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题名: 几类含氮化合物的合成、分离及其抗HIV-1、 HBV活性研究
作者: 程辟
学位类别: 博士
答辩日期: 2008-05-28
授予单位: 中国科学院昆明植物研究所
授予地点: 昆明植物研究所
导师: 陈纪军
关键词: 含氮化合物 ; 合成 ; 夜花藤 ; 生物碱 ; 分离 ; HIV-1 ; HBV ; 生物活性
学位专业: 植物学
中文摘要: 本论文由五章组成,第一、二章主要介绍了N-乙酰基-b-芳基-1,2-脱氢芳香乙胺和1-取代-6,7-二甲氧基(羟基)-1,2,3,4-四氢异喹啉衍生物的合成及其体外抗 HIV-1 活性,第三章的主要内容为喹啉-2-酮和1,4-苯并二氮啅的合成及其抗体外抗HBV活性研究,第四章为防己科植物夜花藤中生物碱成分的分离、结构鉴定及其体外抗HBV活性研究,第五章为综述,简要的介绍了近年来Picted-Spengler反应的研究进展。通过以上工作,我们合成含氮化合物124个,其中首次合成的化合物67个,从夜花藤中分离得到生物碱13个,其中新化合物2个。部分化合物对HIV-1或HBV表现出较好的抑制活性。 第一章 N-乙酰基-b-芳基-1,2-脱氢芳香乙胺衍生物的合成与体外抗 HIV-1活性研究 非核苷类逆转录酶抑制剂 (NNTRIs) 是一类与核苷结构、作用机理迥异的特异性抑制HIV-RT的化合物。该类抑制剂具有结构多样性、高效低毒以及可以与其它药物协同作用等特性。我们的前期研究首次发现b-芳基-硝基乙烯 (NOF,1) 能够有效抑制HIV-1 RT,但是这类化合物在C8166细胞中的毒性较大导致其体外治疗指数 (TI) 较低。对NOF类化合物的硝基进行还原-乙酰化得到N-乙酰基-b-芳基-1,2-脱氢芳香乙胺衍生物 (6),将化合物6中酰胺氮原子进一步烷基化得到N-乙酰基-N-烷基-b-芳基-1,2-脱氢芳香乙胺 (9)。这两类化合物在C8166中的细胞毒性明显降低,同时保持了对HIV-1 RT的抑制作用并具有明显的构效关系。 以各种芳香醛为起始原料通过Henry反应合成23个NOF类化合物 (1)。当芳环为邻位单取代苯环时,化合物1相对于其它异构体具有较好的抗HIV-1 RT活性。例如邻位溴代化合物1b (Ar = 2-Br-phenyl) 在200 g/mL浓度下能够抑制95.74%的HIV-1 RT (IC50 = 0.2024 mM),而它的间位和对位异构体 (1c 和1d) 却没有活性;将原化合物1还原-乙酰化得到24个化合物6,其抗HIV-1 RT构效关系与化合物1一致,即Ar为邻位取代苯时对HIV-1 RT具有较好的抑制作用。例如,化合物6b (Ar = 2-Br-pheny) 在200 g/mL浓度下对HIV-1 RT的抑制率为54.35%,在C8166细胞中的半数毒性浓度CC50为0.241 mM, 治疗指数为1.8;通过对化合物6的N-烷基化反应,选择性的合成了20个N-乙酰基-N-烷基-b-芳基-1,2-脱氢芳香乙胺 (9) 类似物。化合物9的体外抗HIV-1活性相对于6有了进一步提高。例如化合物9i (Ar = 2-Br-phenyl, R = 3,5-diflurophenyl) 在200 g/mL浓度下对HIV-1 RT的抑制率为88.89%,其体外抗HIV-1 EC50值为0.004 mM, CC50值为0.116 mM,治疗指数达到29。化合物6b和9i的结构式如下: 第二章 1-芳香基-6,7-二甲氧基(羟基)-1,2,3,4-四氢异喹啉的合成与抗 HIV-1 活性研究 一些天然存在的四氢异喹啉生物碱具有一定程度的体外抗HIV-1活性。通过化学合成简单四氢异喹啉类生物碱来寻找具有抗HIV-1药物先导对四氢异喹啉生物碱在抗HIV-1活性研究方面具有重要的意义。以3,4-二甲氧基苯乙胺或3,4-二羟基苯乙胺 (dopamine) 与各种芳香醛通过Pictet-Spengler反应合成了36个1-芳基-6,7-二甲氧基 (羟基)-1,2,3,4-四氢异喹啉衍生物。 体外抗HIV-1活性筛选表明1-芳基-6,7-羟基-1,2,3,4-四氢异喹啉的细胞毒性较1-芳基-6,7-二甲氧基-1,2,3,4-四氢异喹啉显著降低。在此基础上,我们发现了三个具有进一步研究价值的1-芳基-6,7-羟基-1,2,3,4-四氢异喹啉衍生物: 6 (1-Ar = 4-methylphenyl),24 (1-Ar = 3-chlorophenyl) 和36 (1-Ar = 2-naphthyl)。上述三个化合物在C8166细胞中的抗HIV-1治疗指数分别为>95,>159,>130,EC50值分别为8.2,4.6,5.3 M。化合物6,24和36的结构式如下: 第三章 喹啉-2-酮和1,4-苯并二氮啅合成与抗HBV活性研究 非核苷类抗HBV化合物结构类型多样,本课题组在随机筛选大量的植物提取物、天然产物单体和人工合成产物的过程中,首次发现4-苯基-6-氯-喹啉-2-酮 (42)对乙型肝炎表面抗原 (HBsAg) 具有一定程度抑制作用,该化合物在HepG 2.2.15细胞中对HBsAg分泌抑制的选择指数 (SI) 为2.6 (IC50 = 0.458 mM)。以对氯苯胺为原料通过多步反应合成了3-取代-4-芳基-6-氯-喹啉-2-酮及其扩环类似物5-芳基-7-氯-1,4-苯并二氮啅衍生物共21个。体外抗HBV活性数据表明3-羟乙基-4-芳基-6-氯-喹啉-2-酮 (化合物E1–E3) 在HepG 2.2.15细胞中对乙型肝炎表面抗原 (HBsAg) 和乙型肝炎e抗原 (HBeAg) 分泌都具有较好的抑制作用,然而5-芳基-7-氯-1,4-苯并二氮啅在体外对两抗分泌抑制作用并不显著。化合物E1-E3对HBsAg的选择指数分别为>16.4, >16.0 和23.2,对HBeAg的选择指数分别为>5.2, >5.5和3.4,其半数细胞毒性浓度CC50值分别为>4.913, >2.994, 1.722 mM。化合物E1-E3具有进一步研究的价值,其结构式如下: 第四章 夜花藤中生物碱的分离与抗HBV活性研究 夜花藤 (Hypserpa nitida Miers),为防己科 (Menispermaceae)夜花藤属 (Hypserpa) 植物,产于中国南部和南亚,在当地为民间药用植物。我们首次对该植物干燥全株的90%乙醇提取物进行了化学成分研究,从其生物碱部分总共分离得到生物碱13个,分别为hypserpamine A (1), phenolbetain (2),尖防己碱 (acutumine 3),N-去甲基尖防己碱 (acutumidine 4),去氯尖防己碱 (dechloroacutumine 5), 异尖防己碱 (dauricumine 6),N-去甲基异尖防己碱 (dauricumidine 7),前荷叶碱 (pronuciferine 8), 奥可梯木种碱 (glaziovine9),(S)-番荔枝碱 (S-reticuline 10),hypserpamine B (11),木兰碱 (magnoflorine 12) 和laurifoline (13)。其中化合物1和11为新的生物碱。使用Hep G2.2.15细胞系,测定了化合物1–13的体外抗HBV活性。具有acutumine类骨架化合物hyserpamine A (1)、acutumindine (4)、dauricumine (6)对乙型肝炎表面抗原 (HBsAg) 具有一定程度的抑制作用,IC50值分别为1.415,2.023和1.312 mM,选择指数在1–2之间。活性最强的化合物为dauricumidine (7),它对HBsAg的IC50值为0.450 mM,选择指数达到了4.13。化合物7的N甲基化合物dauricumine (6) HBsAg的IC50值仅为1.312 (SI=1.67)。原阿朴啡类生物碱pronuciferine (8) 和glaziovine (9) 对HBsAg的活性较强,IC50值分别为 0.042和0.008 mM,但是这类化合物在Hep G2.2.15细胞系中的毒性较大,因此选择指数小于1。季铵盐类阿朴啡生物碱11–13在Hep G2.2.15中的毒性相对于原阿朴啡生物碱显著降低,但是其活性降低也非常明显,SI均小于1。化合物7的结构式如下: 第五章 Pictet-Spengler 反应研究进展 Pictet-Spengler (P-S) 反应是合成四氢异喹啉和b-咔啉衍生物的有效方法,在构建含氮杂环体系中占有非常重要的地位。本章对近年来P-S反应的催化体系、反应的选择性,改进型的P-S反应以及固相P-S反应进行了文献综。
英文摘要: This dissertation is composed of five chapters, in which N-acetyl-b-aryl-1,2-didehydroethylamines and 1-aryl-6,7-dihydroxyl(methoxy)-1,2,3,4-tetrahydro isoquinolines derivatives were synthesized and assayed for their in vitro anti-HIV-1 activity in chapter 1 and 2 respectively; synthesis and in vitro anti-HBV activity of quinolin-2-ones and 1,4-benzo-diazepines were provided in chapter 3; isolation, structure elucidation, anti-HBV activity on alkaloids from Hypserpa nitida Miers. (Menispermaceae) were introduced in chapter 4. In the last chapter, recent progresses of Pictet-Spengler reaction were summarized based on leteratures. Based on the above research, 124 nitrogen-contaning compounds, among which 67 were new, were synthesized, and, 13 alkaloids including two new compounds were isolated from Hypserpa nitida. Parts of the compounds showed good inhibitory activity against HIV-1 or HBV. Chapter 1 Synthesis and in vitro anti-HIV-1 activity of N-acetyl-b-aryl-1,2-didehydroethylamines Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are a class of HIV-RT inhibitors with different structures and mechanism of action compared with nucleosides. NNTRIs are structurally diverse, high efficient, low toxic and can be used combined with other anti-HIV medicines. In our previous study, it was found that b-nitroolefins (NOF 1) inhibited HIV-1 RT efficiently, but this kind of compounds were highly cytotoxic in C8166 cells, which led to low therapeutic index (TI). A reduction-acetylation of NOF provided 24 N-acetyl-b-aryl-1,2-didehydroethylamine derivatives (6), and a successively alkylation of nitrogen atom in compounds 6 gave N-acetyl-N-alkyl-b-aryl-1,2-didehydroethylamines (9). Compounds 6 and 9 could inhibit HIV-1 RT with obvious structure-activity relationships and highly decreased cytotoxicity. 23 b-nitroolefins (1) were synthesized via Henry reaction with various aromatic aldehydes as starting materials. When Ar was ortho-monosubstituted phenyl, compounds 1 possessed higher enzymatic activity compared with other isomers. For example, compound 1b (Ar = 2-Br-phenyl) could inhibitor 95.74% HIV-1 RT at a concentration of 200 g/mL (IC50 = 0.2024 mM), while, its meta (1c) and para (1d) isomers exhibited no enzymatic activity. A reduction-acetylation of compounds 1 afforded compounds 6 with the same anti-HIV-1 RT structure-activity relationships as compounds 1: ortho substituted compound possessed higher enzymatic activity compared with other isomers. For example, compound 6b (Ar = 2-Br-pheny) could inhibit 54.35% HIV-1 RT at a concentration of 200 g/mL (IC50 = 0.2024 mM), with a CC50 value of 0.241 mM and TI of 1.8. 20 derivatives of N-alkyl-b-aryl-1,2-didehydroethylamines (9) were selectively synthesized through a N-alkylation of compounds 6. Compounds 9 possessed higher in vitro anti-HIV-1 activity compared with 6. For example, compound 9i (Ar = 2-Br-pheny, R = 3,5-diflurobenzyll) could inhibitor 88.89% HIV-1 RT at a concentration of 200 g/mL with EC50 value of 0.004 mM and CC50 value of 0.116 mM (TI = 29). The structures of compounds 6b and 9i were showed as follows: Chapter 2 Synthesis and in vitro anti-HIV-1 activity of 1-aryl-6,7-dihydroxyl(methoxy)-1,2,3,4-tetrahydroisoquinolines Several naturally occurring tetrahydroisoquinoline alkaloids showed in vitro anti-HIV-1 activity. Discovery of anti-HIV-1 lead compounds through chemical synthesis of simple tetrahydroisoquinoline is important to anti-HIV-1 SAR study on tetrahydroisoquinoline. 36 derivatives of 1-aryl-6,7-dihydroxyl(methoxy)- 1,2,3,4-tetrahydroisoquinolines were synthesized using 3,4-dihydroxy-phenyl- ethylamine or dopamine and various aromatic aldehydes as starting materials. An anti-HIV-1 activity screening in vitro showed that 1-aryl-6,7-dihydroxyl- 1,2,3,4-tetra-hydroisoquinolines possessed significantly decreased cytotoxicity compared with 1-aryl-6,7-methoxy-1,2,3,4-tetra- hydroisoquinolines. Based on the above study, three 1-aryl-6,7-dihydroxyl-1,2,3,4-tetrahydroisoquinolines were discovered for further study: compounds 6 (1-Ar = 4-methylphenyl), 24 (1-Ar = 3-chlorophenyl) and 36 (1-Ar = 2-naphthyl) showed TI values of >95, >159 and >130 with EC50 values of 8.2, 4.6 and 5.3 M in C8166 cells, respectively. The following were the structures of compounds 6, 24 and 36: Chapter 3 Synthesis and in vitro anti-hepatitis B virus activities of quinolin-2-one and 1,4-benzodiazepine derivatives Non-nucleoside HBV inhibitors were structurally diverse, a rational screening of extracts of plants, pure natural products and synthetic compounds in our group suggested that 4-phenyl-6-chloro-quinolin-2-one (42) possessed moderate activity to inhibit the secretion of HBV surface antigen (HBsAg) in HBV-infected Hep G2.2.15 cells with selective index (SI) value of 2.6 (IC50 = 0.458 mM). 21 derivatives of 3-substituted-4-aryl-6-chloro-quinolin-2-ones and 5-aryl-7-chloro-1,4-benzo- diazepines (ring expanded analogs of 42) were synthesized with 4-chloroaniline as starting material. The anti-HBV activities in Hep G 2.2.15 cells of the synthesized compounds suggested that 3-hydroxylethyl-4-aryl-6-chloro-quinolin-2-one (compounds E1–E3) could inhibit both HBsAg and HBeAg secretions, while 5-aryl-7-chloro-1,4-benzodiazepines showed no significant suppressant activity on HBsAg and HBeAg secretions. Compounds E1–E3 showed SI values of >16.4, >16.0, 23.2 against HBsAg, and >5.2, >5.5, 3.4 against HBeAg with CC50 values of >4.913, >2.994, 1.722 mM. Compounds E1–E3 deserved further study, and the structrures were outlined as follows: Chapter 4 Isolation and Anti-Hepatitis B virus activity of alkaloids from Hypserpa nitida Hypserpa nitida Miers. (Menispermaceae), distributed in China and south Asia, is a folk medicinal herb. First separation of alkaloids part of the 90% EtOH extract of dry whole plant of H. nitida yielded 13 alkaloids: hypserpanine A (1), phenolbetain (2), acutumine (3), acutumidine (4), dechloroacutumine (5), dauricumine (6), dauricumidine (7), pronuciferine (8), glaziovine (9), S-reticuline (10), hypserpanine B (11) magnoflorine (12) and laurifoline (13). Compounds 1 and 11 were new alkaloids. The anti-HBV activities of compounds 1–13 were evaluated in vitro using the Hep G2.2.15 cell line stably transfected with the HBV genome. The alkaloids with acutumine core structure, such as hyperpamine A (1), acutumidine (4) and dauricumine (6), had inhibitory activity on the secretion of HBsAg with IC50 values of 1.415, 2.023 and 1.312 mM (2 > SI > 1). The most active acutumine alkaloid, dauricumidine (7), showed anti-HBsAg activity with IC50 of 0.450 mM (SI = 4.13), while its N-methylated derivative dauricumine (6) only showed IC50 values of 1.312 (SI =1.67). The proaporphine alkaloids, pronuciferine (8) and glaziovine (9), exhibited high inhibitory potential against HBsAg with IC50 value of 0.042 and 0.008 mM respectively. But these two compounds were cytotoxic in Hep G2.2.15 cells, as a result, compound 8 only showed SI value of 1.19. The quaternary aporphine alkaloids 11–13 were inactive to HBsAg and HBeAg, but the cytotoxicities of these compounds in Hep G2.2.15 cells were obvious lower than those of proaporphine alkaloids 8–9. The structure of compound 7 was listed as follows: Chapter 5 Progress in Pictet-Spengler Reaction Pictet-Spengler (P-S) reaction is a methodology to synthesize tetrahydroisoquino- line and b-carboline derivatives effectively and plays an important role in construction of N-containing heterocyclic system. In this chapter, the catalytic system, reaction selectivity and the improvement of P-S reaction were reviewed together with an introduction of solid phase P-S reaction based on literatures.
语种: 中文
内容类型: 学位论文
URI标识: http://ir.kib.ac.cn/handle/151853/308
Appears in Collections:昆明植物所硕博研究生毕业学位论文_学位论文

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Recommended Citation:
几类含氮化合物的合成、分离及其抗HIV-1、 HBV活性研究.程辟[d].中国科学院昆明植物研究所,2008.20-25
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