Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 125
Filtrar
6.
Chem Res Toxicol ; 34(2): 656-668, 2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-33347274

RESUMO

Hepatic steatosis (fatty liver) is a severe liver disease induced by the excessive accumulation of fatty acids in hepatocytes. In this study, we developed reliable in silico models for predicting hepatic steatosis on the basis of an in vivo data set of 1041 compounds measured in rodent studies with repeated oral exposure. The imbalanced nature of the data set (1:8, with the "steatotic" compounds belonging to the minority class) required the use of meta-classifiers-bagging with stratified under-sampling and Mondrian conformal prediction-on top of the base classifier random forest. One major goal was the investigation of the influence of different descriptor combinations on model performance (tested by predicting an external validation set): physicochemical descriptors (RDKit), ToxPrint features, as well as predictions from in silico nuclear receptor and transporter models. All models based upon descriptor combinations including physicochemical features led to reasonable balanced accuracies (BAs between 0.65 and 0.69 for the respective models). Combining physicochemical features with transporter predictions and further with ToxPrint features gave the best performing model (BAs up to 0.7 and efficiencies of 0.82). Whereas both meta-classifiers proved useful for this highly imbalanced toxicity data set, the conformal prediction framework also guarantees the error level and thus might be favored for future studies in the field of predictive toxicology.


Assuntos
Simulação por Computador , Fígado Gorduroso/induzido quimicamente , Hidrocarbonetos Acíclicos/efeitos adversos , Hidrocarbonetos Aromáticos/efeitos adversos , Aprendizado de Máquina , Bases de Dados Factuais , Humanos , Modelos Moleculares , Conformação Molecular
7.
Insect Biochem Mol Biol ; 102: 11-20, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30243802

RESUMO

Hydrocarbon biosynthesis in insects involves the elongation of fatty acyl-CoAs to very-long chain fatty acyl-CoAs that are then reduced and converted to hydrocarbon, with the last step involving the oxidative decarbonylation of an aldehyde to hydrocarbon and carbon dioxide. Cytochromes P450 in the 4G family decarbonylate aldehydes to hydrocarbon. All insect acyl-CoA reductases studied to date reduce fatty acyl-CoAs to alcohols. The results of the work reported herein demonstrate that CYP4G55 and CYP4G56 from the mountain pine beetle, Dendroctonus ponderosae, expressed as fusion proteins with house fly cytochrome P450 reductase (CPR), convert both long chain aldehydes and long chain alcohols to hydrocarbons. CYP4G55 and CYP4G56 appear to prefer primary alcohols to aldehydes as substrates. These data strongly suggest that hydrocarbon biosynthesis in insects occurs by the two-step reduction of very long chain fatty acyl-CoAs to alcohols, which are then oxidized to aldehydes and then oxidatively decarbonylated to hydrocarbon by CYP4G enzymes. In addition, both CYP4G55 and CYP4G56 fusion proteins convert C10 alcohols and aldehydes to hydrocarbons, including the conversion of (Z)-7-decenal, a putative intermediate in the exo-brevicomin pheromone biosynthetic pathway, to (Z)-3-nonene. These data demonstrate that the highly conserved CYP4G enzymes accept a broad range of carbon chain lengths, including C10 and C18, and have evolved to function in cuticular hydrocarbon biosynthesis and pheromone production.


Assuntos
Aldeídos/metabolismo , Besouros/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Ácidos Graxos/metabolismo , Álcoois Graxos/metabolismo , Hidrocarbonetos Acíclicos/metabolismo , Proteínas de Insetos/metabolismo , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/metabolismo
8.
J Am Chem Soc ; 140(32): 10109-10112, 2018 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-30049213

RESUMO

The first enantioselective palladium-catalyzed decarboxylative allylic alkylation of fully substituted acyclic enol carbonates providing linear α-quaternary ketones is reported. Investigation into the reaction revealed that the use of an electron-deficient phosphinooxazoline ligand renders the enolate geometry of the starting material inconsequential, with the same enantiomer of product obtained in the same level of selectivity regardless of the starting ratio of enolates. As a result, a general method toward acyclic all-carbon quaternary stereocenters has been developed.


Assuntos
Hidrocarbonetos Acíclicos/síntese química , Paládio/química , Catálise , Hidrocarbonetos Acíclicos/química , Estrutura Molecular
9.
Org Biomol Chem ; 16(11): 1791-1806, 2018 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-29464265

RESUMO

Chemical C-glycosylation has been well developed to improve stereoselectivity in recent years. Due to its high efficiency to build C-glycosides or O-cyclic compounds, C-glycosylation has found widespread use in the synthesis of biologically active molecules. This review highlights the C-glycosylation methods that have been practised in the total synthesis of natural products and pharmaceuticals in the past decade.


Assuntos
Produtos Biológicos/síntese química , Técnicas de Química Sintética/métodos , Preparações Farmacêuticas/síntese química , Produtos Biológicos/química , Glicosídeos/síntese química , Glicosídeos/química , Glicosilação , Hidrocarbonetos Acíclicos/síntese química , Hidrocarbonetos Acíclicos/química , Hidrocarbonetos Cíclicos/síntese química , Hidrocarbonetos Cíclicos/química , Preparações Farmacêuticas/química , Estereoisomerismo
10.
Ecotoxicol Environ Saf ; 151: 28-34, 2018 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-29304415

RESUMO

Seeking new efficient hydrocarbon-degrading yeast stains was the main goal of this study. Because microorganisms are greatly affected by the environmental factors, the biodegradation potentiality of the microorganisms varies from climatic area to another. This induces research to develop and optimize the endemic organisms in bioremediation technology. In this study, 67 yeast strains were tested for their growth potentiality on both aliphatic and aromatic hydrocarbons. The most efficient six strains were identified using sequence analysis of the variable D1/D2 domain of the large subunit 26S ribosomal DNA. The identity of these strains was confirmed as Yamadazyma mexicana KKUY-0160, Rhodotorula taiwanensis KKUY-0162, Pichia kluyveri KKUY-0163, Rhodotorula ingeniosa KKUY-0170, Candida pseudointermedia KKUY-0192 and Meyerozyma guilliermondii KKUY-0214. These species are approved for their ability to degrade both aliphatic and aromatic hydrocarbons for the first time in this study. Although, all of them were able to utilize and grow on both hydrocarbons, Rhodotorula taiwanensis KKUY-0162 emerged as the best degrader of octane, and Rhodotorula ingeniosa KKUY-170 was the best degrader of pyrene. GC-MS analysis approved the presence of many chemical compounds that could be transitional or secondary metabolites during the utilization of the hydrocarbons. Our results recommend the application of these yeast species on large scale to approve their efficiency in bioremediation of oil-contamination of the environment. Using these yeasts, either individually or in consortia, could offer a practical solution for aquatic or soil contamination with the crude oil and its derivatives in situ.


Assuntos
Hidrocarbonetos Acíclicos/análise , Hidrocarbonetos Aromáticos/análise , Poluentes do Solo/análise , Poluentes Químicos da Água/análise , Leveduras/crescimento & desenvolvimento , Biodegradação Ambiental , Cromatografia Gasosa-Espectrometria de Massas , Petróleo/análise , Filogenia , Rhodotorula/genética , Rhodotorula/crescimento & desenvolvimento , Leveduras/genética
11.
Bull Exp Biol Med ; 162(4): 445-450, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28243919

RESUMO

We revealed empirical dependences between common logarithm of a ratio of rat oral LD50 to LCa50 for adult fish and lgP for 50 different chemicals; and common logarithm of a ratio of the oral LD50 in rodents to LCe50 for fish embryos and lgP for 30 different chemicals. The dependences were obtained by constructing a trend line between experimental points and calculation of Pearson's R correlation coefficient as a measure of regression significance. These dependences can show the influence of substance lipophilicity on its toxicity for aquatic organisms comparing to mammals.


Assuntos
Embrião não Mamífero/efeitos dos fármacos , Hidrocarbonetos Acíclicos/toxicidade , Hidrocarbonetos Aromáticos/toxicidade , Hidrocarbonetos Halogenados/toxicidade , Medicamentos sob Prescrição/toxicidade , Testes de Toxicidade Aguda/normas , Administração Oral , Animais , Concentração Inibidora 50 , Dose Letal Mediana , Modelos Lineares , Camundongos , Ratos , Especificidade da Espécie , Testes de Toxicidade Aguda/estatística & dados numéricos , Peixe-Zebra
12.
Eur J Med Chem ; 125: 225-232, 2017 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-27662033

RESUMO

In this communication we describe the construction of four succinic-based cationic lipids, their formulation with plasmid DNA (pDNA), and an evaluation of their in vitro gene delivery into Chinese hamster ovarian (CHO-K1) cells. The cationic lipids employed in this work possess either a dimethylamine or trimethylamine headgroup, and a macrocyclic or an acyclic hydrophobic domain composed of, or derived from two 16-atom, succinic-based acyl chains. The synthesized lipids and a co-lipid of neutral charge, either cholesterol or 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), were formulated in an overall 3:2 cationic-to-neutral lipid molar ratio, then complexed with plasmid DNA (pDNA). The relative transfection performance was evaluated via a comparison between matched versus mismatched formulations defined by the rigidity relationship between the lipids employed. Gel electrophoresis was used to characterize the binding of the lipid formulations with plasmid DNA and the relative degree of plasmid degradation using a DNase I degradation assay. Small angle X-ray diffraction (SAXD) was employed to characterize the packing morphology of the lipid-DNA complexes. In general, the succinic unit embedded within the hydrophobic domain of the cationic lipids was found to improve lipid hydration. The transfection assays revealed a general trend in which mismatched formulations that employed a rigid lipid combined with a non-rigid (or flexible) lipid, outperformed the matched formulations. The results from this work suggest that the design of the cationic lipid structure and the composition of the lipoplex formulation play key roles in governing the transfection performance of nonviral gene delivery agents.


Assuntos
DNA/metabolismo , Lipídeos/química , Succinatos/química , Transfecção/métodos , Animais , Células CHO , Cátions/química , Cricetinae , Cricetulus , DNA/química , Técnicas de Transferência de Genes/normas , Hidrocarbonetos Acíclicos , Interações Hidrofóbicas e Hidrofílicas , Compostos Macrocíclicos , Plasmídeos , Succinatos/metabolismo , Transfecção/normas
13.
Zh Evol Biokhim Fiziol ; 53(1): 23-32, 2017 01.
Artigo em Russo | MEDLINE | ID: mdl-30695439

RESUMO

The metabolic profile of plasma of white non-linear rats was investigated under normal conditions and after chronic inhalational exposure to low doses of aliphatic hydrocarbons with the number of carbon atoms from 6 to 10. Metabolic profile was determined with combination of gas chromatography-mass spectrometry and high performance, high resolution liquid chromatography-mass spectrometry with subsequent use of chemometrical methods for data treatment and presentation. It was shown that continuous 90-day exposure to a mixture of C6-C10 saturated hydrocarbons at concentration of 160 ± 20.5 mg/m³ results in various impairments of metabolic processes in liver and kidneys. Exposure to hydrocarbons at doses of 31.4 ± 5.6 mg/m³ and 5.2 ± 1.8 mg/m³ evoked significantly smaller changes. Novel metabolic markers of the toxic effect of low concentrations of C6-C10 aliphatic hydrocarbons were revealed. The ratio of concentrations of pyrophosphoric and oxalic acids in rat blood plasma was found to be the most sensitive marker called <>. A hypothesis is put forward about the redox balance violation as the leading pathogenetic mechanism of neuropathies and concomitant pathologies associated with hydrocarbon chronic intoxication.


Assuntos
Hidrocarbonetos Acíclicos/toxicidade , Rim/metabolismo , Fígado/metabolismo , Metaboloma/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Rim/patologia , Fígado/patologia , Oxirredução/efeitos dos fármacos , Ratos
14.
Eur J Med Chem ; 114: 345-64, 2016 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-27043173

RESUMO

Nociceptin/orphanin FQ (N/OFQ) and N/OFQ peptide (NOP) receptor are expressed and distributed in various regions such as central nervous system (CNS), peripheral nervous system, immune system, and peripheral tissues. N/OFQ and NOP receptor have important roles on a variety of physiological, pathophysiological, regulatory, and dysregulatory mechanisms in the living body. Both activation and blockade of NOP receptor function have displayed clinical potential of NOP receptor agonists and antagonists for the treatment of various diseases or pathophysiological conditions, respectively. Potent and selective NOP receptor agonists/antagonists are also useful tools to investigate the various mechanisms mediated by NOP receptor-N/OFQ system. As the present study, a series of (4-arylpiperidine substituted-methyl)-[bicyclic (hetero)cycloalkanobenzene] analogs was designed, synthesized, and biologically evaluated in vitro to seek and identify potent and selective, small-molecules of nonpeptide NOP receptor antagonists, which resulted in the discovery of novel potent small-molecule 15 with high human NOP receptor selectivity over human µ receptor. The structure-activity relationship (SAR) of the potency and selectivity, structure-metabolic stability relationship (SMR), and SAR of hERG (human ether-a-go-go related gene) potassium ion channel binding affinity for the analogs in the present studies in vitro provided or suggested significant and/or useful structural determinants and insights for the respective purposes. The superior profiles of compound 15 are discussed with a viewpoint of multisite interactions between ligand and NOP receptor, together with the results of previous NOP receptor agonist/antagonist studies.


Assuntos
Descoberta de Drogas , Hidrocarbonetos Acíclicos/farmacologia , Piperidinas/farmacologia , Receptores Opioides/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Relação Dose-Resposta a Droga , Humanos , Hidrocarbonetos Acíclicos/síntese química , Hidrocarbonetos Acíclicos/química , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/química , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade
15.
Org Lett ; 17(11): 2688-91, 2015 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-25966029

RESUMO

The arylation of secondary acyclic amides has been achieved with diaryliodonium salts under mild and metal-free conditions. The methodology has a wide scope, allows synthesis of tertiary amides with highly congested aryl moieties, and avoids the regioselectivity problems observed in reactions with (diacetoxyiodo)benzene.


Assuntos
Amidas/química , Hidrocarbonetos Acíclicos/química , Iodo/química , Metais/química , Oniocompostos/química , Sais/química , Derivados de Benzeno/química , Estrutura Molecular , Temperatura
16.
Macromol Rapid Commun ; 36(2): 190-4, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25238594

RESUMO

The acyclic diene metathesis (ADMET) polymerization of 6-hydroxy-1,10-undecadiene (M1) and 6-acetoxy-1,10-undecadiene (M2) by the action of two different catalysts, i.e., the second-generation Grubbs-Hoveyda system ([RuCl2(IMesH2)(CH-2-(2-PrO-C6H4)]) (1) and the dicationic ruthenium alkylidene [Ru(DMF)3(IMesH2)(CH-2-(2-PrO-C6H4)] (2, IMesH2 = 1,3-dimesitylimidazolin-2-ylidene) is reported. Biphasic conditions using 1-butyl-2,3-dimethylimidazolium tetrafluoroborate ([BDMIM(+)BF4(-)]) and 1,2,4-trichlorobenzene (TCB) are applied. Under the chosen conditions (T = 75 °C, 20 mbar), the use of catalyst 1 results only in the formation of low-molecular-weight polymers (Mn ≤ 10,000 g mol(-1)), while catalyst 2 allows for the high yield synthesis of high-molecular-weight polymers (Mn ≤ 40,000 g mol(-1), yields ≤ 99%). Irrespective of the catalyst used, all polymers display a high trans-content (>95%). Notably, Ru-contamination of the target polymers without any additional purification is as low as 1.2 ppm with catalyst 2. Together with the high yields and high molecular weights, the low Ru-contaminations clearly illustrate the advantages of the biphasic setup.


Assuntos
Hidrocarbonetos Acíclicos/química , Polienos/química , Polimerização , Polímeros/química , Rutênio/química , Boratos , Ácidos Bóricos/química , Catálise , Cátions/química , Clorobenzenos/química , Imidazóis/química , Espectroscopia de Ressonância Magnética , Modelos Químicos , Estrutura Molecular , Peso Molecular , Polímeros/síntese química , Espectrofotometria Infravermelho
17.
Chem Commun (Camb) ; 51(1): 145-8, 2015 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-25387082

RESUMO

The introduction of a thin layer of TiO2 on ß-SiC allows a significant improvement of the cobalt dispersion. This catalyst exhibits an excellent and stable catalytic activity for the Fischer-Tropsch synthesis (FTS) with high C5+ selectivity, which contributes to the development of a new active catalyst family in the gas-to-liquid process.


Assuntos
Compostos Inorgânicos de Carbono/química , Cobalto/química , Hidrocarbonetos Acíclicos/síntese química , Compostos de Silício/química , Titânio/química , Catálise , Gases/química , Hidrocarbonetos Acíclicos/química , Tamanho da Partícula
18.
Bioorg Med Chem Lett ; 24(24): 5731-5737, 2014 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-25453810

RESUMO

This Letter describes the discovery of a number of functionalized bisimidazoles bearing a cyclohexylphenyl, piperidylphenyl, or bicyclo[2,2,2]octylphenyl motif as HCV NS5A inhibitors. Compounds 2c, 4b and 6 have demonstrated low single-digit nM potency in gt-1a replicon and double-digit pM potency in gt-1b replicon, respectively. Moreover, both 4b and 6 have, respectively, exhibited good oral bioavailability in rats with a favorable liver/plasma ratio of the drug concentration.


Assuntos
Antivirais/química , Descoberta de Drogas , Hidrocarbonetos Acíclicos/química , Imidazóis/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Replicação Viral/efeitos dos fármacos , Animais , Antivirais/farmacocinética , Antivirais/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/virologia , Avaliação Pré-Clínica de Medicamentos , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Hepatite C/virologia , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/virologia , Masculino , Modelos Moleculares , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Replicon/efeitos dos fármacos , Relação Estrutura-Atividade , Células Tumorais Cultivadas
19.
Org Lett ; 16(21): 5540-3, 2014 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-25310274

RESUMO

We report here an enantioselective formal synthesis of vinigrol involving a 1-2-3 strategy: one pot and two reactions with the formation of three rings leading to the core structure of vinigrol from its stereochemically well-defined acyclic precursor.


Assuntos
Diterpenos/síntese química , Hidrocarbonetos Acíclicos/química , Diterpenos/química , Estrutura Molecular , Estereoisomerismo
20.
J Am Chem Soc ; 136(23): 8209-12, 2014 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-24856045

RESUMO

Angularly substituted trans-fused hydroindanes are now accessible by the direct and convergent union of trimethylsilyl (TMS)-alkynes with 4-hydroxy-1,6-enynes by a process that forges three C-C bonds, one C-H bond, and two new stereocenters. The annulation is proposed to proceed by initial formation of a Ti-alkyne complex (with a TMS-alkyne) followed by regioselective alkoxide-directed coupling with the enyne, stereoselective intramolecular cycloaddition, elimination of phenoxide, 1,3-metallotropic shift, and stereoselective protonation of the penultimate allylic organometallic intermediate. Several examples are given to demonstrate the compatibility of this reaction with substrates bearing aromatic and aliphatic substituents, and an empirical model is presented to accompany the stereochemical observations.


Assuntos
Compostos Bicíclicos com Pontes/química , Compostos Bicíclicos com Pontes/síntese química , Hidrocarbonetos Acíclicos/química , Alcinos/química , Ciclização , Reação de Cicloadição , Estrutura Molecular , Estereoisomerismo , Compostos de Trimetilsilil/química
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...