金银花抗病毒有效成分双抗素类似物的合成与活性研究
摘要
双抗素(A1)是本课题组从民间用于治疗感冒的常用中药金银花中发现的一个对鸡胚内流感病毒和呼吸道合胞病毒有明显抑制作用的新成分,其结构独特,分子中含少见的六元过氧键环系,是首次发现的天然含过氧环抗病毒有效成分,是值得重视的创新药物先导物。
本课题从双抗素及其类似物的全合成研究入手,研究了双抗素类分子中过氧键环系的合成途径和形成规律,过氧半缩醛的糖苷化以及糖基脱保护的方法,合成了双抗素结构类似物和简化物,研究了其抗病毒作用,并对实验中的出现的特殊现象的反应机制进行了研究。
主要完成了如下研究工作:
一、建立了双抗素类分子中过氧键环系的形成方法,即通过过氧化氢对邻苯二甲醛的分子内加成形成环过氧二半缩醛。首次研究了苯环上取代基对邻苯二甲醛类化合物过氧键环系形成的影响:当苯环上存在吸电子取代基有利于过氧键环系的形成,给电子取代基的存在则不利于过氧键的形成。
二、以化合物19为底物,研究了双抗素类分子中过氧半缩醛羟基的糖苷化和脱乙酰保护基的方法,合成了双抗素类似物30a,30b。对该方法总结如下:以糖基三氯乙酰亚胺酯作为糖基给体,三氟化硼乙醚为催化剂,或者以硫营为糖基给体,NIS/AgOTf为催化剂,是相对适宜的糖苷化条件。首次研究了过氧缩醛糖苷脱乙酰保护基的方法,发现接近中性的化合物二丁基氧化锡是相对适宜的脱乙酰基试剂。光活纯化合物30a,30b的绝对构型通过与绝对构型已知的化合物29a,29b和双抗素比较CD谱的方法加以确定。
三、合成了双抗素类分子的系列简化物,首次研究了这类化合物的抗病毒活性,并对其构效关系和抗病毒机制进行了初步探讨。
四、首次研究了在酸或碱性条件下,该类过氧化物中过氧键断裂的机理。
五、发现一个NaBH_4还原毗啶二羧酸酯类化合物的新反应,首次研究了其反应机理。
Shuangkangsu, a new component with unusual 1,2-dioxane skeleton first isolated by our group from Jinyinhua, one of TCM (traditional Chinese medicine) has a significant activity of inhibition of influenza virus in chicken embryo and respiratory syncytial virus in cells. The particular skeleton of the leading compound is valuable for new drug research and development.
For studying the total synthesis of Shuangkangsu and its analogs, in this work, the methods for the formation and glucosylation of [1,2]dioxane-3,6-diol as well as the method for removal of acetyl protective group in compounds 26a, 26b have been studied. Analogs of Shuangkangsu were synthesized and tested for antiviral activities. Meanwhile, some reaction mechanisms in this work have also been studied.
1. The method for the formation of [1,2]dioxane-3,6-diol, which is intramolecular addition of hydrogen peroxide to 1,2-dialdehyde was established. The effect of substituents in aromatic ring on the formation of [1,2]dioxane-3,6-diol was firstly discussed. Electron-withdrawing substituents can promote the formation of [1,2]dioxane-3,6-diol, and vice versa.
2. The pure homochiral analogs 30a, 30b of Shuangkangsu were successfully synthesized from compound 19. The glucosylation methods for hydroxyl of substrate 19 was developed: The substrate 19 reacted with the alkyl thioglycoside donor by treat with N-Iodosuccinimide and Silver Trifluoromethanesulfonate, or reacted with the glycosyl trichloroacetimidate donor by treat with boron trifluoride ether complex. The method for removing the acetyl protective group in 3,6-O-glycosyl-[1,2]dioxane was firstly studied. Dibutyltin oxide was the proper reagent to remove the acetyl protective group in compounds 26a, 26b. By comparison the CD spectra of compounds 29a, 29b and Shuangkangsu, the absolute configuration of 30a, 30b were determined to (1R, 4R) and (1S, 4S).
3. Some analogs of Shuangkangsu were tested for antiviral activities, the structure-activities relationship (SAR) and antiviral mechanism of this kind of compounds were firstly discussed.
4. The decomposition mechanisms of the peroxides under acidic or basic conditions were firstly discussed.
5. A novel reaction, pyridine ring reduced by sodium borohydride, was observed and the reaction mechanism was firstly discussed.
本课题从双抗素及其类似物的全合成研究入手,研究了双抗素类分子中过氧键环系的合成途径和形成规律,过氧半缩醛的糖苷化以及糖基脱保护的方法,合成了双抗素结构类似物和简化物,研究了其抗病毒作用,并对实验中的出现的特殊现象的反应机制进行了研究。
主要完成了如下研究工作:
一、建立了双抗素类分子中过氧键环系的形成方法,即通过过氧化氢对邻苯二甲醛的分子内加成形成环过氧二半缩醛。首次研究了苯环上取代基对邻苯二甲醛类化合物过氧键环系形成的影响:当苯环上存在吸电子取代基有利于过氧键环系的形成,给电子取代基的存在则不利于过氧键的形成。
二、以化合物19为底物,研究了双抗素类分子中过氧半缩醛羟基的糖苷化和脱乙酰保护基的方法,合成了双抗素类似物30a,30b。对该方法总结如下:以糖基三氯乙酰亚胺酯作为糖基给体,三氟化硼乙醚为催化剂,或者以硫营为糖基给体,NIS/AgOTf为催化剂,是相对适宜的糖苷化条件。首次研究了过氧缩醛糖苷脱乙酰保护基的方法,发现接近中性的化合物二丁基氧化锡是相对适宜的脱乙酰基试剂。光活纯化合物30a,30b的绝对构型通过与绝对构型已知的化合物29a,29b和双抗素比较CD谱的方法加以确定。
三、合成了双抗素类分子的系列简化物,首次研究了这类化合物的抗病毒活性,并对其构效关系和抗病毒机制进行了初步探讨。
四、首次研究了在酸或碱性条件下,该类过氧化物中过氧键断裂的机理。
五、发现一个NaBH_4还原毗啶二羧酸酯类化合物的新反应,首次研究了其反应机理。
Shuangkangsu, a new component with unusual 1,2-dioxane skeleton first isolated by our group from Jinyinhua, one of TCM (traditional Chinese medicine) has a significant activity of inhibition of influenza virus in chicken embryo and respiratory syncytial virus in cells. The particular skeleton of the leading compound is valuable for new drug research and development.
For studying the total synthesis of Shuangkangsu and its analogs, in this work, the methods for the formation and glucosylation of [1,2]dioxane-3,6-diol as well as the method for removal of acetyl protective group in compounds 26a, 26b have been studied. Analogs of Shuangkangsu were synthesized and tested for antiviral activities. Meanwhile, some reaction mechanisms in this work have also been studied.
1. The method for the formation of [1,2]dioxane-3,6-diol, which is intramolecular addition of hydrogen peroxide to 1,2-dialdehyde was established. The effect of substituents in aromatic ring on the formation of [1,2]dioxane-3,6-diol was firstly discussed. Electron-withdrawing substituents can promote the formation of [1,2]dioxane-3,6-diol, and vice versa.
2. The pure homochiral analogs 30a, 30b of Shuangkangsu were successfully synthesized from compound 19. The glucosylation methods for hydroxyl of substrate 19 was developed: The substrate 19 reacted with the alkyl thioglycoside donor by treat with N-Iodosuccinimide and Silver Trifluoromethanesulfonate, or reacted with the glycosyl trichloroacetimidate donor by treat with boron trifluoride ether complex. The method for removing the acetyl protective group in 3,6-O-glycosyl-[1,2]dioxane was firstly studied. Dibutyltin oxide was the proper reagent to remove the acetyl protective group in compounds 26a, 26b. By comparison the CD spectra of compounds 29a, 29b and Shuangkangsu, the absolute configuration of 30a, 30b were determined to (1R, 4R) and (1S, 4S).
3. Some analogs of Shuangkangsu were tested for antiviral activities, the structure-activities relationship (SAR) and antiviral mechanism of this kind of compounds were firstly discussed.
4. The decomposition mechanisms of the peroxides under acidic or basic conditions were firstly discussed.
5. A novel reaction, pyridine ring reduced by sodium borohydride, was observed and the reaction mechanism was firstly discussed.
引文
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