新型含羟基内酯环的双螺杂-N-甲基异噁唑烷类化合物的合成及构效关系研究

项目名称： 新型含羟基内酯环的双螺杂-N-甲基异噁唑烷类化合物的合成及构效关系研究

项目编号： No.21062019

项目类型： 地区科学基金项目

立项/批准年度： 2011

项目学科： 生物科学

项目作者： 穆赫塔尔·伊米尔艾山

作者单位： 新疆大学

项目金额： 12万元

中文摘要： 异噁唑环类由于其抗癌，抗肿瘤，抗菌，抑制Cdc25A酶等广泛的生物活性，而倍受关注。研究表明,将几个不同骨架的杂环引入到某些分子中,可改善母体分子生物活性，以便寻找高活性医药前体化合物，本项目以甘露醇为起始原料，经多步反应得到的氯代肟与马来酰亚胺的偶极环加成得到稠杂环并异恶唑啉; Me3OBF4作为N-甲基化试剂与异噁唑啉反应, 得到N-甲基异噁唑啉盐; 已活化异噁唑啉进一步用乙酸乙酯、丙二酸二乙酯、硝基甲烷等亲和试剂反应得到多手型中心的取代N-甲基异恶唑烷，其经HCl处理得到了一系列含羟基内酯环的螺稠杂异噁唑烷类化合物,其结构经光谱法确证,并测定化合物对与癌症、白血病、淋巴瘤相关的Cdc25酶和SHP-1酶抑制活性，部分衍生物显示较好生物活性。经亲核加成及合环等法，将羟基内酯环引入到异噁唑环后，由于新型螺杂环空间结构的改变，其显示更广泛的生物活性，揭示其所显示的活性与结构之间规律，探讨其构效关系。对异噁唑环结构的修饰，从而得到结构新颖、活性广谱的前体化合物，无论从药理学还是从合成角度考虑，螺杂异噁唑类化合物都具有很高的研究价值，可在一个新的领域内为医药的基础研究及应用研究提供理论依。

中文关键词： 羟基内酯环；螺杂环化合物; N-甲基异噁唑烷；生物活性；构效关系

英文摘要： Isoxazole derivatives have attracted much attention because of its wide range of biological activities such as anticancer, antitumor, antibacterial, and cell division cycle inhibiting phosphatase enzymes. Research has shown that the introduction of different heterocycles to some molecules can improve the biological activity of the original molecules. In this project, it is proposed to synthesize a new type of spiro-heterocyclic compounds containing an isoxazole ring. Using D-mannitol as the starting material, and by applying dipolar cyclo-addition, N-methylation, nucleophilic addition and ring closing reactions in order to introduce hydroxy a lactone ring into an isoxazole ring. The purpose is to investigate the reaction mechanisms and to find highly active pharmaceutical precursors. By modifying an isoxazole ring structure one can change the spatial structure of fused heterocyclic molecules into a new structure, broad-spectrum activity of the precursor compound. Nevertheless, from a pharmacological or synthetic standpoint, spiro- heterocyclic compounds are considered to have much more research value, and will (maybe change "will" to "can", or "may"?) provide theoretical evidence for the basic and applied studies of medicine in this new field.

英文关键词： Hydroxy lactone; spiro-heterocyclic compound; N-methylisoxazolidine; bioactivity; Structure-Activity Relationship