坛紫菜多糖的化学结构修饰及其构效关系研究
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摘要
坛紫菜,属红藻门,红毛菜科,紫菜属植物。是我国大规模养殖的重要经济海藻之一,主要产于我国南方沿海如福建、广东、浙江等地。坛紫菜含有较多的蛋白质、碳水化合物、维生素和矿物质,具有很高的营养价值。紫菜多糖是紫菜的主要组成成分之一,也是紫菜的主要活性成分之一。但坛紫菜多糖本身溶解性差,溶液粘度大限制了其药理应用。为了改进坛紫菜多糖的性能,提高其生物活性,扩大其药理应用范围,本论文以产于福建沿海的坛紫菜提取的坛紫菜多糖为原料,对其进行化学结构修饰,并测定了其体内外生物活性。
紫菜多糖作为硫酸酯多糖,硫酸化对其活性有直接影响。为了探讨硫酸化程度和位置与紫菜多糖生物活性之间的构效关系,本文对紫菜多糖进行选择性硫酸化修饰,分别在伯羟基、非伯羟基和所有羟基进行硫酸化修饰,采用羟基保护与去除方法和“一锅法”的合成策略,成功合成了不同取代位置的选择性硫酸化修饰产物。体外活性实验表明,具有高取代度的全硫酸化产品抗氧化活性和抗凝血活性最高,伯羟基硫酸化产品具有比非伯羟基硫酸化产品更好的抗氧化活性,而后者具有比前者更优的抗凝血活性。
为了进一步研究紫菜多糖的基团取代与其生物活性之间的构效关系,本文首次对不同分子量紫菜多糖进行乙酰化、苯甲酰化和磷酸化修饰,获得一系列的紫菜多糖衍生物,并且研究了各衍生物的体外抗氧化活性。结果表明,不同的修饰基团、分子量及其官能团连接位置对生物活性均有不同影响。在所有衍生物中,苯甲酰化产品具有非常显著的抗氧化活性。
本文首次将把抗肿瘤药5-氟尿嘧啶(5-Fu)以双官能团合成法负载在紫菜多糖上。合成了几种不同分子量的复合物,并在不同介质中37 ?C条件下模拟体外释放过程,对数据进行释放动力学分析。缓释试验表明,低分子量复合物能很好的延长5-Fu的释放时间,利于活性成分的吸收,提高了其生物利用度,并利用作为载体的紫菜多糖具有与5-Fu相似的药效,达到提高药物的协同效应的目的。
本研究具有重要的应用价值。坛紫菜多糖作为一个有前景的抗衰老药物,是一种天然产品,没有明显的毒副作用。同时能与5-Fu联合以及制备复合物,均能有效增强5-Fu的抑瘤活性,并能降低毒副作用,对于开发多糖载体缓释药物具有广阔前景。
Porphyra haitanensis, distributes naturally in intertidal zone of Fujian,Guangdong and Zhejiang provinces coast areas. Porphyra is not only an important economic alga, but also has been used traditionally to treat nephritic and urinary diseases etc. The basis chemical constituents in Porphyra were mainly protein, carbohydrate, vitamin and mineral. Porphyran, which was polysaccharide extracted from Porphyra is an important active composition. In the studies, we used porphyran extracted previously as raw material, modified with chemical structure and determined their bioactivities.
In order to study on the relationship between chemical modification of the porphyran and their biological activity, we made the regioselective sulfated modifications on the primary and secondary hydroxyl groups and prepared the no-regioselective oversulfated derivatives. And what’s more, we evaluated their antioxidant and anticoagulant activities in vitro and characterized the relationship between activities and chemical and structural characteristics. With methods of protection and removal of hydroxyl group and tactics of“One-pot Synthesis”, several different derivatives were prepared. The bioactivity results indicated that fully sulfated derivatives which had high degree of substitution showed the most excellent antioxidant activities and anticoagulant activities. And sulfated derivative on the primary groups showed the better antioxidant activities than derivative on the secondary hydroxyl group, but the later showed the better anticoagulant activities than the former. And what is more, the acetylated, phosphorylated and benzoylated derivatives were prepared. The bioactivity data showed that different function groups and molecular weight took affect on the bioactivities. Among the derivatives, the benzoylated derivative showed the most remarkable antioxidant activities.
The research firstly carried out fixation of 5-Fu to porphyran at 6-O through acetyl spacer group via ester bond. The chemical characteristic and release behavior of 5-FU from the conjugate obtained were studied in vitro at 37 ?C in three different medium. Analysis of release data indicated that the drug release durations of these conjugates were extremely correlated with the concentration of drug loading, the pH of media and molecular weight of the conjugates.
The anticancer activities of conjugate in vitro and in vivo were also studied. For the leukemia cell HL-60, the nature porphyran showed no anticancer activity on the lower concentration, but the conjugate showed some activity. For the liver cancer cell BEL-7402, the conjugate showed better activity. At the same time, antitumor activities in vivo of conjugate were investigated. The results indicated that the conjugate showed antitumor and immunomdulation activities in different degree and could enhance antitumor activities of 5-Fu and improve immunocompetence damaged by 5-Fu.
The research had important application value. As a potential anti-aging medicine, porphyran had no obvious toxic and side-effect. And it was prepared as with 5-Fu conjugate which could effectively enhance the antitumor activity of 5-Fu. Porphyran has broad prospects as a drug carrier.
紫菜多糖作为硫酸酯多糖,硫酸化对其活性有直接影响。为了探讨硫酸化程度和位置与紫菜多糖生物活性之间的构效关系,本文对紫菜多糖进行选择性硫酸化修饰,分别在伯羟基、非伯羟基和所有羟基进行硫酸化修饰,采用羟基保护与去除方法和“一锅法”的合成策略,成功合成了不同取代位置的选择性硫酸化修饰产物。体外活性实验表明,具有高取代度的全硫酸化产品抗氧化活性和抗凝血活性最高,伯羟基硫酸化产品具有比非伯羟基硫酸化产品更好的抗氧化活性,而后者具有比前者更优的抗凝血活性。
为了进一步研究紫菜多糖的基团取代与其生物活性之间的构效关系,本文首次对不同分子量紫菜多糖进行乙酰化、苯甲酰化和磷酸化修饰,获得一系列的紫菜多糖衍生物,并且研究了各衍生物的体外抗氧化活性。结果表明,不同的修饰基团、分子量及其官能团连接位置对生物活性均有不同影响。在所有衍生物中,苯甲酰化产品具有非常显著的抗氧化活性。
本文首次将把抗肿瘤药5-氟尿嘧啶(5-Fu)以双官能团合成法负载在紫菜多糖上。合成了几种不同分子量的复合物,并在不同介质中37 ?C条件下模拟体外释放过程,对数据进行释放动力学分析。缓释试验表明,低分子量复合物能很好的延长5-Fu的释放时间,利于活性成分的吸收,提高了其生物利用度,并利用作为载体的紫菜多糖具有与5-Fu相似的药效,达到提高药物的协同效应的目的。
本研究具有重要的应用价值。坛紫菜多糖作为一个有前景的抗衰老药物,是一种天然产品,没有明显的毒副作用。同时能与5-Fu联合以及制备复合物,均能有效增强5-Fu的抑瘤活性,并能降低毒副作用,对于开发多糖载体缓释药物具有广阔前景。
Porphyra haitanensis, distributes naturally in intertidal zone of Fujian,Guangdong and Zhejiang provinces coast areas. Porphyra is not only an important economic alga, but also has been used traditionally to treat nephritic and urinary diseases etc. The basis chemical constituents in Porphyra were mainly protein, carbohydrate, vitamin and mineral. Porphyran, which was polysaccharide extracted from Porphyra is an important active composition. In the studies, we used porphyran extracted previously as raw material, modified with chemical structure and determined their bioactivities.
In order to study on the relationship between chemical modification of the porphyran and their biological activity, we made the regioselective sulfated modifications on the primary and secondary hydroxyl groups and prepared the no-regioselective oversulfated derivatives. And what’s more, we evaluated their antioxidant and anticoagulant activities in vitro and characterized the relationship between activities and chemical and structural characteristics. With methods of protection and removal of hydroxyl group and tactics of“One-pot Synthesis”, several different derivatives were prepared. The bioactivity results indicated that fully sulfated derivatives which had high degree of substitution showed the most excellent antioxidant activities and anticoagulant activities. And sulfated derivative on the primary groups showed the better antioxidant activities than derivative on the secondary hydroxyl group, but the later showed the better anticoagulant activities than the former. And what is more, the acetylated, phosphorylated and benzoylated derivatives were prepared. The bioactivity data showed that different function groups and molecular weight took affect on the bioactivities. Among the derivatives, the benzoylated derivative showed the most remarkable antioxidant activities.
The research firstly carried out fixation of 5-Fu to porphyran at 6-O through acetyl spacer group via ester bond. The chemical characteristic and release behavior of 5-FU from the conjugate obtained were studied in vitro at 37 ?C in three different medium. Analysis of release data indicated that the drug release durations of these conjugates were extremely correlated with the concentration of drug loading, the pH of media and molecular weight of the conjugates.
The anticancer activities of conjugate in vitro and in vivo were also studied. For the leukemia cell HL-60, the nature porphyran showed no anticancer activity on the lower concentration, but the conjugate showed some activity. For the liver cancer cell BEL-7402, the conjugate showed better activity. At the same time, antitumor activities in vivo of conjugate were investigated. The results indicated that the conjugate showed antitumor and immunomdulation activities in different degree and could enhance antitumor activities of 5-Fu and improve immunocompetence damaged by 5-Fu.
The research had important application value. As a potential anti-aging medicine, porphyran had no obvious toxic and side-effect. And it was prepared as with 5-Fu conjugate which could effectively enhance the antitumor activity of 5-Fu. Porphyran has broad prospects as a drug carrier.
引文
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