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1.
Eur J Med Chem ; 186: 111829, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31757526

RESUMO

The implication of DNA methylation in cancer is today clearly established. Despite that nucleoside analogues are currently used for leukaemia treatment, their low stability in physiological conditions and their lack of selectivity arise the need for the identification of non-nucleoside DNA methyltransferase inhibitors. Here, we describe the synthesis and pharmacological characterisation of a novel class of DNA methyltransferase inhibitors: the 3-halo-3-nitroflavanones. We showed that 3-bromo-3-nitroflavanones 3b and 4a have a micromolar DNMT inhibition and an increased potency in a cell reporter model. Interestingly they are significantly more stable than the reference compounds and induce a low cytotoxicity, supporting them as new candidates for the development of non-cytotoxic cell-reprogramming epi-drugs for anticancer treatment.


Assuntos
Antineoplásicos/farmacologia , DNA (Citosina-5-)-Metiltransferases/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Flavanonas/farmacologia , Nitrocompostos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , DNA (Citosina-5-)-Metiltransferases/metabolismo , Metilação de DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Flavanonas/química , Células HCT116 , Humanos , Estrutura Molecular , Nitrocompostos/síntese química , Nitrocompostos/química , Relação Estrutura-Atividade
2.
Lett Appl Microbiol ; 70(3): 181-188, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31784998

RESUMO

(R)-m-Nitrophenyl-1,2-ethanediol (m-NPED) is a versatile and highly value-added chiral building block for the synthesis of some bioactive compounds, such as (R)-Nifenalol. To efficiently produce (R)-m-NPED through the enantioconvergent hydrolysis of racemic (rac-) m-nitrostyrene oxide (m-NSO) using the whole resting cells of Escherichia coli/pCold-pveh2 intracellularly expressing PvEH2, an epoxide hydrolase from Phaseolus vulgaris, two reaction systems were investigated. In the Na2 HPO4 -NaH2 PO4 buffer (50 mmol l-1 , pH 7·0) system, merely 15 mmol l-1 rac-m-NSO was successfully subjected to enantioconvergent hydrolysis, producing (R)-m-NPED with 86·0% enantiomeric excess (eep ) and 177·6 mg l-1  h-1 space-time yield (STY). The experimental result indicated that there is inhibitory effect of rac-m-NSO at high concentration on PvEH2. To efficiently increase the concentration of rac-m-NSO and the STY of (R)-m-NPED, petroleum ether was first selected to construct an organic/aqueous two-phase system. Then, both the volume ratio (vo /vb ) of petroleum ether to phosphate buffer and the weight ratio (wc /ws ) of E. coli/pCold-pveh2 dry cells to rac-m-NSO were optimized as 2 : 8 and 5 : 1, respectively. In the optimized petroleum ether/phosphate buffer two-phase system, the enantioconvergent hydrolysis of rac-m-NSO at 40 mmol l-1 (6·6 mg ml-1 ) was carried out at 25°C for 12 h using 33·0 mg ml-1 vacuum freeze-dried cells of E. coli/pCold-pveh2, producing (R)-m-NPED with 87·4% eep , 82·3% yield and 502·4 mg l-1  h-1 STY. SIGNIFICANCE AND IMPACT OF THE STUDY: Epoxide hydrolases play a crucial role in producing enantiopure epoxides and/or vicinal diols. However, numerous biocatalytic reactions of organic compounds, such as epoxides, in aqueous phase suffered various restrictions. Herein, the enantioconvergent hydrolysis of rac-m-NSO in two reaction systems was investigated using the whole cells of Escherichia coli/pCold-pveh2. As a result, the concentration of rac-m-NSO and the space-time yield of (R)-m-NPED in organic/aqueous two-phase system were significantly increased, when compared with those in aqueous phase. To our knowledge, this is the first report about the production of (R)-m-NPED from rac-m-NSO at an elevated concentration by PvEH2 in the two-phase system.


Assuntos
Alcanos/química , Epóxido Hidrolases/metabolismo , Escherichia coli/metabolismo , Nitrocompostos/síntese química , Phaseolus/metabolismo , Biocatálise , Compostos de Epóxi , Hidrólise/efeitos dos fármacos , Phaseolus/enzimologia , Estereoisomerismo
3.
Molecules ; 24(24)2019 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-31847419

RESUMO

Carbohydrates are abundant renewable resources and are a feedstock for green chemistry and sustainable synthesis of the future. Among the hexoses and the pentoses present in biomass, mannitol was selected in the present project as a valuable platform, directly available from the chiral pool, to build highly functionalized molecules. Starting from (R)-2,3-O-cyclohexylidene glyceraldehyde, which is easily prepared in a large scale from D-mannitol, an enantiopure chiral nitro alkene was prepared by reaction with nitromethane, and its reactivity studied. Organocatalytic Michael addition of dimethyl malonate, ß-keto esters, and other nucleophiles on the nitro alkene afforded high stereoselectivity and densely functionalized chiral molecules, which were further synthetically developed, leading to five-membered lactones and bicyclic lactams. Preliminary studies showed that the metal-free catalytic reaction on the chiral nitro alkene can be performed under continuous flow conditions, thus enabling the use of (micro)mesofluidic systems for the preparation of enantiomerically pure organic molecules from the chiral pool.


Assuntos
Manitol/química , Nitrocompostos/química , Catálise , Técnicas de Química Sintética , Teoria da Densidade Funcional , Ésteres , Espectroscopia de Ressonância Magnética , Manitol/análogos & derivados , Estrutura Molecular , Nitrocompostos/síntese química , Nitrocompostos/farmacologia , Estereoisomerismo
4.
Nat Commun ; 10(1): 3410, 2019 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-31363083

RESUMO

Nitroaromatics and nitroheteroaromatics serve as key building blocks and intermediates in synthesis, and form the core scaffold of a vast number of materials, dyes, explosives, agrochemicals and pharmaceuticals. However, their synthesis relies on harsh methodologies involving excess mineral acids, which present a number of critical drawbacks in terms of functional group compatibility and environmental impact. Modern, alternative strategies still suffer from significant limitations in terms of practicality, and a general protocol amenable to the direct C-H functionalization of a broad range of aromatics has remained elusive. Herein we introduce a bench-stable, inexpensive, easy to synthesize and recyclable nitrating reagent based on saccharin. This reagent acts as a controllable source of the nitronium ion, allowing mild and practical nitration of both arenes and heteroarenes displaying an exceptional functional group tolerance.


Assuntos
Nitrocompostos/química , Ácidos/química , Catálise , Estrutura Molecular , Nitrocompostos/síntese química
5.
Luminescence ; 34(7): 707-714, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31294932

RESUMO

Spiropyran (SP) and its derivatives operate between their ring opening and closing forms as a versatile molecular platform for the fluorescence detection of cations and anions, using a colour change for signalling. A functionalized SP fluorescence probe, L, was prepared and characterized. Probe L can detect Ca2+ with a fluorescence 'turn-on' response in ethanol solution. It selectively binds Ca2+ to form a 1:1 ligand/metal complex, which produced a new emission band centred at 604 nm. The sensing result was clearly observed by the solution colour change from colourless to pink under visible light, and from blue to red under ultraviolet light. The detection limit was calculated to be 4.53 × 10-8  M for Ca2+ . The probe provides another possibility that SP-based derivatives could be used for the development and detection of metal ions in environmental and physiological systems.


Assuntos
Benzopiranos/química , Cálcio/análise , Corantes Fluorescentes/química , Indóis/química , Nitrocompostos/química , Benzopiranos/síntese química , Colorimetria , Teoria da Densidade Funcional , Corantes Fluorescentes/síntese química , Indóis/síntese química , Estrutura Molecular , Nitrocompostos/síntese química
6.
Curr Top Med Chem ; 19(13): 1075-1091, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31223089

RESUMO

BACKGROUND: Considering the need for the development of new antitumor drugs, associated with the great antitumor potential of thiophene and thiosemicarbazonic derivatives, in this work we promote molecular hybridization approach to synthesize new compounds with increased anticancer activity. OBJECTIVE: Investigate the antitumor activity and their likely mechanisms of action of a series of N-substituted 2-(5-nitro-thiophene)-thiosemicarbazone derivatives. METHODS: Methods were performed in vitro (cytotoxicity, cell cycle progression, morphological analysis, mitochondrial membrane potential evaluation and topoisomerase assay), spectroscopic (DNA interaction studies), and in silico studies (docking and molecular modelling). RESULTS: Most of the compounds presented significant inhibitory activity; the NCIH-292 cell line was the most resistant, and the HL-60 cell line was the most sensitive. The most promising compound was LNN-05 with IC50 values ranging from 0.5 to 1.9 µg.mL-1. The in vitro studies revealed that LNN-05 was able to depolarize (dose-dependently) the mitochondrial membrane, induceG1 phase cell cycle arrest noticeably, promote morphological cell changes associated with apoptosis in chronic human myelocytic leukaemia (K-562) cells, and presented no topoisomerase II inhibition. Spectroscopic UV-vis and molecular fluorescence studies showed that LNN compounds interact with ctDNA forming supramolecular complexes. Intercalation between nitrogenous bases was revealed through KI quenching and competitive ethidium bromide assays. Docking and Molecular Dynamics suggested that 5-nitro-thiophene-thiosemicarbazone compounds interact against the larger DNA groove, and corroborating the spectroscopic results, may assume an intercalating interaction mode. CONCLUSION: Our findings highlight 5-nitro-thiophene-thiosemicarbazone derivatives, especially LNN-05, as a promising new class of compounds for further studies to provide new anticancer therapies.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , DNA de Neoplasias/efeitos dos fármacos , Nitrocompostos/farmacologia , Tiofenos/farmacologia , Tiossemicarbazonas/farmacologia , Inibidores da Topoisomerase II/farmacologia , Adulto , Antineoplásicos/síntese química , Antineoplásicos/química , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , DNA Topoisomerases Tipo II/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Nitrocompostos/síntese química , Nitrocompostos/química , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/química , Tiossemicarbazonas/síntese química , Tiossemicarbazonas/química , Inibidores da Topoisomerase II/síntese química , Inibidores da Topoisomerase II/química , Células Tumorais Cultivadas
7.
Artigo em Inglês | MEDLINE | ID: mdl-30857466

RESUMO

The current research article involves one pot synthesis of novel substituted 1-nitro-10H-phenothiazines via Smiles rearrangement. These substituted phenothiazines undergo oxidation to yield 10H-phenothiazine-5,5-dioxides (sulfones) while on treatment with ß-D-ribofuranose-1-acetate-2,3,5-tribenzoate yield ribofuranosides. These compounds were screened for their antimicrobial vitalities (in vitro) against selected strains of bacteria and fungi. The characterization of synthesized compounds was done by elemental and spectral studies.


Assuntos
Anti-Infecciosos/síntese química , Nitrocompostos/síntese química , Nucleosídeos/química , Fenotiazinas/síntese química , Sulfonas/química , Anti-Infecciosos/farmacologia , Proteínas de Bactérias/química , Benzoatos/química , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Fungos/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Simulação de Acoplamento Molecular , Estrutura Molecular , Nitrocompostos/farmacologia , Oxirredução , Fenotiazinas/farmacologia , Relação Estrutura-Atividade , Sulfonas/farmacologia
8.
Chem Rec ; 19(2-3): 394-423, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30019511

RESUMO

The significant advancements in asymmetric organocascade reactions have been accomplished during the past decades, paving the way to the efficient and stereoselective construction of structurally complex scaffolds from simple and readily available starting materials. Nitro-containing cyclic compounds have become a privileged molecular library given their broad and promising activities in various therapeutic areas. In various approaches to build these valuable scaffolds, the utility of γ-nitrocarbonyl intermediates is one of the most efficient approaches due to its high efficiency, reliability and versatility. The strategies and catalyst systems described here highlight recent advances in the enantioselective synthesis of nitro-containing cyclic molecules via organocascade strategies based on γ-nitrocarbonyl intermediates. Various organocatalysts with distinct activation modes have found application in providing these sophisticated compounds. This review is organized according to the types of organocatalyst. These methods are of importance for the construction of complex chiral cyclic frameworks and the design of new pharmaceutical compounds. We believe that compounds based on nitro-containing cyclic skeletons have the potential to provide novel therapeutic agents and useful biological tools.


Assuntos
Cicloparafinas/síntese química , Compostos Heterocíclicos/síntese química , Nitrocompostos/síntese química , Catálise , Técnicas de Química Sintética/métodos , Estereoisomerismo
9.
J Labelled Comp Radiopharm ; 62(3): 126-131, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30589452

RESUMO

Imidacloprid (IC) is an important crop-protecting insecticide worldwide and commonly used for seed treatment. However, only few data are available on human toxicity of IC. Having in view the metabolic studies at low doses in humans and residue analysis of IC in food and consumer products, we elaborated the synthesis and prepared 13 C2 ,15 N-IC with three stable isotopes of the "heavy" atoms in positions 1, 2, and 3 of the pyridine ring. By using readily available and affordable starting materials, 15 NH4 Cl and 13 C4 -acetic anhydride, the target compound has been prepared in eight steps with an overall yield of 13%.


Assuntos
Inseticidas/síntese química , Neonicotinoides/síntese química , Nitrocompostos/síntese química , Isótopos de Carbono , Isótopos de Nitrogênio , Piridinas/química
10.
J Labelled Comp Radiopharm ; 61(14): 1089-1094, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30347484

RESUMO

O-(1-Fluoropropan-2-yl)-O-(4-nitrophenyl) methylphosphonate is a reactive organophosphate ester (OP) developed as a surrogate of the chemical warfare agent sarin that forms a similar covalent adduct at the active site serine of acetylcholinesterase. The radiolabeled O-(1-[18 F]fluoropropan-2-yl)-O-(4-nitrophenyl) methylphosphonate ([18 F] fluorosarin surrogate) has not been previously prepared. In this paper, we report the first radiosynthesis of this tracer from the reaction of bis-(4-nitrophenyl) methylphosphonate with 1-[18 F]fluoro-2-propanol in the presence of DBU. The 1-[18 F]fluoro-2-propanol was prepared by reaction of propylene sulfite with Kryptofix 2.2.2 and [18 F] fluoride ion. The desired tracer O-(1-[18 F]fluoropropan-2-yl)-O-(4-nitrophenyl) methylphosphonate was obtained in a >98% radiochemical purity with a 2.4% ± 0.6% yield (n = 5, 65 minutes from start of synthesis) based on starting [18 F] fluoride ion and a molar activity of 49.9 GBq/µmol (1.349 ± 0.329 Ci/µmol, n = 3). This new facile radiosynthesis routinely affords sufficient quantities of [18 F] fluorosarin surrogate in high radiochemical purity, which will further enable the tracer development as a novel radiolabeled OP acetylcholinesterase inhibitor for assessment of OP modes of action with PET imaging in vivo.


Assuntos
Nitrocompostos/química , Nitrocompostos/síntese química , Organofosfonatos/química , Organofosfonatos/síntese química , Tomografia por Emissão de Pósitrons , Sarina , Técnicas de Química Sintética , Traçadores Radioativos , Radioquímica
11.
J Am Chem Soc ; 140(38): 12290-12295, 2018 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-30176214

RESUMO

A rare-earth metal/alkali metal bimetallic catalyst proved particularly effective for enantioselectively coupling nitroalkanes and α-keto esters in an anti-selective manner to afford synthetically versatile, densely functionalized, and optically active α-nitro tertiary alcohols. A chiral diamide ligand captured two distinct metal cations, giving rise to a catalytically competent solid-phase heterobimetallic catalyst by simple mixing via self-assembly. The advantage of the solid-phase asymmetric catalyst was realized by successful application to the enantio- and diastereoselective reaction in a continuous-flow platform. The use of closely related solvents in terms of structures and polarity parameters, THF and its methylated congener 2-Me-THF, had an unexpectedly large solvent effect both on the reaction rate and the stereoselectivity. The nitroaldol products share a privileged unit for active pharmaceutical ingredients, as demonstrated by the streamlined enantioselective synthesis of the marketed antifungal agents efinaconazole and albaconazole.


Assuntos
Álcoois/síntese química , Ésteres/química , Furanos/química , Cetonas/química , Nitrocompostos/química , Catálise , Ésteres/síntese química , Neodímio/química , Nitrocompostos/síntese química , Quinazolinas/síntese química , Sódio/química , Solventes/química , Estereoisomerismo , Triazóis/síntese química
12.
Bioorg Med Chem Lett ; 28(18): 3064-3066, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30119957

RESUMO

A series of oxime-functionalized nitrofuranylamides were designed, synthesized and evaluated for their in vitro anti-mycobacterial activities against MTB H37Rv and drug-resistant clinical isolates. Among them, two compounds 7a and 7b exhibited excellent activity against the three tested strains. Both of them were comparable to the first-line anti-TB agents INH and RIF against MTB H37Rv, and were far more potent than INH and RIF against MDR-TB 16833 and 16995 strains. Thus, both of them could act as leads for further optimization.


Assuntos
Amidas/farmacologia , Antituberculosos/farmacologia , Desenho de Fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Nitrocompostos/farmacologia , Oximas/farmacologia , Amidas/síntese química , Amidas/química , Antituberculosos/síntese química , Antituberculosos/química , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Estrutura Molecular , Nitrocompostos/síntese química , Nitrocompostos/química , Oximas/química , Relação Estrutura-Atividade
13.
Macromol Rapid Commun ; 39(15): e1800319, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29924433

RESUMO

In recent years, merocyanine photoacids have been utilized to control various chemical processes using visible light and have found applications in materials, energy, and biomedical areas. Molecular merocyanine photoacids are commonly used in the previous works. Covalently linking the photoacids to polymers improves their compatibility with different media, avoids leakage problems, and allows a localized proton concentration to be produced. However, the phenolic and indolinium moieties of the photoacids make them difficult to be polymerized with common methods. In this work, the monomer of a merocyanine photoacid is converted to a spiropyran in situ by adding trimethylamine to a dimethyl sulfoxide (DMSO) solution of the monomer. Free radical polymerization yields the polymers of the spiropyran, which is acidified to regenerate the photoacid. The photoacid polymers prepared show good solubility, photoacidity, and reversibility. Irradiating a thin film of a photoacid polymer doped with methyl orange through a mask copies the pattern of the mask to the film. The pattern can be erased by heating the film at 80 °C for 10 min, and a new pattern is created by irradiation through a different mask.


Assuntos
Benzopiranos/química , Benzopiranos/síntese química , Indóis/química , Indóis/síntese química , Nitrocompostos/síntese química , Polímeros/síntese química , Radicais Livres/síntese química , Radicais Livres/química , Luz , Estrutura Molecular , Nitrocompostos/química , Processos Fotoquímicos , Polimerização , Polímeros/química
14.
Macromol Rapid Commun ; 39(20): e1800133, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29786904

RESUMO

A photoresponsive host-guest supramolecular complex (WP5⊃G) constructed by water-soluble pillar[5]arene (WP5) and spiropyran derivative (G) is presented. The spontaneous isomerization of G from spiropyran (SP) form to ring-opened merocyanine (MC) form happens either alone or in WP5⊃G in aqueous media. Irradiated by visible light, G can be converted into SP form completely and the hydrophilicity will be changed. G and WP5⊃G are both verified to self-assemble into nanospheres. Upon exposure to visible light, WP5⊃G reassemble into nanovesicles due to the change of supra-amphiphilicity, while G alone does not have this transition. Obviously, WP5 takes the key role that activates the photoinduced morphological transition.


Assuntos
Benzopiranos/química , Calixarenos/química , Indóis/química , Nanosferas/química , Nitrocompostos/química , Tensoativos/química , Benzopiranos/síntese química , Calixarenos/síntese química , Portadores de Fármacos/síntese química , Portadores de Fármacos/química , Humanos , Indóis/síntese química , Luz , Nitrocompostos/síntese química , Compostos de Amônio Quaternário , Solubilidade , Tensoativos/síntese química , Água/química
15.
Chembiochem ; 19(12): 1264-1270, 2018 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-29516677

RESUMO

There is a need for methods to chemically incorporate photocleavable labels into synthetic and biologically sourced nucleic acids in a chemically defined and reversible manner. We have previously demonstrated that the light-cleaved diazo di-methoxy nitro phenyl ethyl (diazo-DMNPE) group has a remarkable regiospecificity for modifying terminally phosphorylated siRNA. Building on this observation, we have identified conditions under which a diazo-DMNPE reagent that we designed (diazo-DMNPE-azide or DDA) is able to singly modify any nucleic acid (RNA, DNA, single-stranded, double-stranded, 3' or 5' phosphate). It can then be modified with any clickable reagent to incorporate arbitrary labels such as fluorophores into the nucleic acid. Finally, native nucleic acid can be regenerated directly through photolysis of the reagent. Use of the described approach should allow for the tagging of any nucleic acid, from any source-natural or unnatural-while allowing for the light-induced regeneration of native nucleic acid.


Assuntos
Azidas/química , Compostos Azo/química , Química Click/métodos , DNA/química , Nitrocompostos/química , RNA/química , Azidas/síntese química , Compostos Azo/síntese química , DNA/síntese química , Indicadores e Reagentes , Nitrocompostos/síntese química , Fosforilação , Fotólise , RNA/síntese química , Coloração e Rotulagem/métodos , Estereoisomerismo
16.
Sci Rep ; 8(1): 2295, 2018 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-29396403

RESUMO

Fatty acid nitroalkene derivatives (NO2-FA) activate Nrf2-regulated antioxidant gene expression and inhibit NF-κB-dependent cytokine expression. To better define NO2-FA structure-function relationships, a series of 22 new chemical entities (NCEs) containing an electrophilic nitroalkene functional group were synthesized and screened for both Nrf2- and NF-κB activities using luciferase-based assays. The structural variables were acyl chain length (11 to 24 carbons) and position of the electrophilic nitroalkene group. In luciferase-based reporter assays, Nrf2 was maximally activated by omega-12 nitroalkene fatty acids while TNFα stimulated NF-κB-inhibition was maximal for omega-5 nitroalkenes. The top pathway-modulating NO2-FAs were a) evaluated for an ability to activate Nrf2-dependent signaling and inhibit NF-κB-dependent inflammatory responses of RAW264.7 cells and b) compared to electrophilic compounds in clinical development. These findings revealed that 8/9-nitro-eicos-8-enoic acid (NCE-10) was collectively the most effective NCE and that both the α and ω acyl chain lengths influence nitroalkene activation of Nrf2 and inhibition of NF-κB signaling. This insight will guide development of more effective non-natural homologs of endogenously-detectable fatty acid nitroalkenes as anti-inflammatory and anti-fibrotic drug candidates.


Assuntos
Alcenos/metabolismo , Ácidos Graxos/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Nitrocompostos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Alcenos/síntese química , Alcenos/química , Animais , Fenômenos Químicos , Ácidos Graxos/síntese química , Ácidos Graxos/química , Genes Reporter , Luciferases/análise , Luciferases/genética , Macrófagos/efeitos dos fármacos , Camundongos , Estrutura Molecular , Nitrocompostos/síntese química , Nitrocompostos/química , Células RAW 264.7
17.
Med Chem ; 14(2): 181-199, 2018 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-28969575

RESUMO

BACKGROUND: Cancers of the lymphatic cells (lymphomas) account for approximately 12% of malignant diseases worldwide. The nitrostyrene scaffold is identified as a lead target structure for the development of particularly effective compounds targeting Burkitt's lymphoma (BL). OBJECTIVES: The aims of the curent study were to synthesise a panel of nitrostyrene compounds and to evaluate their activity in Burkitt's lymphoma (BL). METHODS: A panel of structurally varied compounds were designed and synthesised using Henry Knoevenagel condensation reactions. Single crystal X-Ray analysis confirmed the E configuration for six examples of these novel structures. A number of nitrostyrene-related compounds were also investigated including 1,3-bis(aryl)-2-nitropropenes together with heterocyclic scaffolds containing the nitrovinyl pharmacophore such as 3-nitro-2-phenyl-2H-chromenes. The antiproliferative activities of the compounds were evaluated using the BL cell lines EBV- MUTU-1 and EBV+ DG- 75 (chemoresistant) to establish preliminary structure-activity relationships. RESULTS: Lead compounds with optimized nitrostyrene scaffolds and 3-nitro-2-phenyl-2Hchromene structures were successfully established with typical IC50 values of 0.45 µM and 0.47 µM in MUTU-1 cells and 1.41 µM and 1.92 µM, respectively, in DG-75 cells. The mechanism of cell death was identified as apoptotic and the lead compound was found to elicit comparable apoptotic effects to Taxol in Burkitt's lymphoma cell lines MUTU-1 and DG-75. CONCLUSION: This class of pharmaceutically active compounds with potential for the treatment of Burkitt`s lymphoma suggest a potential role for nitrostyrene based agents in chemotherapy.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linfoma de Burkitt/tratamento farmacológico , Nitrocompostos/farmacologia , Estirenos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linfoma de Burkitt/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Nitrocompostos/síntese química , Nitrocompostos/química , Relação Estrutura-Atividade , Estirenos/síntese química , Estirenos/química
18.
Bioorg Med Chem ; 25(20): 5260-5267, 2017 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-28789912

RESUMO

We explored the facile alkylation of 4-nitrobenzotriazole under basic conditions and the synthesized derivatives were tested for their potential ADP induced platelet aggregation inhibition activity in comparison with standard drug ticagrelor (selective P2Y12 inhibitor). The nitro group at 4-position is highly activating toward alkylation reactions (under strong basic conditions) and resulted in formation of degradation product like 3-nitrobenzene-1,2-diamine which make isolation of alkyl products very difficult. We optimized the reaction under mild basic condition (potassium carbonate and DMF) which is devoid of any degradation product. This is perhaps the first report of 4-nitrobenzotriazole derivatives possessing platelet aggregation inhibitory activity. Generally activity increases with increase in length of alkyl chain and 1-alkyl positional isomers were found to be more potent than 2-alkyl isomers. The benzoyl derivative was found to be the most potent [compound 22; (4-Nitro-1H-benzotriazol-1-yl)(phenyl)methanone; IC50=0.65±0.10mM] which may be attributed to electronegative oxygen atom and aromatic ring. Benzyl derivatives [compound 20; 1-Benzyl-4-nitro-1H-benzotriazole; IC50=0.81±0.08mM, compound 21; 2-Benzyl-4-nitro-2H-benzotriazole; IC50=0.82±0.19mM] and sulfonyl derivative [compound 23; 1-[(4-Methylphenyl)sulfonyl]-4-nitro-1H-benzotriazole; IC50=0.82±0.19mM] are also found to be highly active. Furthermore, all compounds possess P2Y12 binding affinity as confirmed by VASP/P2Y12 phosphorylation assay.


Assuntos
Plaquetas/efeitos dos fármacos , Nitrocompostos/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Triazóis/farmacologia , Alquilação , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Nitrocompostos/síntese química , Nitrocompostos/química , Triazóis/síntese química , Triazóis/química
19.
Angew Chem Int Ed Engl ; 56(41): 12755-12759, 2017 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-28731542

RESUMO

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 , Estereoisomerismo
20.
Biomaterials ; 139: 151-162, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28618345

RESUMO

Most chemotherapeutic drugs commonly suffer from several shortcomings, including the lack of aqueous solubility, limited stability and adverse side effects. Although caging strategy has recently been employed as an effective approach to conceal and stabilize these drugs to achieve light-activated cancer therapy, it is plagued by the sophisticated drug modification process and deleterious solvent usage. In addition, using UV or Visible light to remove photocaged group is restricted to its limited tissue penetration ability in and phototoxicity. In this paper, by anchoring photochromic spiropyran on the mesoporous silica coated upconversion nanoparticles (UCNP-SP), we design a NIR-controlled cage mimicking system. Our results indicate that hydrophobic drug can be concealed inside the channels of the nanocarrier with high stability and "uncaged" via NIR irradiation-triggered hydrophobicity-hydrophilicity switch of the spiropyran molecules, finally inducing drug release and recovering their bioactivity. Moreover, under NIR illumination, the UV/Visible emissions from UCNP can also efficaciously initiate the generation of reactive oxygen species (ROS) by Curcumin, further improving the therapeutic efficiency. Both in vitro and in vivo experimental results validate that NIR irradiated nanosystem can produce remarkably enhanced antitumor efficiency.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Fármacos Fotossensibilizantes/uso terapêutico , Animais , Antineoplásicos/química , Antineoplásicos/efeitos da radiação , Benzopiranos/síntese química , Benzopiranos/química , Linhagem Celular Tumoral , Sobrevivência Celular , Curcumina/química , Curcumina/farmacologia , Liberação Controlada de Fármacos , Interações Hidrofóbicas e Hidrofílicas , Indóis/síntese química , Indóis/química , Luz , Substâncias Luminescentes/química , Camundongos , Nanopartículas/química , Nitrocompostos/síntese química , Nitrocompostos/química , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/efeitos da radiação , Espécies Reativas de Oxigênio , Dióxido de Silício/química
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