基于苯并咪唑结构单元的小分子化合物的合成及阴离子跨膜转运活性

发布时间：2018-09-05 19:11

【摘要】：细胞是维持机体正常生命活动的基本单元,通过镶嵌于细胞膜上的通道蛋白与外界进行物质交换。一旦细胞膜上的通道蛋白发生结构或功能异常,将会导致一系列疾病,统称为“离子通道病”。因此,如果能够找到一类化合物替换功能失调的通道蛋白,恢复其离子跨膜转运功能,则可发展成为治疗药物。目前报道的阴离子转运体主要分为两类:具有阴离子跨膜转运作用的天然产物和人工合成的小分子阴离子转运体。近年来,研究人员利用胆酸、方酰胺、多酰胺、杯芳烃和(硫)脲等设计合成了各种具有较强阴离子跨膜转运活性的有机小分子化合物。苯并咪唑因具有分子量小、易于合成、较好的生物相容性以及能够通过氢键与阴离子结合等优点,成为一个构筑人工小分子阴离子转运体的备受关注的结构模块。但是,目前报道的苯并咪唑类化合物的离子跨膜转运活性较低。为了提高苯并咪唑类化合物的离子跨膜转运活性,本文设计合成了两类化合物。第一系列化合物是1,3-双(2-苯并咪唑基)苯1及其苯并咪唑甲基化物2、对位异构体3、邻位异构体4和单苯并咪唑衍生物5。化合物1和3-5通过邻苯二胺分别与不同位置取代的苯二甲酸和苯甲酸缩合得到,而化合物2则通过化合物1的甲基化得到。第二系列化合物是在化合物1的基础上,引入甲基和硝基等不同电性的取代基得到的衍生物6-11。该类化合物是由4位不同基团取代的邻苯二胺与间苯二甲酸或间苯二甲醛缩合得到。化合物1-11的结构经过ESI-MS,HR-ESI-MS,1H NMR 和 13C NMR 表征。以卵磷脂(EYPC)脂质体为模型,用荧光分光光谱法详细研究了化合物1-11的阴离子跨膜转运活性。结果表明,化合物1和化合物6-11均具有较好的阴离子跨膜转运活性;转运机制为Cl-/NO3-逆向转运,并伴随少量Cl-/H+同向转运。而化合物2-5基本不具有阴离子跨膜转运活性。另外,化合物1和化合物6-11均以运载体形式发挥离子跨膜转运作用。对第二系列化合物,吸电基团取代的化合物6-10的离子跨膜转运活性显著高于甲基取代物11。特别是硝基取代的化合物10,其活性是化合物1的789倍。初步构效关系研究表明,苯并咪唑单元N-H结构是化合物1发挥离子跨膜转运作用的核心结构;只有当两个苯并咪唑单元位于苯环的间位时,才具有最好的阴离子跨膜转运活性;在苯并咪唑单元上引入吸电子基团可显著提高化合物的离子跨膜转运活性。这些初步构效关系,可望为今后基于1,3-双(2-苯并咪唑基)苯的高效阴离子转运体的合理设计提供一定的参考。
[Abstract]:The cell is the basic unit to maintain the normal life activity of the body. It is exchanged with the outside world by the channel protein embedded in the cell membrane. Once the channel protein on the cell membrane is abnormal in structure or function, it will lead to a series of diseases, collectively known as "ion channel disease." Therefore, if a class of compounds can be found to replace dysfunctional channel proteins and recover their ion transmembrane transport function, they can be developed as therapeutic drugs. The reported anionic transporters are mainly divided into two categories: natural products with anion transmembrane transport and synthetic small molecular anion transporters. In recent years, a variety of organic small molecules with strong anionic transmembrane transport activity have been synthesized by using cholic acid, formamide, polyamide, calixarene and (thiourea). Because of its small molecular weight, easy synthesis, good biocompatibility and the ability to combine with anions through hydrogen bonds, benzimidazole has become a concerned structural module for the construction of artificial small molecular anionic transporters. However, the ion transmembrane transport activity of benzimidazole compounds reported at present is relatively low. In order to improve the ion transmembrane transport activity of benzimidazole compounds, two kinds of compounds were designed and synthesized. The first series of compounds are 1: 3- bis (2-benzimidazolyl) benzene 1 and its methylates 2, para-isomer 3, o-isomer 4 and monobenzimidazole derivative 5. Compounds 1 and 3-5 were obtained by condensation of o-phenylenediamine with substituted phthalic acid and benzoic acid respectively, while compound 2 was obtained by methylation of compound 1. On the basis of compound 1, the second series of compounds were obtained by introducing different electrical substituents such as methyl and nitro groups. This kind of compound is obtained by condensation of 4 different groups of o-phenylenediamine with isophthalic acid or isophthalic acid. The structure of compound 1-11 was characterized by ESI-MS,HR-ESI-MS,1H NMR and 13C NMR. The anion transmembrane transport activity of compound 1-11 was studied by fluorescence spectrophotometry using lecithin (EYPC) liposome as a model. The results showed that both compound 1 and compound 6-11 had good anion transmembrane transport activity, and the mechanism of transport was reverse transport of Cl-/NO3- with a small amount of Cl-/H in the same direction. However, compound 2-5 had little anion transmembrane transport activity. In addition, compounds 1 and 6-11 both play a transmembrane transport role in the form of carriers. For the second series of compounds, the ion transport activity of 6-10 was significantly higher than that of methyl substituted compounds. In particular, the activity of nitro-substituted compound 10 is 789 times that of compound 1. The preliminary study of structure-activity relationship shows that N-H structure of benzimidazole unit is the core structure of compound 1 for ion transmembrane transport, and only when two benzimidazole units are located in the intermediate position of the benzene ring, the best anion transmembrane transport activity can be obtained. The introduction of electron-absorbing groups into benzimidazole unit can significantly improve the ion transmembrane transport activity of the compounds. These preliminary structure-activity relationships are expected to provide a reference for the rational design of the efficient anion transporters based on 1 ~ 3- bis (2-benzimidazolyl) benzene in the future.
【学位授予单位】：南方医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R914

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