【摘要】 为了设计合成具有较强神经细胞氧化损伤保护作用及较好理化性质的灯盏乙素苷元4’-L-氨基酸衍生物,以灯盏乙素苷元为先导化合物,根据主动转运原理在改善口服药物生物利用度应用上取得的成功经验,采用拼合设计原理在先导化合物的4’-羟基上引入L-氨基酸酯、醚结构,设计、合成灯盏乙素苷元4’-L-氨基酸衍生物。采用H2O2诱导PC12细胞氧化损伤模型对设计化合物进行了体外抗氧化活性评价,同时进行了目标化合物理化性质研究。结果发现设计的化合物均具有抗氧化活性,5个化合物抗氧化活性优于VE,灯盏乙素苷元L-氨基酸醚类化合物在缓冲液中稳定性(t1/2 9～92 h)优于酯类衍生物(t1/2 0.5 h),灯盏乙素苷元L-氨基酸酯类衍生物18、19与醚类衍生物22、24～27的水溶解度分别为1 796～4 100μg·mL-1和27.7～81.1μg·mL-1,两者水溶性分别达到灯盏乙素的120～280倍和2～6倍。以上研究提示L-氨基酸前药设计策略可适用于灯盏乙素苷元的结构修饰,以获得具有较好抗氧化活性及理化性质的灯盏乙素苷元前药。更多还原

【Abstract】 To design and synthesize a series of novel scutellarein 4’-L-amino acid prodrugs with more potent anti-oxidative activity and improved physicochemical properties.Scutellarein was used as lead compound,according to successful experience of improving bioavailability of oral administration drugs by active transport mechanism,principle of hybridization was used to introducing L-amino acid structural fragments at 4’-position of scutellarein to design and synthesize target scutellarein 4’-L-amino acid prodrugs.The synthetic compounds were tested on their physicochemical properties and in vitro anti-oxidative activity against H2O2 induced oxidative damage in PC12 cells.Five compounds were found to have more potent anti-oxidative activity than positive control VE.Moreover the physicochemical properties of synthesized compounds were evaluated,and the results revealed that L-amino acid ether derivatives are more stable(t1/2 9-92 h) than their corresponding ester derivatives(t1/2 0.5 h).Water solubility of scutellarein 4’-L-amino acid ester and ether derivatives were 1 796-4 100 μg·mL-1 and 27.7-81.1 μg·mL-1 respectively,in comparison with scutellarin,the solubility of compounds 18,19 and 22,24-27 increased about 120-280 fold and 2-6 fold respectively.All these results suggested that L-amino acid prodrug strategy has significant potential in scutellarein prodrug design.更多还原