双活性蔗渣木聚糖酯化衍生物的分子构建与抗HIV作用机制研究

Xylan has been payed close attention to, especially chemical, pharmaceutical, functional materials, environment, food and many other fields because of its unique biological activities in recent years. The anti-HIV activity of xylan sulfate has been showen. However, its anti-HIV activity is not enough. Therefore, it is very significant for academic to study highly efficient antiHIV activity xylan esterified derivatives. The product of bagasse xylan sulfate was synthesized through the esterification by using bagasse xylan from biomass renewable resources and sodium nitrilotriacetic sulfonate as esterifying agent. The project will construct six kinds of double activity bagasse esterified xylan derivatives further through the catalytic esterification by introducing the second antiHIV activity groups and using ferrocenecarboxylic acid, p-ferrocenyl benzene monocarboxylic acid, 3,4,5-trihydroxybenzoic acid, p-hydroxybenzoic acid, sulfosalicylic acid and acetylsalicylic acid as reactants. The chain structure, conformation and optimized configuration of six products are researched in unit molecule by using MS molecular simulation method and the senior structure of product molecules are constructed. The antiHIV activity of different degree of substitution or the content of the biologically active group on target products are measured and contrasted. The chain structure and space conformation, the relationship between chain conformation of primary structure or senior structure and biological activity of two-step modified products are also studied. The project will further research the mechanism of anti-HIV action.

木聚糖具有独特的生物活性，近年来已引起化工、医药、功能材料、环境、食品等众多领域的关注。目前，已经发现木聚糖的硫酸酯化衍生物具有一定的抗HIV活性作用。但是，其抗HIV活性效果并不是很理想。因此，研究开发具有高效抗HIV活性的木聚糖衍生物显得尤为重要。 在前期酯化反应合成蔗渣木聚糖硫酸酯的基础上，进一步与二茂铁甲酸、二茂铁乙酸、二茂铁丙酸、对-二茂铁苯甲酰基、对-二茂铁苯乙酰基、对-二茂铁苯丙酰基反应，引入第二种抗HIV活性基团，得到6种具有双活性的抗HIV活性蔗渣木聚糖衍生物；采用分子模拟计算方法，模拟计算目标产物的链结构与构象。用MS（Material Studio）得到修饰产物的分子优化构型，并对木聚糖以及木聚糖衍生物链状结构进行模拟，构建目标产物分子的高级结构。进一步研究目标产物的体外抗HIV活性以及构效关系，分析抗HIV作用机制。

以蔗渣木聚糖为主要原料，合成氨基三磺酸钠作为硫酸酯化剂，在水相条件下合成了蔗渣木聚糖硫酸酯。再选取二茂铁甲酸、对二茂铁苯甲酸、1,1-二茂铁双甲酸、磺基水杨酸、对羟基水杨酸、阿魏酸等10余种活性有机酸酯化剂进行第二步羧酸酯化改性，分别构建合成了磺酸基蔗渣木聚糖二茂铁甲酸酯、磺酸基蔗渣木聚糖对二茂铁甲酸酯、磺酸基蔗渣木聚糖-1,1-二茂铁双甲酸酯、磺酸基蔗渣木聚糖对羟基水杨酸酯和磺酸基蔗渣木聚糖磺基水杨酸酯等数十种蔗渣木聚糖羧酸双酯化系列衍生物，通过单因素试验确定了优化工艺条件；采用IR、TG-DTG、XRD和SEM对五种产物的结构进行了表征，并采用Schrödinger中的Glide模块将HIV-1整合酶受体与目标产物配体进行对接模拟，研究蔗渣木聚糖双酯化衍生物的抗HIV活性机理。. 用分子模拟法对蔗渣木聚糖以及数十种双活性蔗渣木聚糖衍生物的结构进行了分子模拟，并且构建了蔗渣木聚糖双酯化系列衍生物的优化构型、无定形结构的空间结构；将分子模拟出的数十种双活性蔗渣木聚糖衍生物的优化构型导入SYBYL中，对其抗HIV活性进行了模拟。. 同时采用分子模拟法对多种目标产物分子进行几何优化，得到在基态下的分子稳定结构。使用Glide以标准精度模式对HIV-1整合酶与配体对接模拟，经过筛选得到综合评价较好的对接模式，分析得到的对接模拟结果，目标产物分子作为配体与HIV-1整合酶受体能够较好的完成对接，目标产物是通过氢键和分子间作用力与HIV-1整合酶相结合，对比三种对接模式的结果，目标配体与受体网格有较好的契合结构状态和结合数据。运用分子对接技术，实现了与受体蛋白的成功对接模拟，证明了产物的抗艾滋病病毒活性，结合活性实验测试结果，初步显示部分木聚糖双酯化衍生物具有较高的抗HIV活性。