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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。
In order to design and synthesize 4’-L-amino acid derivatives of scutellarin with better protection of neurons against oxidative damage and with better physical and chemical properties, scutellarin was used as the lead compound. According to the principle of active transport, Bioavailability and application of successful experience, the introduction of L-amino acid esters, ether structure on the 4’-hydroxyl of lead compounds using the principle of split design, design, synthesis of scutellarin 4’-L-amino acid derivatives. The H2O2-induced oxidative damage model in PC12 cells was used to evaluate the anti-oxidative activity of the designed compounds in vitro. The physical and chemical properties of the target compounds were also studied. The results showed that all of the designed compounds had antioxidant activity, and the antioxidant activity of five compounds was better than that of VE. The stability of scutellarin L-amino acid ethers (t1 / 29 ~ 92 h) was better than that of ester (T1 / 2 0.5 h), scutellarin L-amino acid ester derivatives 18,19 and ether derivatives 22,24 ~ 27 water solubility of 1 796 ~ 4 100μg · mL-1 And 27.7 ~ 81.1μg · mL-1, respectively. The water-solubility of them reached 120 ~ 280 times and 2 ~ 6 times respectively. The above studies suggest that the design strategy of L-amino acid prodrugs can be applied to the structural modification of scutellarin to obtain the scutellarin prodrug with good antioxidant activity and physicochemical properties.