RESUMO
Poly(ß-l-malic acid) (PMLA) together with its derivatives is an aliphatic polyester with superior bio-properties for anti-tumor drugs. In order to surmount the obstacles of low drug loading and rapid premature release during the circulation of polyester-based micelles, micelles based on poly(ß-benzyl malate)-b-polyethylene glycol (PBM-PEG) were developed in this study. The micelles had high drug loading capacity (>20 wt%) and held robust stability, owing to the π-π stacking interactions between polymer chains, and between the polymer and drug. Computer simulation also confirmed that there was the strongest binding free energy between PBMs, and PBM and doxorubicin (DOX), compared with other polyesters. A cell-penetrating moiety (TAT) was employed, and furthermore, a protective outer shell (PEG5k) was also introduced via a matrix metalloproteinase-2 (MMP-2) cleavable peptide. Before reaching the tumor site, the TAT peptide was shielded by long chain PEG, and the micelles showed low bioactivity. While at the tumor tissues where MMP-2 was highly expressed, the cleavage of the linker leads to the exposure of TAT, thus enhancing the cellular internalization. The desired therapeutic consequent was also observed, with no accompanying systemic toxicity detected. Our findings indicated that this MMP-2 sensitive PBM polymeric micelle would be a promising antitumor drug carrier with enhanced therapeutic effects.
Assuntos
Antineoplásicos/uso terapêutico , Portadores de Fármacos/química , Micelas , Neoplasias/tratamento farmacológico , Poliésteres/química , Polietilenoglicóis/química , Animais , Antineoplásicos/química , Linhagem Celular Tumoral , Doxorrubicina/química , Doxorrubicina/uso terapêutico , Portadores de Fármacos/síntese química , Liberação Controlada de Fármacos , Feminino , Humanos , Camundongos Endogâmicos BALB C , Neoplasias/patologia , Oligopeptídeos/química , Poliésteres/síntese química , Polietilenoglicóis/síntese química , Eletricidade Estática , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A transition metal-free process for the regioselective synthesis of pyrrolo[1,2-a]quinoxalines under mild conditions in one-pot is described. The reaction afforded a variety of products in good to excellent yields. Indolo[1,2-a]quinoxalines were also synthesized from indole-2-carboxamides under the same conditions.
Assuntos
Pirróis/síntese química , Quinoxalinas/síntese química , Cristalografia por Raios X , Modelos Moleculares , Estrutura Molecular , Pirróis/química , Quinoxalinas/química , EstereoisomerismoRESUMO
The paper describes a convenient and facile methodology for the regioselective synthesis of fused oxazepinone scaffolds. This process is an efficient construction of the oxazepinone scaffold by a one-pot coupling/Smiles rearrangement/cyclization approach. This transition metal-free process has potential applications in the synthesis of biologically and medicinally relevant compounds.