【摘要】：白楊素、鷹嘴豆芽素A都屬于黃酮類(lèi)化合物,來(lái)源廣泛且具有眾多的生理活性。研究表明,這兩類(lèi)化合物都存在溶解性較差、吸收少的問(wèn)題；另外,白楊素、鷹嘴豆芽素A在被吸收后迅速被糖醛酸化或磺酸化而被代謝掉,導(dǎo)致這兩種化合物活性降低；這兩大原因限制了它們的應(yīng)用。針對(duì)其溶解性和代謝位點(diǎn)進(jìn)行化學(xué)改造,是獲得活性?xún)?yōu)異化合物的一條重要途徑。糖類(lèi)分子是生物體內(nèi)一類(lèi)重要的分子,涉及眾多的信號(hào)傳導(dǎo)。引入糖單元可以改善母體化合物的穩(wěn)定性、溶解性以及靶向性,從而改善先導(dǎo)化合物的生理活性。本文對(duì)白楊素、鷹嘴豆芽素A的易代謝位點(diǎn)進(jìn)行糖基化改造,通過(guò)引入糖單元以期改善其溶解性和生理活性。 本論文主要分為以下幾部分： 1.設(shè)計(jì)、合成糖基化白楊素衍生物四大類(lèi)。 第一類(lèi)：以白楊素和乙酰溴代糖為原料,弱堿性條件下用相轉(zhuǎn)移催化法,經(jīng)過(guò)2步簡(jiǎn)單的反應(yīng)得到了12個(gè)白楊素糖苷類(lèi)衍生物。 第二類(lèi)：以水楊醛或香草醛為原料,在相轉(zhuǎn)移催化的條件下與乙酰溴代糖成苷,再將醛基氧化成羧基,最終在脫水劑作用下與白楊素成酯,合成了通過(guò)水楊酸或香草酸連接的糖苷化芳酸白楊素酯類(lèi)衍生物,共12個(gè)。 第三類(lèi)：以白楊素、溴丙炔和疊氮糖為原料,運(yùn)用點(diǎn)擊化學(xué)的方法合成設(shè)計(jì)了引入三氮唑結(jié)構(gòu)的糖基化三氮唑白楊素衍生物,共8個(gè)。第四類(lèi)：以水楊醛或香草醛、溴丙炔和疊氮糖為原料,運(yùn)用點(diǎn)擊化學(xué)的方法合成糖基化三氮唑芳醛,再經(jīng)將醛基氧化成羧基,最終在脫水劑作用下與白楊素成酯,合成了通過(guò)水楊酸或香草酸連接的糖苷化三氮唑芳酸白楊素酯類(lèi)衍生物,共8個(gè)。 2.合成糖基化鷹嘴豆芽素A衍生物兩大類(lèi)。 第一類(lèi)：以鷹嘴豆芽素A和乙酰溴代糖為原料,弱堿性條件下用相轉(zhuǎn)移催化法合成得到了12個(gè)鷹嘴豆芽素A糖苷類(lèi)衍生物。 第二類(lèi)：以鷹嘴豆芽素A、溴丙炔和疊氮糖為原料,運(yùn)用點(diǎn)擊化學(xué)的方法合成設(shè)計(jì)了引入三氮唑結(jié)構(gòu)的糖基化三氮唑鷹嘴豆芽素A衍生物,共8個(gè)。以上所得到的化合物的結(jié)構(gòu)經(jīng)1H-NMR、13C-NMR、IR、ESI-MS和元素分析鑒定。 3.活性研究。本部分對(duì)糖基化三氮唑白楊素及鷹嘴豆芽素A的8個(gè)衍生物做了抗缺氧活性研究。部分衍生物在常壓密閉缺氧模型中均表現(xiàn)出較好的抗缺氧活性,其中化合物C5, C8, E6, E7的活性?xún)?yōu)于母體及陽(yáng)性藥乙酰唑胺。
[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.
【學(xué)位授予單位】：蘭州大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類(lèi)號(hào)】：R914

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