, the ligand was immobilized onto vinyl silica via poly(3-mercaptopropyl-methylsiloxane) (PMPMS) as crosslinker by a photoinitiated double click reaction in which functionalization with chiral ligand and crosslinking to vinylsilica occurred simultaneously in one synthesis step. PMPMS-bonded CSPs were prepared from suspension (slurry method) or solventless after coating of the polythiol onto the vinylsilica surface (film method). Optimization by a design of experiment approach showed that the reaction time is the prime variable to optimize the surface coverage of chiral selector which also increased with PMPMS concentration. When the film formation of the latter approach was assisted by a minute volume of toluene during photo-click immobilization, selector coverage could be significantly increased to 0.73 µmol/m2 in a 2 h synthesis compared to 0.44 µmol/m2 by the solventless film method and 0.47 µmol/m2 by the slurry method under otherwise comparable conditions. The solvent assistance improved the chromatographic efficiency of the film method and resulted equal minimal reduced plate height of 2.6 as the slurry method for a chiral probe (Fmoc-Phe). The mass transfer resistance was around factor 2 smaller with the solvent-assisted film method as compared to the film approach without toluene, presumably due to a more homogenous distribution of the thin polymer film owing to lower dynamic viscosity in presence of toluene.


Assuntos
Cromatografia/métodos , Química Click/métodos , Luz , Dióxido de Silício/química , Compostos de Sulfidrila/química , Ligantes , Concentração Osmolar , Estereoisomerismo , Compostos de Sulfidrila/síntese química , Fatores de Tempo
3.
J Chromatogr A ; 1621: 461078, 2020 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-32312546

RESUMO

A new derivatization reagent, N-(naphthalen-1-yl)-2-oxopropanehydrazonoyl chloride (UOSA54), was prepared and coupled with four drugs, bearing primary amino, secondary amino or mercapto functional groups. Glucosamine sulfate (GLU), cysteine (CYS), captopril (CAP), and vildagliptin (VIL), were used as representative reactive analytes. The prepared reagent was successfully coupled with the targeted analytes in the presence of triethylamine (TEA) as hydrochloride acceptor and acetonitrile as solvent. The resulting reaction products were separated by high-performance liquid chromatography and monitored simultaneously by diode array and triple quad mass spectrometry detectors. Enhanced DAD and electrospray ionization-MS (ESI-MS) responses were observed for the derivatized products. Complete derivatization of VIL was achieved after heating at 65 ± 3 °C for 4 min, while other analytes were derivatized instantaneously at room temperature. Both, the ESI-ionization suppression, due to the excess reagent, and matrix effect, due to co-eluted biogenic plasma constituents, were negligible. The derivatized GLU, CYS, CAP, and VIL showed a maximum absorption wavelength at 376, 417, 340, and 376 nm, with MS-limit of quantification value of 250.0, 2.0, 2.5, and 3.0 pg/µL, respectively. The relative ESI-MS response of UOSA54 derivatization products was within the range of 0.6-4.1 compared with dansylated products. The method was optimized and validated for optimal reaction product stability, sensitivity, linearity, range, precision, and accuracy. The percentage recovery was exceeding 97.2%, with an RSD value of less than 4.0%. The limit of quantification of targeted analytes was ranged from 80.0 to 0.7 pg/µL.


Assuntos
Aminas/análise , Cromatografia Líquida/métodos , Iminas/análise , Espectrometria de Massas/métodos , Compostos de Sulfidrila/análise , Cromatografia Líquida de Alta Pressão , Compostos de Dansil/química , Fluorenos/síntese química , Fluorenos/química , Reprodutibilidade dos Testes , Compostos de Sulfidrila/síntese química , Compostos de Sulfidrila/química
4.
Soft Matter ; 16(12): 3039-3049, 2020 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-32129364

RESUMO

Glycoproteins are involved in the pathogenesis and development of many diseases and are used as biomarkers for disease diagnosis. It is highly desirable to develop highly sensitive and selective methods for the detection of glycoproteins without the use of antibodies. Imprinting of proteins represents one of the most challenging tasks. Glycoprotein imprinted self-assembled monolayers (SAMs) were created, for the first time, from an oligo(ethylene glycol) (OEG) terminated 1,2-dithiolane derivative linked through an alkyl chain incorporated with two amide groups (DHAP) and combined functional thiols of p-mercaptophenylboronic acid (PMBA) and p-aminothiophenol (PATP) in aqueous media, without the use of polymerization initiators. Combined action of PMBA and PATP was essential for the development of boronate recognition sites for glycoproteins at the physiological pH, attributed to the water molecule-mediated Lewis acid-base interactions between the electron-deficient PMBA and the electron-rich PATP. DHAP played key roles not only in cementation of imprinted cavities by means of double hydrogen bond networks through the amide groups but also in resistance to nonspecific protein binding by terminal OEG moieties, as well as hydrogen bond binding sites from the amide groups exposed to imprinted cavities. The created glycoprotein imprinted SAMs showed excellent recognition selectivity of target glycoproteins. The strategy for tailor-made glycoprotein imprinted SAMs explores a new avenue to the creation of intelligent biomaterials and fabrication of chemosensors.


Assuntos
Ácidos Borônicos/química , Glicoproteínas/análise , Impressão Molecular/métodos , Polímeros/química , Compostos de Sulfidrila/química , Compostos de Anilina/síntese química , Compostos de Anilina/química , Animais , Ácidos Borônicos/síntese química , Bovinos , Cavalos , Humanos , Polímeros/síntese química , Compostos de Sulfidrila/síntese química , Propriedades de Superfície
5.
Carbohydr Polym ; 236: 116021, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32172841

RESUMO

In this work, a facile click reaction strategy is employed to form hydrogels in situ with cytocompatibility, biodegradability, self-healing property and resistance to protein. The thiol-functionalized zwitterionic carboxybetaine methacrylate copolymer, which take part as a cross-linker in the "thiol-ene" click reaction with the methacrylated hyaluronic acid. The hydrogels are obtained under the physiological condition without the presence of any copper catalyst and UV light. The hydrogel consisting of zwitterionic component shows an obvious reduction in protein adsorption and cell adhesion and avoid non-targeted factor interference in the biological experiments. The hydrogels also demonstrate adjustable degradation behavior. Human mesenchymal stem cells (hMSCs) are easily encapsulated into the hydrogels and remains metabolically active, indicating the excellent biocompatibility of the hydrogels. Additionally, the result of the cytokine secretion assays (IL-6 and TNF-α) has shown that this clickable hydrogel can serve to suppress inflammatory reactions and is beneficial for in vivo applications. Based on the above results, this clickable hydrogel with excellent performance can be an amenable platform for 3D cell encapsulation.


Assuntos
Ácido Hialurônico/análogos & derivados , Hidrogéis/química , Ácidos Polimetacrílicos/química , Compostos de Sulfidrila/química , Animais , Adesão Celular/efeitos dos fármacos , Encapsulamento de Células/métodos , Sobrevivência Celular/efeitos dos fármacos , Química Click , Humanos , Ácido Hialurônico/síntese química , Ácido Hialurônico/toxicidade , Hidrogéis/síntese química , Hidrogéis/toxicidade , Interleucina-6/metabolismo , Ativação de Macrófagos/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Camundongos , Ácidos Polimetacrílicos/síntese química , Ácidos Polimetacrílicos/toxicidade , Células RAW 264.7 , Compostos de Sulfidrila/síntese química , Compostos de Sulfidrila/toxicidade , Fator de Necrose Tumoral alfa/metabolismo
6.
Molecules ; 25(1)2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31948062

RESUMO

Thioether containing peptides were obtained following three synthetic routes. In route A, halo acids esterified on 2-chlorotrityl(Cltr) resin were reacted with N-fluorenylmethoxycarbonyl (Fmoc) aminothiols. These were either cleaved from the resin to the corresponding (Fmoc-aminothiol)carboxylic acids, which were used as key building blocks in solid phase peptide synthesis (SPPS), or the N-Fmoc group was deprotected and peptide chains were elongated by standard SPPS. The obtained N-Fmoc protected thioether containing peptides were then condensed either in solution, or on solid support, with the appropriate amino components of peptides. In route B, the thioether containing peptides were obtained by the reaction of N-Fmoc aminothiols with bromoacetylated peptides, which were synthesized on Cltr-resin, followed by removal of the N-Fmoc group and subsequent peptide elongation by standard SPPS. In route C, the thioether containing peptides were obtained by the condensation of a haloacylated peptide synthesized on Cltr-resin and a thiol-peptide synthesized either on 4-methoxytrityl(Mmt) or trityl(Trt) resin.


Assuntos
Peptídeos/química , Peptídeos/síntese química , Compostos de Sulfidrila/química , Compostos de Sulfidrila/síntese química , Técnicas de Síntese em Fase Sólida
7.
Molecules ; 25(2)2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31936303

RESUMO

The diaminedithiol (N2S2) tetradentate ligand constitutes a useful chelating molecule for preparing 99mTc-labeled compounds of high in vivo stability in high radiochemical yields. However, since the thiol groups in the N2S2 ligand are easy to be oxidized to disulfide bonds, they need to be protected with an appropriate protecting group, which hinders the broad applications of the N2S2 ligand for radiopharmaceuticals. In this study, a Zn chelate of N2S2 was evaluated as a precursor for purification-free 99mTc-labeled N2S2 under the mild and simple procedure. Zn-N2S2 was prepared by reacting Zn acetate with N2S2, and the Zn-N2S2 remained stable under aerobic conditions at room temperature. 99mTc-N2S2 was obtained over 90% radiochemical yields at room temperature by a one-pot reaction, consisting of Zn-N2S2 (10-5 M), 99mTcO4-, ethylenediaminetetraacetic acid (EDTA), and a reducing agent (Sn2+) at pH = 5.5 to 7.5. 99mTc-N2S2 was also obtained over 90% radiochemical yields when the reaction was conducted in the presence of an equimolar amount of IgG antibody. These findings indicate the Zn complex of N2S2 ligand constitutes a stable and useful precursor to prepare 99mTc-labeled N2S2 compounds in high yields under the mild and simple procedure.


Assuntos
Compostos de Organotecnécio/química , Compostos de Sulfidrila/química , Zinco/química , Cromatografia Líquida de Alta Pressão , Cromatografia de Fase Reversa , Ligantes , Compostos de Organotecnécio/síntese química , Compostos de Sulfidrila/síntese química
8.
J Pharm Biomed Anal ; 177: 112871, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31539712

RESUMO

Osimertinib is a "third-generation'' oral, irreversible, tyrosine kinase inhibitor. It is used in the treatment of non-small cellular lung carcinoma and spares wild-type EGFR. Due to its reactive nature, osimertinib is, in addition to oxidative routes, metabolized through GSH coupling and subsequent further metabolism of these conjugates. The extent of the non-oxidative metabolism of osimertinib is unknown, and methods to quantify this metabolic route have not been reported yet. To gain insight into this metabolic route, a sensitive bioanalytical assay was developed for osimertinib, the active desmethyl metabolite AZ5104, and the thio-metabolites osimertinibs glutathione, cysteinylglycine, and cysteine conjugates was developed. The ease of synthesis of these metabolites was a key-part in the development of this assay. This was done through simple one-step synthesis and subsequent LC-purification. The compounds were characterized by NMR and high-resolution mass spectrometry. Sample preparation was done by a simple protein crash with acetonitrile containing the stable isotopically labeled internal standards for osimertinib and the thio-metabolites, partial evaporation of solvents, and reconstitution in eluent, followed by UHPLC-MS/MS quantification. The assay was successfully validated in a 2-2000 nM calibration range for all compounds except the glutathione metabolite, where the LLOQ was set at 6 nM due to low accuracy at 2 nM. Limited stability was observed for osimertinib, AZ5104, and the glutathione metabolite. The clinical applicability of the assay was demonstrated in samples of patients treated with 80 mg osimertinib once daily, containing all investigated compounds at detectable and quantifiable levels.


Assuntos
Acrilamidas/farmacocinética , Compostos de Anilina/farmacocinética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Monitoramento de Medicamentos/métodos , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacocinética , Acrilamidas/administração & dosagem , Acrilamidas/sangue , Acrilamidas/metabolismo , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Compostos de Anilina/administração & dosagem , Compostos de Anilina/sangue , Compostos de Anilina/metabolismo , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/genética , Cromatografia Líquida de Alta Pressão/métodos , Dipeptídeos/sangue , Dipeptídeos/síntese química , Dipeptídeos/metabolismo , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Glutationa/sangue , Glutationa/síntese química , Glutationa/metabolismo , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/genética , Pessoa de Meia-Idade , Mutação , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/metabolismo , Espectroscopia de Prótons por Ressonância Magnética , Compostos de Sulfidrila/sangue , Compostos de Sulfidrila/síntese química , Compostos de Sulfidrila/metabolismo , Espectrometria de Massas em Tandem/métodos
9.
Molecules ; 24(23)2019 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-31766740

RESUMO

N-mercaptoalkylglycine residues were inserted into peptides by reacting N-free amino groups of peptides, which were initially synthesized on 2-chlorotrityl resin (Cltr) using the Fmoc/tBu method, with bromoacetic acid and subsequent nucleophilic replacement of the bromide by reacting with S-4-methoxytrityl- (Mmt)/S-trityl- (Trt) protected aminothiols. The synthesized thiols containing peptide-peptoid hybrids were cleaved from the resin, either protected by treatment with dichloromethane (DCM)/trifluoroethanol (TFE)/acetic acid (AcOH) (7:2:1), or deprotected (fully or partially) by treatment with trifluoroacetic acid (TFA) solution using triethylsilane (TES) as a scavenger.


Assuntos
Glicina/química , Peptídeos/química , Estrutura Molecular , Peptoides/química , Técnicas de Síntese em Fase Sólida , Compostos de Sulfidrila/síntese química , Compostos de Sulfidrila/química
10.
Int J Nanomedicine ; 14: 7017-7038, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31564863

RESUMO

Background: Fabrication of a smart drug delivery system that could dramatically increase the efficiency of chemotherapeutic drugs and reduce the side effects is still a challenge for pharmaceutical researchers. By the emergence of nanotechnology, a huge window was opened towards this goal, and a wide type of nanocarriers were introduced for delivering the chemotherapeutic to the cancer cells, among them are cyclodextrins with the ability to host different types of hydrophobic bioactive molecules through inclusion complexation process. Aim: The aim of this study is to design and fabricate a pH-responsive theranostic nanocapsule based on cyclodextrin supramolecular nano-structure. Materials and methods: This nanostructure contains iron oxide nanoparticles in the core surrounded with three polymeric layers including polymeric ß-cyclodextrin, polyacrylic acid conjugated to sulfadiazine, and polyethylenimine functionalized with ß-cyclodextrin. Sulfadiazine is a pH-responsive hydrophobic component capable of making inclusion complex with ß-cyclodextrin available in the first and third layers. Doxorubicin, as an anti-cancer drug model, was chosen and the drug loading and release pattern were determined at normal and acidic pH. Moreover, the biocompatibility of the nanocapsule (with/without drug component) was examined using different techniques such as MTT assay, complement activation, coagulation assay, and hemolysis. Results: The results revealed the successful preparation of a spherical nanocapsule with mean size 43±1.5 nm and negatively charge of -43 mV that show 160% loading efficacy. Moreover, the nanocapsule has an on/off switching release pattern in response to pH that leads to drug released in low acidic pH. The results of the biocompatibility tests indicated that this nano drug delivery system had no effect on blood and immune components while it could affect cancer cells even at very low concentrations (0.3 µg mL-1). Conclusion: The obtained results suggest that this is a "switchable" theranostic nanocapsule with potential application as an ideal delivery system for simultaneous cancer diagnosis and therapy.


Assuntos
Nanocápsulas/química , Polietilenoimina/química , Nanomedicina Teranóstica , beta-Ciclodextrinas/química , Animais , Doxorrubicina/química , Doxorrubicina/farmacologia , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Compostos Férricos/química , Hemólise/efeitos dos fármacos , Humanos , Concentração de Íons de Hidrogênio , Células MCF-7 , Camundongos , Nanocápsulas/ultraestrutura , Tempo de Tromboplastina Parcial , Tempo de Protrombina , Eletricidade Estática , Compostos de Sulfidrila/síntese química , Compostos de Sulfidrila/química , Difração de Raios X , beta-Ciclodextrinas/síntese química
11.
Arch Pharm (Weinheim) ; 352(11): e1900089, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31463965

RESUMO

A new series of 2,4-disubstituted-2-thiopyrimidines 6a-t, 9a, and 9b was efficiently designed and synthesized as antiangiogenic and cytotoxic agents. Compounds 6j, 6l, and 6d showed IC50 values of 1.23, 3.78, and 3.84 µM, respectively, against the vascular endothelial growth factor receptor-2 (VEGFR-2). Most of the synthesized 2-thiouracils showed antiproliferative activity against the HepG2 cell line (hepatocellular carcinoma) in the micromolar range, for instance, 9b, 6l, 6m, 6n, and 6j displayed IC50 = 7.92, 8.35, 8.51, 9.59, and 13.06 µM, respectively, relative to sorafenib (III; IC50 = 10.99 µM). Also, compounds 6j, 9a, 6m, and 6s (IC50 = 15.21, 16.96, 17.68, and 18.15 µM, respectively) are the most potent compounds against the UO-31 cell line. Further evaluation of the effect of the synthesized candidates on VEGFR-2 in the HepG2 cell line demonstrated that compounds 6j and 6l exhibit VEGFR-2 inhibitory activity of 87% and 84%, respectively, relative to sorafenib (III; 92%). In silico docking of the synthesized hits into the binding site of VEGFR-2 showed their ability to perform the main binding interactions with the key amino acids in the binding site. Studying the in silico predicted ADME (absorption, distribution, metabolism, and excretion) parameters for the synthesized thiouracils demonstrated that they have favorable pharmacokinetic and drug-likeness properties. These results demonstrate that the 2,4-disubstituted thiouracils 6 and 9 have not only favorable antiangiogenic and antiproliferative activity but also satisfy the criteria required for the development of orally bioavailable drugs. Consequently, they represent a biologically active scaffold that should be further optimized for future discovery of potential hits.


Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Desenho de Fármacos , Neovascularização Patológica/tratamento farmacológico , Pirimidinas/farmacologia , Compostos de Sulfidrila/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/química , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células Hep G2 , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-Atividade , Compostos de Sulfidrila/síntese química , Compostos de Sulfidrila/química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
12.
Nat Commun ; 10(1): 3555, 2019 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-31391472

RESUMO

Poly-substituted aromatic sulfur compounds are widely found in pharmaceuticals, agrochemicals and organic materials. However, the position that a sulfur moiety can be introduced to is largely restricted to a pre-functionalized site; otherwise, use of electronically biased substrates or auxiliary groups that direct catalysis is required. Here we report a general ortho thiolation of common aryl and heteroaryl iodides via palladium-norbornene cooperative catalysis. Using this approach, an aryl or alky sulfur moiety can be site-selectively introduced at the arene ortho position without using sterically or electronically biased substrates. The arene ipso functionalization is simultaneously achieved through Heck, Suzuki or Sonogashira termination. The reaction is enabled by a unique class of electrophiles in palladium-norbornene cooperative catalysis, which are sulfenamides derived from seven-membered lactams. The broad substrates scope and high chemoselectivity could make this method attractive for synthesis of complex sulfur-containing aromatic compounds.


Assuntos
Técnicas de Química Sintética/métodos , Iodetos/química , Compostos de Sulfidrila/síntese química , Amidas/química , Catálise , Norbornanos/química , Paládio/química , Enxofre/química
13.
Int J Mol Sci ; 20(11)2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31141990

RESUMO

Chlorothiophenols (CTPs) are known to be key and direct precursors of polychlorinated thianthrene/dibenzothiophenes (PCTA/DTs). Self/cross-coupling of the chlorothiophenoxy radicals (CTPRs), sulfydryl-substituted phenyl radicals and thiophenoxyl diradicals evolving from CTPs are initial and important steps for PCTA/DT formation. In this study, quantum chemical calculations were carried out to investigate the homogenous gas-phase formation of PCTA/DTs from self/cross-coupling of 2,4-dichlorothiophenoxy radical (R1), 2-sulfydryl-3,5-dichlorophenyl radical (R2) and 3,5-dichlorothiophenoxyl diradical (DR) at the MPWB1K/6-311+G(3df,2p)//MPWB1K/6-31+G(d,p) level. The rate constants of crucial elementary steps were deduced over 600-1200 K, using canonical variational transition state theory with a small curvature tunneling contribution. For the formation of PCTAs, the S•/σ-C• condensation with both thiophenolic sulfur in one radical and ortho carbon in the other radical bonded to single electron is the most efficient sulfur-carbon coupling mode, and the ranking of the PCTA formation potential is DR + DR > R2 + DR > R1 + DR > R1 + R2 > R1 + R1. For the formation of PCDTs, the σ-C•/σ-C• coupling with both ortho carbon in the two radicals bonded to single electron is the energetically favored carbon-carbon coupling mode, and the ranking of the PCDT formation potential is: R2 + DR > R2 + R2 > R1 + DR > R1 + R2 > R1 + R1. The PCTA/DTs could be produced from R1, R2 and DR much more readily than PCDD/DFs from corresponding oxygen substituted radicals.


Assuntos
Compostos Heterocíclicos/síntese química , Compostos de Sulfidrila/síntese química , Tiofenos/síntese química , Simulação por Computador , Cinética
14.
Mikrochim Acta ; 186(3): 180, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30771096

RESUMO

A fluorimetric method is described for the determination of alkaline phosphatase (ALP) activity. It is based on the use of polyethyleneimine-coated silver nanoclusters (AgNCs), which display an intense blue fluorescence peaking at 450 nm (under 375 nm excitation). ALP catalyzes the dephosphorylation of the thiophosphate amifostine to generate a thiol that binds to the AgNCs and causes its fluorescence to be quenched. Under the optimal experimental conditions, fluorescence linearly drops in the 0.08-2.0 U L-1 ALP activity range, and the limit of detection is 0.02 U L-1. The method was successfully applied to the determination of ALP activity in spiked human serum samples. Graphical abstract Alkaline phosphatase (ALP) catalyzes the degradation of amifostine with a generation a thiol product. The thiol quenches the fluorescence of silver nanoclusters, and a method for the detection of ALP down to 0.02 U L-1 was developed.


Assuntos
Fosfatase Alcalina/sangue , Ensaios Enzimáticos/métodos , Fluorometria/métodos , Nanopartículas Metálicas/química , Prata/química , Fosfatase Alcalina/química , Amifostina/química , Fluorescência , Humanos , Limite de Detecção , Nanopartículas Metálicas/efeitos da radiação , Polietilenoimina/química , Compostos de Sulfidrila/síntese química , Raios Ultravioleta
15.
Comput Biol Chem ; 78: 260-272, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30597437

RESUMO

Structural and molecular properties of HL, 4-amino-5-(2,2-dichloro-1-methylcyclopropyl)-4H-1,2,4-triazole-3-thiol toward the transition metal ions namely Fe(III), Co(II) and Ni(II) had been studied using elemental analyses, magnetic, electronic, FT- IR, 1H-NMR and Thermal analyses (TGA and DTA). The interpretation of thermal decomposition stages had been evaluated. The computations had been done by software of Gaussian 09W package. The geometries of triazole-thiole ligand and its metal chelates were fully optimized using density functional theory B3LYP method. (DFT)/GENECP level by implementing Def2TZVP basis set was used for Fe, Co and Ni-atoms; and basis set 6-311++G (d, p) was used for remainder atoms. There are no symmetry constrains had been applied during geometry optimization. The mixed basis set was selected due to its flexibility. HOMO and LUMO energy values for chelates, chemical hardness and electronegativity had been calculated. NBO calculations had been done at the same level using (NBO 3.1) program involved in the software of Gaussian 09W for measurement qualitatively the intra-molecular delocalization in systems under investigation. The first 15, 85, 65 and 65 low-lying excited states for ligand and Fe, Co and Ni chelates respectively had been calculated within the vertical linear-response. TD-DFT approximation at the same level of theory was used to calculate the electronic absorption spectra of the studied compounds. Their structures are confirmed by successful correlation between experimental and theoretical calculations. The ligand and its metal chelates had been examined against two bacteria such as Gram-positive (Staphylococcus aureus ATTC 12600), GraM-Negative (Escherichia coli ATTC 11775) and two fungus (Aspergillus flavus and Candida albicans) and molecular docking using Auto Dock tools were utilized.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Quelantes/farmacologia , Complexos de Coordenação/farmacologia , Compostos de Sulfidrila/farmacologia , Triazóis/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Antifúngicos/síntese química , Antifúngicos/química , Aspergillus/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Quelantes/síntese química , Quelantes/química , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Teoria da Densidade Funcional , Escherichia coli/efeitos dos fármacos , Ligantes , Testes de Sensibilidade Microbiana , Teoria Quântica , Software , Staphylococcus aureus/efeitos dos fármacos , Compostos de Sulfidrila/síntese química , Compostos de Sulfidrila/química , Temperatura , Triazóis/síntese química , Triazóis/química
16.
Cardiovasc Res ; 115(2): 292-301, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30010817

RESUMO

Aims: Oxidative stress and inflammation play a pathogenic role in atherosclerosis. Thioredoxin-1 (Trx-1) is an anti-oxidative, anti-inflammatory protein with atheroprotective effects. However, in vivo cleavage of Trx-1 generates a truncated pro-inflammatory protein, Trx-80, which compromises the therapeutic use of Trx-1. Here we analysed whether the thioredoxin-mimetic peptide (TxMP), CB3 might exert anti-oxidative, anti-inflammatory, and atheroprotective effects in ApoE2.Ki mice. Methods and results: We synthesized a small TxMP, Ac-Cys-Pro-Cys-amide, CB3 and characterized its antioxidant and anti-inflammatory effects on cultured peritoneal murine macrophages. CB3 significantly and dose-dependently reduced the level of reactive oxygen species in lipopolysaccharides (LPS)-activated macrophages. In addition, it efficiently lowered LPS-induced inflammatory process through NF-κB inhibition, as evidenced by the reduced secretion of monocyte chemoattractant protein-1, interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α by macrophages. Nevertheless, CB3 did not affect cholesterol accumulation in macrophages. A daily-administered dose of 10 µg/g body weight CB3 to ApoE2.Ki mice on high fat diet did not affect plasma of total cholesterol and triglycerides levels but significantly reduced the plasma levels of pro-inflammatory cytokines (IL-33 and TNF-α) and oxidative markers. In contrast, it significantly induced the plasma levels of anti-inflammatory proteins (adiponectin, IL-10). In addition, CB3 reduced the number of pro-inflammatory M1 macrophages in spleen and decreased the ratio of M1/M2 macrophages in atherosclerotic lesion areas. Finally, CB3 significantly reduced the surface area of aortic lesions. Conclusions: Our results clearly showed that similar to the full length Trx-1, CB3 exerts protective effects, by reducing inflammation and oxidative stress in macrophages and in ApoE2.Ki mice. The atheroprotective effect of CB3 opens promising therapeutic approaches for treatment of atherosclerosis.


Assuntos
Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Doenças da Aorta/prevenção & controle , Aterosclerose/prevenção & controle , Dieta Hiperlipídica , Mediadores da Inflamação/metabolismo , Mimetismo Molecular , Oligopeptídeos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Placa Aterosclerótica , Compostos de Sulfidrila/farmacologia , Animais , Anti-Inflamatórios/síntese química , Antioxidantes/síntese química , Aorta/efeitos dos fármacos , Aorta/metabolismo , Aorta/patologia , Doenças da Aorta/genética , Doenças da Aorta/metabolismo , Doenças da Aorta/patologia , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Células Cultivadas , Modelos Animais de Doenças , Feminino , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Oligopeptídeos/síntese química , Transdução de Sinais , Compostos de Sulfidrila/síntese química , Tiorredoxinas/metabolismo
17.
Mini Rev Med Chem ; 19(15): 1255-1275, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-29600761

RESUMO

Objective & Methodology: New hybrids of thiopyrimidine-five/six heterocyclic rings were synthesized and in vitro evaluated for their antiproliferative activity against three human cancer cell lines, namely HCT116 (human colorectal carcinoma), PC-3 (human prostate adenocarcinoma) and HepG2 (human liver carcinoma) cell lines. The most potency was elicited by the target candidates against the viability of HCT116 cell lines. It was higher than that obtained by the positive control 5-Fluorouracil (IC50 range; 0.11-0.49 µM, IC50, 5-FU; 1.10 µM). Results: Cell cycle analysis and apoptosis activation revealed that compound 20 induced G2/M phase arrest and apoptosis in HCT116 cells. In addition, compound 20 activates the caspases-9 and -3, a process which might mediate the apoptosis of HCT116 cells. Quantitative structure activity relationship study was done and revealed a high predictive power R2 suggesting goodness of the models. Conclusion: Furthermore, there is a good agreement between the observed pIC50 and the predicted pIC50 values, in addition, the low RMSD and standard error values indicate the accuracy of the model. Antimicrobial evaluation revealed that some of these compounds exhibited significant activities against the tested pathogenic bacteria and fungi, wherein compounds 7a, 14, 15a, 21a, produced the most potent and broad spectrum antibacterial and antifungal potency that was equivalent to that revealed by Vibramycin and Ketoconazole (MIC; 125 µg/mL). Moreover, compounds 15a, 21c, investigated dual potent antimicrobial and anticancer activity.


Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Antifúngicos/síntese química , Antifúngicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Pirimidinas/farmacologia , Relação Quantitativa Estrutura-Atividade , Compostos de Sulfidrila/farmacologia , Antibacterianos/química , Antifúngicos/química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Fungos/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Compostos de Sulfidrila/síntese química , Compostos de Sulfidrila/química
18.
Pak J Pharm Sci ; 31(6 (Supplementary): 2697-2708, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30587482

RESUMO

The research was aimed to unravel the enzymatic potential of sequentially transformed new triazoles by chemically converting 4-methoxybenzoic acid via Fischer's esterification to 4-methoxybenzoate which underwent hydrazinolysis and the corresponding hydrazide (1) was cyclized with phenyl isothiocyanate (2) via 2-(4-methoxybenzoyl)-N-phenylhydrazinecarbothioamide (3); an intermediate to 5-(4-methoxyphenyl)-4-phenyl-4H-1,2,4-triazol-3-thiol (4). The electrophiles; alkyl halides 5(a-g) were further reacted with nucleophilic S-atom to attain a series of S-alkylated 5-(4-methoxyphenyl)-4-phenyl-4H-1,2,4-triazole-3-thiols 6(a-g). Characterization of synthesized compounds was accomplished by contemporary spectral techniques such as FT-IR, 1H-NMR, 13C-NMR and EI-MS. Excellent cholinesterase inhibitory potential was portrayed by 3-(n-heptylthio)-5-(4-methoxyphenyl)-4-phenyl-4H-1,2,4-triazole; 6g against AChE (IC50; 38.35±0.62µM) and BChE (IC50; 147.75±0.67µM) enzymes. Eserine (IC50; 0.04±0.01µM) was used as reference standard. Anti-proliferative activity results ascertained that derivative encompassing long straight chain substituted at S-atom of the moiety was the most potent with 4.96 % cell viability (6g) at 25µM and with 2.41% cell viability at 50µMamong library of synthesized derivatives. In silico analysis also substantiated the bioactivity statistics.


Assuntos
Inibidores da Colinesterase/síntese química , Simulação por Computador , Simulação de Acoplamento Molecular/métodos , Compostos de Sulfidrila/síntese química , Triazóis/síntese química , Inibidores da Colinesterase/metabolismo , Células HCT116 , Humanos , Compostos de Sulfidrila/metabolismo , Triazóis/metabolismo
19.
J Am Chem Soc ; 140(42): 13594-13598, 2018 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-30351134

RESUMO

The synthesis of thiolactone monomers that mimic natural nucleosides and engage in robust ring opening polymerizations (ROP) is herein described. As each repeat unit contains a thioester functional group, dynamic rearrangement of the polymer is feasible via thiol-thioester exchange, demonstrated here by depolymerization of the polymers and coalescing of two polymers of different molecular weight or chemical composition. This approach constitutes the first step toward a platform that enables for the routine synthesis of sequence controlled polymers via dynamic template directed synthesis.


Assuntos
DNA/química , Lactonas/química , Polimerização , Polímeros/química , Compostos de Sulfidrila/química , DNA/síntese química , Lactonas/síntese química , Modelos Moleculares , Polímeros/síntese química , Compostos de Sulfidrila/síntese química
20.
Molecules ; 23(10)2018 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-30322175

RESUMO

A custom-designed series of unsymmetrical spiroalkanedithiols having tailgroups comprised of a terminally fluorinated chain and a hydrocarbon chain of varying lengths were synthesized and used to prepare self-assembled monolayers (SAMs) on gold substrates. The specific structure of the adsorbates was of the form [CH3(CH2)n][CF3(CF2)7(CH2)8]C[CH2SH]2, where n = 7, 9, and 15 (designated as F8H10-C10, F8H10-C12, and F8H10-C18, respectively). The influence of the length of the hydrocarbon chain in the bidentate dithiol on the structure and interfacial properties of the monolayer was explored. A structurally analogous partially fluorinated monodentate alkanethiol and the corresponding normal alkanethiols were used to generate appropriate SAMs as reference systems. Measurements of ellipsometric thickness showed an unexpectedly low film thickness for the SAMs derived from the bidentate adsorbates, possibly due to disruptions in interchain packing caused by the fluorocarbon chains (i.e., phase-incompatible fluorocarbon-hydrocarbon interactions), ultimately giving rise to loosely packed and disordered films. Analysis by X-ray photoelectron spectroscopy (XPS) were also consistent with a model in which the films were loosely packed; additionally, the XPS spectra confirmed the attachment of the sulfur headgroups of the bidentate adsorbates onto the gold substrates. Studies of the SAMs by polarization modulation-infrared reflection-adsorption spectroscopy (PM-IRRAS) suggested that as the length of the hydrocarbon chain in the adsorbates was extended, a more ordered surface was achieved by reducing the tilt of the fluorocarbon segment. The wettability data indicated that the adsorbates with longer alkyl chains were less wettable than those with shorter alkyl chains, likely due to an increase in interchain van der Waals forces in the former.


Assuntos
Alcanos/síntese química , Ouro/química , Compostos de Sulfidrila/síntese química , Alcanos/química , Halogenação , Estrutura Molecular , Espectroscopia Fotoeletrônica , Compostos de Sulfidrila/química , Propriedades de Superfície , Molhabilidade
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