RESUMO
Previous studies have shown that flavones bind to P-glycoprotein (Pgp) with higher affinity than isoflavones, flavanones, and glycosylated derivatives. In the present work, a series of C- or O-substituted hydrophobic derivatives of chrysin were synthesized to further investigate structural requirements of the A ring toward Pgp modulation. Increasing hydrophobicity at either position 6, 8, or 7 increased the affinity of in vitro binding to a purified cytosolic domain of Pgp, but only benzyl and 3,3-dimethylallyl C-substitution produced a high maximal quenching of the protein intrinsic fluorescence. Inhibition of membrane Pgp within leukemic cells, characterized by intracellular drug accumulation, was specifically produced by isoprenylated derivatives, with 8-(3,3-dimethylallyl)chrysin being even more efficient than the commonly used cyclosporin A.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos/síntese química , Flavonoides/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Flavonoides/química , Flavonoides/metabolismo , Humanos , Ligação Proteica , Espectrometria de Fluorescência , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
A benzophenone glycoside has been isolated from Davallia solida. Its structure was elucidated by chemical and spectral means as 4-O-beta-D-glucopyranosyl-2,6,4'-trihydroxybenzophenone. It bound with moderate affinity to the purified C-terminal cytosolic domain of P-glycoprotein, but the binding affinity was 6- to 10-fold increased for its aglycone derivative and other related benzophenones.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Benzofenonas/metabolismo , Citosol/metabolismo , Benzofenonas/síntese química , Benzofenonas/isolamento & purificação , Sítios de Ligação/fisiologia , Fatores Biológicos/isolamento & purificação , Fatores Biológicos/metabolismo , Resistencia a Medicamentos Antineoplásicos , Extratos Vegetais , Estrutura Terciária de Proteína/fisiologiaRESUMO
Bioguided fractionation of the roots of Citrus sinensis (Rutaceae) led to the isolation and identification of five coumarins, namely, clausarin, suberosin, poncitrin, xanthyletin and thamnosmonin, seven acridones, namely, acrimarine B, 2-methoxycitpressine I, citpressine I, buntanine, acrimarine E, honyumine and acrimarine C, and one terpenoid, namely, limonin. Among these compounds, clausarin, 2-methoxycitpressine I and acrimarine E inhibited P-glycoprotein-mediated drug efflux in K562/R7 human leukemic cells over-expressing P-glycoprotein.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Acridinas/isolamento & purificação , Acridinas/farmacologia , Citrus sinensis/química , Cumarínicos/isolamento & purificação , Cumarínicos/farmacologia , Acridonas , Linhagem Celular Tumoral , Humanos , Estrutura Molecular , Raízes de Plantas/químicaRESUMO
Phytochemical investigation of the leaves of Umbilicus pendulinus afforded in addition to 2-O-caffeoyl malate, isoquercitrin and Z-venusol, the new isomer E-venusol. Special NMR experiments were carried out to elucidate the configuration of the two latter compounds.
Assuntos
Ácidos Cafeicos/isolamento & purificação , Glicosídeos/isolamento & purificação , Malatos/isolamento & purificação , Fenilpropionatos/isolamento & purificação , Plantas Medicinais/química , Quercetina/análogos & derivados , Ácidos Cafeicos/química , Cromatografia Líquida de Alta Pressão , Europa (Continente) , Liofilização , Glicosídeos/química , Lectinas/química , Espectroscopia de Ressonância Magnética , Malatos/química , Fenilpropionatos/química , Folhas de Planta/química , Lectinas de Plantas , Quercetina/química , Quercetina/isolamento & purificação , Espectrometria de Massas de Bombardeamento Rápido de Átomos , Espectrofotometria UltravioletaRESUMO
Dimethylallyl (DMA) derivatives of a naturally occurring xanthone (decussatin 1) were prepared. Their activity as potential P-glycoprotein inhibitors was monitored by affinity of direct binding and compared to that of corresponding DMA-flavones. Both classes of compounds exhibited the same structure-activity relationships. Decreasing polarity enhanced the binding affinity for the P-glycoprotein C-terminal cytosolic domain since DMA derivatives were more active, but unsubstituted hydroxyl group close to the carbonyl was required for efficient activity.