糖基化白杨素、鹰嘴豆芽素A衍生物的合成及其活性研究

发布时间：2018-08-17 17:59

【摘要】：白杨素、鹰嘴豆芽素A都属于黄酮类化合物,来源广泛且具有众多的生理活性。研究表明,这两类化合物都存在溶解性较差、吸收少的问题；另外,白杨素、鹰嘴豆芽素A在被吸收后迅速被糖醛酸化或磺酸化而被代谢掉,导致这两种化合物活性降低；这两大原因限制了它们的应用。针对其溶解性和代谢位点进行化学改造,是获得活性优异化合物的一条重要途径。糖类分子是生物体内一类重要的分子,涉及众多的信号传导。引入糖单元可以改善母体化合物的稳定性、溶解性以及靶向性,从而改善先导化合物的生理活性。本文对白杨素、鹰嘴豆芽素A的易代谢位点进行糖基化改造,通过引入糖单元以期改善其溶解性和生理活性。本论文主要分为以下几部分： 1.设计、合成糖基化白杨素衍生物四大类。第一类：以白杨素和乙酰溴代糖为原料,弱碱性条件下用相转移催化法,经过2步简单的反应得到了12个白杨素糖苷类衍生物。第二类：以水杨醛或香草醛为原料,在相转移催化的条件下与乙酰溴代糖成苷,再将醛基氧化成羧基,最终在脱水剂作用下与白杨素成酯,合成了通过水杨酸或香草酸连接的糖苷化芳酸白杨素酯类衍生物,共12个。第三类：以白杨素、溴丙炔和叠氮糖为原料,运用点击化学的方法合成设计了引入三氮唑结构的糖基化三氮唑白杨素衍生物,共8个。第四类：以水杨醛或香草醛、溴丙炔和叠氮糖为原料,运用点击化学的方法合成糖基化三氮唑芳醛,再经将醛基氧化成羧基,最终在脱水剂作用下与白杨素成酯,合成了通过水杨酸或香草酸连接的糖苷化三氮唑芳酸白杨素酯类衍生物,共8个。 2.合成糖基化鹰嘴豆芽素A衍生物两大类。第一类：以鹰嘴豆芽素A和乙酰溴代糖为原料,弱碱性条件下用相转移催化法合成得到了12个鹰嘴豆芽素A糖苷类衍生物。第二类：以鹰嘴豆芽素A、溴丙炔和叠氮糖为原料,运用点击化学的方法合成设计了引入三氮唑结构的糖基化三氮唑鹰嘴豆芽素A衍生物,共8个。以上所得到的化合物的结构经1H-NMR、13C-NMR、IR、ESI-MS和元素分析鉴定。 3.活性研究。本部分对糖基化三氮唑白杨素及鹰嘴豆芽素A的8个衍生物做了抗缺氧活性研究。部分衍生物在常压密闭缺氧模型中均表现出较好的抗缺氧活性,其中化合物C5, C8, E6, E7的活性优于母体及阳性药乙酰唑胺。
[Abstract]:All of them belong to flavonoids and have a wide range of physiological activities. The results showed that the solubility and absorption of the two compounds were poor, and the activity of the two compounds was decreased due to their rapid metabolism by uronic acid or sulfonic acid. These two major reasons limit their application. Chemical modification of its solubility and metabolic sites is an important way to obtain active compounds. Carbohydrate molecules are a kind of important molecules in organism, which involve many signal transduction. The introduction of sugar units can improve the stability, solubility and targeting of the parent compounds, thus improving the physiological activities of the lead compounds. In this paper, glycosylation was carried out on the readily metabolized sites of poplar and chickpein A, and sugar units were introduced to improve their solubility and physiological activity. This paper is divided into the following parts: 1. Design and synthesis of glycosylated white poplar derivatives. In the first kind, 12 salicylidene glycosides derivatives were obtained by phase transfer catalysis under weak basic conditions using aluminol and acetyl bromosugars as raw materials. The second kind: using salicylic aldehyde or vanillin as raw material, under the condition of phase transfer catalysis, to form glycosides with acetyl brominated sugar, then oxidize aldehydes to carboxyl groups, and finally form esters with salicylidene in the presence of dehydrating agents. A total of 12 glycosylated alicylsalicylic acid derivatives, which were connected with salicylic acid or vanillic acid, were synthesized. The third category: the glycosylated triazolidin derivatives with triazole structure were synthesized by click-chemical method from aluminol, bromopyne and azidosaccharide. The fourth kind: using salicylaldehyde or vanillin, bromopyne and azide as raw materials, glycosylated triazolyl aromatic aldehydes were synthesized by means of click-chemical method, and then the aldehydes were oxidized to carboxyl groups, and finally, in the presence of dehydrating agents, the glycosylated triazolyl aromatic aldehydes were synthesized. The glycosylated triazolyl alicylalicylic acid ester derivatives, which are connected by salicylic acid or vanillic acid, have been synthesized, with a total of 8. 2. 2. Two kinds of glycosylated chickpein A derivatives were synthesized. In the first kind, 12 glycosides were synthesized by phase transfer catalysis from chickpetins A and acetyl bromosugars under weak basic conditions. In the second category, eight glycosylated triazolium chickpetrin A derivatives were synthesized by click-chemical method using chickpetins A, bromopyne and azide as raw materials. The structures of the compounds were identified by 1H-NMR-13C-NMR-IRESI-MS and elemental analysis. Activity study. The antihypoxia activities of eight derivatives of glycosylated triazolidin and chickpein A were studied. Some of the derivatives showed good anti-hypoxia activity in the model of atmosphere-closed hypoxia. The activities of compounds C _ 5, C _ 8, E _ 6 and E _ 7 were superior to those of the parent and the positive drug acetazolamide.
【学位授予单位】：兰州大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R914

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