RESUMO
SAR of N-alkylated isoxazolones as p38 MAP kinase inhibitors was realized. The data herein show the possibility of transferring the SAR study and evaluation from N-1-substituted imidazole to isoxazolones. Optimization of substituent was realized.
Assuntos
Oxazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Espectroscopia de Ressonância Magnética , Espectroscopia de Infravermelho com Transformada de FourierRESUMO
The crystal structure of the title compound, C(15)H(11)FN(2)O(3), was determined as part of a study on the biological activity of isoxazolone derivatives as p38 mitogen-activated protein kinase (MAPK) inhibitors. The dihedral angles between rings are isoxazole/benzene = 55.0â (3)°, isoxazole/pyridine = 33.8â (2)° and benzene/pyridine = 58.1â (2)°.
RESUMO
The crystal structure of the title compound, C(16)H(16)FN(2)O(2) (+)·I(-), was determined as part of a study of the biological activity of isoxazolone derivatives as p38 mitogen-activated protein kinase (MAPK) inhibitors. The X-ray crystal structure of 4-[4-(4-fluoro-phenyl)-2-methyl-5-oxo-2,5-dihydro-isoxazol-3-yl]-1-methyl-pyridinium iodide showed the presence of the regioisomer 4-[3-(4-fluoro-phenyl)-2-methyl-5-oxo-2,5-dihydro-isoxazol-4-yl]-1-methyl-pyridinium iodide. The synthesis of the former compound was achieved by reacting 4-(4-fluoro-phenyl)-3-(4-pyridyl)isoxazol-5(2H)-one after treatment with Et(3)N in dimethyl-formamide, with iodo-methane. The unexpected formation of the regioisomer could be explained by a rearrangement occurring via aziridine of the isoxazolone compound. The regioisomers have site occupancies of 0.632â (4)/0.368â (4). The two six members rings make a dihedral angle of 66.8â (2)°.
RESUMO
Polyethylene glycol (PEG) is a widely used modification for drug delivery systems. It reduces undesired interaction with biological components, aggregation of complexes and serves as a hydrophilic linker of ligands for targeted drug delivery. However, PEGylation can also lead to undesired changes in physicochemical characteristics of chitosan/siRNA nanoplexes and hamper gene silencing. To address this conflicting issue, PEG-chitosan copolymers were synthesized with stepwise increasing degrees of PEG substitution (1.5% to 8.0%). Subsequently formed PEG-chitosan/siRNA nanoplexes were characterized physicochemically and biologically. The results showed that small ratios of chitosan PEGylation did not affect nanoplex stability and density. However, higher PEGylation ratios reduced nanoplex size and charge, as well as cell uptake and final siRNA knockdown efficiency. Therefore, we recommend fine-tuning of PEGylation ratios to generate PEG-chitosan/siRNA delivery systems with maximum bioactivity. The degree of PEGylation for chitosan/siRNA nanoplexes should be kept low in order to maintain optimal nanoplex efficiency.
Assuntos
Quitosana/análogos & derivados , Polietilenoglicóis/química , RNA Nuclear Pequeno/administração & dosagem , Linhagem Celular Tumoral , Sobrevivência Celular , Quitosana/síntese química , Quitosana/química , Portadores de Fármacos , Citometria de Fluxo , Técnicas de Silenciamento de Genes , Proteínas de Fluorescência Verde/genética , Humanos , Concentração de Íons de Hidrogênio , Indicadores e Reagentes , Nanopartículas , Oxazinas/química , Tamanho da Partícula , Polietilenoglicóis/síntese química , RNA Nuclear Pequeno/química , RNA Nuclear Pequeno/genética , Solubilidade , Xantenos/químicaRESUMO
Pharmaceutical companies are facing an increasing interest in new target identification and validation. In particular, extensive efforts are being made in the field of protein kinase inhibitors research and development, and the past ten years of effort in this field have altered our perception of the potential of kinases as drug targets. Therefore, in the drug discovery process, the selection of relevant, susceptible protein kinase targets combined with searches for leads and candidates have become a crucial approach. The success of recent launches of protein kinase inhibitors (Gleevec, Imatinib, Sutent, Iressa, Nexavar, Sprycel) gave another push to this field. Numerous other kinase inhibitors are currently undergoing clinical trials or clinical development. Some questions are nevertheless unanswered, mostly related to the great number of known kinases in the human genome, to their similarity with each other, to the existence of functionally redundant kinases for specific pathways, and also because the connection between particular pathways and diseases is not always clear. The review is leading the reader through a panoramic view of protein kinase inhibition with a major focus on MAPK, successful examples and clinical candidates.
Assuntos
Proteínas Quinases Ativadas por Mitógeno/efeitos dos fármacos , Antineoplásicos/química , Antineoplásicos/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Genoma Humano , Humanos , Estrutura Molecular , Transdução de Sinais/efeitos dos fármacos , Especificidade por SubstratoRESUMO
In a continuous effort to develop improved p38 MAP (mitogen-activated protein) kinase inhibitors, we focused our attention on the suitability of the isoxazole ring as a bioisosteric replacement for the imidazole ring of SB-203580. 3,4- and 4,5-disubstituted as well as 3,4,5-trisubstituted isoxazole derivatives were synthesized. These compounds were tested in an in vitro enzyme-linked immunosorbent assay of isolated p38 MAP kinase and for inhibitory potency against cytochrome P450. Compound 4 a displays a highly promising profile for development as an anti-inflammatory agent owing to its enhanced suppression of cytokine release, decreased affinity for cytochrome P450 and a twofold decrease in IC50 toward isolated p38 MAP kinase.