海洋糖脂glycolipids simplexides和系列鞘糖脂类化合物的合成及其生物活性研究
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摘要
糖脂(glycolipids)是指含有糖基配体的脂类化合物,依脂质部分的不同可分为鞘糖脂(glycosphingolipids,GSL)、甘油糖脂(glycoglycerolipids)、含有磷酸多萜醇衍生的糖脂(polyprenol phosphate glycoside)和类固醇衍生的糖脂(steryl glycoside)。糖脂及其衍生物被认为在细胞生长、分化、凋亡方面具有重要的调节作用,并且某些是潜在的治疗药物。已有证据表明糖脂分子参与免疫应答过程。免疫抑制剂在临床上主要用于治疗自身免疫性疾病和防止脏器移植排斥,但目前常规使用的免疫抑制类药物大多治疗窗狭窄、价格昂贵,而且多具严重毒副作用,因此新型免疫抑制剂的开发研究已成为医药研发领域的热点。本文主要对具有免疫抑制活性的海洋天然糖脂glycolipids simplexides及系列鞘糖脂类衍生物进行了合成和生物学方面的研究,以期探究此类化合物的构效关系,为开发新型免疫抑制剂奠定坚实基础。
(1)本文发展了一条简洁高效的(1→4)-分枝半乳糖脂的合成路线,采用“一锅法”合成策略,首次完成了具有免疫抑制活性且结构新颖的三个海洋糖脂bis(hexadecyl)methyl 4-O-(α-D-glucopyranosyl)-β-D-galactopyranoside (1a) ,bis(heptadecyl)methyl 4-O-(α-D-glucopyranosyl)-β-D-galactopyranoside (1b)和bis(octadecylselyl)methyl 4-O-(α-D-glucopyranosyl)-β-D-galactopyranoside (1c)的全合成。发展了p-methylphenyl 2, 3, 4 tri-O-benzyl-6-O-tert-butyldiphenylsilyl -1-thio-β-D-glucopyranoside供体,利用该供体可以高选择性的形成葡萄糖α-糖苷键。通过改变两步糖苷化反应体系这一关键步骤,以较高的“一锅法”糖苷化产率得到前体化合物18a-c,脱除保护基后便得目标化合物1a-c。
(2)本文设计并合成15个鞘糖脂类衍生物:β-半乳糖鞘糖脂及不含脂肪酸的β-半乳糖鞘糖脂,鞘氨醇种类包括神经鞘氨醇、二氢鞘氨醇及植物鞘氨醇;半乳糖2-OH衍生化的鞘糖脂;鞘氨醇长链衍生化的鞘糖脂。
找到一条通用的、适合不同糖基供体的合成二氢鞘糖脂的路线。由关键中间体34出发,Pd/C氢解后得到双键还原及苄基脱除的化合物35,35与叠氮化钠发生SN2历程的亲和取代反应,叠氮基亲核取代35上的磺酸酯后,构型发生翻转,得到含有叠氮基的二氢鞘氨醇36。36经过保护基操作后便可直接用于糖苷化反应。
发展了3, 4, 6-tri-O-acetyl-2-O-Lev-α-D-galactopyranosyl trichloroacetimidate供体,利用该供体可以简便有效的制备2-OH衍生化的半乳糖鞘糖脂。
(3)通过对T1-T20的抗真菌(Candida albicans, Candida parapsilosis, Candida tropicalis)活性测定,初步了解了二氢鞘氨醇的抗真菌构效关系:①游离氨基是活性必须基团;②糖基部分在此处不仅是作为药动基团,而且有可能是药效基团,与抗真菌活性的特异性具有重要关系。③疏水性长链脂肪烃为活性必须结构。
Glycolipids are membrane components composed of lipids that are covalently bonded to monosaccharides or polysaccharides. The occurrence of glycolipids which contain glycosphingolipids, glycoglycerolipids, polyprenol phosphate glycoside and sterol glycosides have an important regulatory role in the cell growth, differentiation and apoptosis, and some of them are potential therapeutic drugs. Recently, glycolipids have been proved to involve in immune response. Immunosuppressive agents are drugs that inhibit or prevent activity of the immune system. They are used in immunosuppressive therapy to prevent the rejection of transplanted organs and tissues. But these drugs are not without side-effects and risks. Because the majority of them act non-selectively, the immune system is less able to resist infections and the spread of malignant cells. In this dissertation, the first synthesis of novel glycolipids simplexides (1a-c) has been achieved through a straightforward and several analogues of glycosphingolipids were designed and synthesized for the future evaluation in immunoregulatory activity.
(1) The first synthesis of three natural glycolipids simplexides (1a-c), which were isolated from the marine sponge Plakortis simplex and claimed to inhibit T cell proliferation, has been concisely accomplished by a reactivity-based one-pot synthetic strategy. The donor of p-methylphenyl 2, 3, 4 tri-O-benzyl-6-O-tert-butyldiphenylsilyl -1-thio-β-D-glucopyranoside can give highα-selectivity of the glycosylation. By performing the first glycosylation in Et2O/CH2Cl2 (V:V, 4:1) and the second in Et2O/CH2Cl2 (V:V, 2:3), one-pot glycosylation took place successfully in good yields.
(2) For further study on the mechanism of the bioactivity, we synthesized a series of glycosphingolipids derivatives. An efficient and practical route to synthesis dihydro-glycosylsphingolipids was developed. The mesylate 34 was converted into dihydrosphingosine 36, by a series of functional group thansformation involving: reduction of the double bond and deprotection of the benzyl groups to the corresponding 35, SN2 replacement of the mesylate group in compound 35 by sodium azide to afford 36. With different glycosyl donors, 36 can be glycosylated directly to achieve dihydro-glycosylsphingolipids.
This paper provides a facile and efficient approach to synthesiz galactosylceramide with a modified 2-position under the use of 3, 4, 6-tri-O-acetyl-2-O-Lev-α-D-galactopyranosyl trichloroacetimidate.
(3) The minimal fungicidal concentration of T1-T20 was determined for Candida albicans, Candida parapsilosis and Candida tropicalis. We tested the possibility that the antifungal activity was manifested through nonspecific amphiphilic properties of long-chain aminolipids. The structure-activity relationship has been described as follows:①The amino-group may play an important role in the activity;②The glycosyl residue is not only a group as pharmacokinetics but also as pharmacodynamics, and has an important relationship with specificity of antifungal activity;③The long alkyl chains are necessary for antifungal activity.
(1)本文发展了一条简洁高效的(1→4)-分枝半乳糖脂的合成路线,采用“一锅法”合成策略,首次完成了具有免疫抑制活性且结构新颖的三个海洋糖脂bis(hexadecyl)methyl 4-O-(α-D-glucopyranosyl)-β-D-galactopyranoside (1a) ,bis(heptadecyl)methyl 4-O-(α-D-glucopyranosyl)-β-D-galactopyranoside (1b)和bis(octadecylselyl)methyl 4-O-(α-D-glucopyranosyl)-β-D-galactopyranoside (1c)的全合成。发展了p-methylphenyl 2, 3, 4 tri-O-benzyl-6-O-tert-butyldiphenylsilyl -1-thio-β-D-glucopyranoside供体,利用该供体可以高选择性的形成葡萄糖α-糖苷键。通过改变两步糖苷化反应体系这一关键步骤,以较高的“一锅法”糖苷化产率得到前体化合物18a-c,脱除保护基后便得目标化合物1a-c。
(2)本文设计并合成15个鞘糖脂类衍生物:β-半乳糖鞘糖脂及不含脂肪酸的β-半乳糖鞘糖脂,鞘氨醇种类包括神经鞘氨醇、二氢鞘氨醇及植物鞘氨醇;半乳糖2-OH衍生化的鞘糖脂;鞘氨醇长链衍生化的鞘糖脂。
找到一条通用的、适合不同糖基供体的合成二氢鞘糖脂的路线。由关键中间体34出发,Pd/C氢解后得到双键还原及苄基脱除的化合物35,35与叠氮化钠发生SN2历程的亲和取代反应,叠氮基亲核取代35上的磺酸酯后,构型发生翻转,得到含有叠氮基的二氢鞘氨醇36。36经过保护基操作后便可直接用于糖苷化反应。
发展了3, 4, 6-tri-O-acetyl-2-O-Lev-α-D-galactopyranosyl trichloroacetimidate供体,利用该供体可以简便有效的制备2-OH衍生化的半乳糖鞘糖脂。
(3)通过对T1-T20的抗真菌(Candida albicans, Candida parapsilosis, Candida tropicalis)活性测定,初步了解了二氢鞘氨醇的抗真菌构效关系:①游离氨基是活性必须基团;②糖基部分在此处不仅是作为药动基团,而且有可能是药效基团,与抗真菌活性的特异性具有重要关系。③疏水性长链脂肪烃为活性必须结构。
Glycolipids are membrane components composed of lipids that are covalently bonded to monosaccharides or polysaccharides. The occurrence of glycolipids which contain glycosphingolipids, glycoglycerolipids, polyprenol phosphate glycoside and sterol glycosides have an important regulatory role in the cell growth, differentiation and apoptosis, and some of them are potential therapeutic drugs. Recently, glycolipids have been proved to involve in immune response. Immunosuppressive agents are drugs that inhibit or prevent activity of the immune system. They are used in immunosuppressive therapy to prevent the rejection of transplanted organs and tissues. But these drugs are not without side-effects and risks. Because the majority of them act non-selectively, the immune system is less able to resist infections and the spread of malignant cells. In this dissertation, the first synthesis of novel glycolipids simplexides (1a-c) has been achieved through a straightforward and several analogues of glycosphingolipids were designed and synthesized for the future evaluation in immunoregulatory activity.
(1) The first synthesis of three natural glycolipids simplexides (1a-c), which were isolated from the marine sponge Plakortis simplex and claimed to inhibit T cell proliferation, has been concisely accomplished by a reactivity-based one-pot synthetic strategy. The donor of p-methylphenyl 2, 3, 4 tri-O-benzyl-6-O-tert-butyldiphenylsilyl -1-thio-β-D-glucopyranoside can give highα-selectivity of the glycosylation. By performing the first glycosylation in Et2O/CH2Cl2 (V:V, 4:1) and the second in Et2O/CH2Cl2 (V:V, 2:3), one-pot glycosylation took place successfully in good yields.
(2) For further study on the mechanism of the bioactivity, we synthesized a series of glycosphingolipids derivatives. An efficient and practical route to synthesis dihydro-glycosylsphingolipids was developed. The mesylate 34 was converted into dihydrosphingosine 36, by a series of functional group thansformation involving: reduction of the double bond and deprotection of the benzyl groups to the corresponding 35, SN2 replacement of the mesylate group in compound 35 by sodium azide to afford 36. With different glycosyl donors, 36 can be glycosylated directly to achieve dihydro-glycosylsphingolipids.
This paper provides a facile and efficient approach to synthesiz galactosylceramide with a modified 2-position under the use of 3, 4, 6-tri-O-acetyl-2-O-Lev-α-D-galactopyranosyl trichloroacetimidate.
(3) The minimal fungicidal concentration of T1-T20 was determined for Candida albicans, Candida parapsilosis and Candida tropicalis. We tested the possibility that the antifungal activity was manifested through nonspecific amphiphilic properties of long-chain aminolipids. The structure-activity relationship has been described as follows:①The amino-group may play an important role in the activity;②The glycosyl residue is not only a group as pharmacokinetics but also as pharmacodynamics, and has an important relationship with specificity of antifungal activity;③The long alkyl chains are necessary for antifungal activity.
引文
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