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题名: 高等真菌生物碱 Flazin 的全合成、结构修饰及其抗HIV和抗肿瘤活性
作者: 汤建国
学位类别: 博士
答辩日期: 2007-05-31
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: 刘吉开
关键词: 高等真菌 ; Flazin ; 全合成 ; 结构修饰 ; 抗HIV ; 抗肿瘤 ; Canthin-6-one ; Vulpinic acid
学位专业: 植物学
中文摘要: 高等真菌“创造指数”高、次生代谢产物化学结构多样且新颖,是一种重要的天然产物新药源。本论文以从高等真菌中发现的Flazin、Canthin-6-one和Vulpinic acid三个生物活性分子为研究模板,开展其全合成、结构修饰、抗HIV和抗肿瘤活性以及构效关系研究,以期得到活性更强、毒副作用更低的抗HIV或抗肿瘤先导化合物。 第一章 Flazin为从点柄粘盖牛肝菌(Suillus granulatus)子实体中分到的β-卡波林生物碱,初筛结果显示Flazin有抗HIV活性(CC50=28.53 μM,EC50=2.36 μM,TI=12.1)。以Flazin为研究模板,利用发展的“一锅煮”合成β-卡波林新方法,以46.5%的总收率全合成了Flazin;然后利用多样性导向合成原理,对其1、3、6、7、9、1’、3’、4’、5’等位点进行结构修饰,构建了一个含179个化合物的Flazin类天然产物化合物库;对其中部分化合物进行了抗HIV和抗肿瘤活性筛选及其构效关系研究,发现了一个具有阻断艾滋病病毒吸附/进入细胞的新化学物质--化合物59a,其体外对HIV-1IIIB实验株的EC50为0.38 μM,治疗指数为312.2,分别为母体化合物的6.2倍和28倍,同时发现化合物59a对HIV-2和临床耐药病毒株等都具有显著的抑制活性;另外还发现了一个具有促进微管蛋白聚合的新化学物质--化合物84j,其体外对肿瘤细胞株Raji、A549、HepG2 的EC50为0.06 μg/mL、0.28 μg/mL、0.16 μg/mL,分别为抗癌药物顺铂的3.3倍、2.1倍和4.4倍。 第二章Canthin-6-one为从变绿红菇(Russula virescens)子实体中分到的β-卡波林生物碱,研究表明Canthin-6-one有抗HIV和抗肿瘤活性。以Canthin-6-one为研究模板,对其A环、D环等位点进行结构修饰,合成了6个Canthin-6-one类化合物,其抗HIV/抗肿瘤活性筛选正在测试中。 第三章Vulpinic acid为从黄粉末牛肝菌(Pulverobletus ravenelii)子实体中分到的不饱和内酯类化合物,研究表明Vulpinic acid有抗HIV活性。以Vulpinic acid为研究模板,对其苯环对位进行结构修饰,合成6个Vulpinic acid类化合物以及6个Vulpinic lactone类化合物和6个Pulvinic acid类化合物,其抗HIV活性筛选正在测试中。 第四章 论文中相关化合物的合成实验及其光谱数据。 第五章 β-卡波林生物碱综述。
英文摘要: Higher fungi with high creative index (CI) can produce a large and diverse variety of secondary metabolites and is one of the new natural drug sources. In search of lead compounds of anti-HIV and anti-cancer, this thesis describes the total synthesis, structure modification, anti-HIV/anti-cancer activity evalution and structure-activity relation study of flazin, canthin-6-one and vulpinic acid from higher fungi. Chapter 1 Flazin isolated from higher fungi Suillus granulatus was found to have anti-HIV activity (CC50=8.53 μM, EC50=2.36 μM, TI=12.1). In order to study its anti-HIV /anti-cancer activity further, Flazin was synthesized in total yield of 46.5% with new “one-pot” synthetic method of β-carboline, and natural product-like library including 179 flazin analogues were also synthesized by modification at position-1, 3, 6, 7, 9, 1’, 3’, 4’ and 5’of flazin with diversity-oriented synthesis (DOS) theroy. Then the anti-HIV and anti-cancer activity of some Flazin analogues in natural product-like library were tested and their structure-activity relations were study. Compound 59a with the molecular mechanism of interfereing the early steps of HIV-1 life cycle was found with the low EC50 values of 0.38 μM and biggest therapeutic index (TI) of 312.2, and compound 84j with the molecular mechanism of polymerizing the microtobule was found with the low EC50 values of 0.06 μg/mL(Raji cell), 0.28 μg/mL (A549 cell), 0.16 μg/mL (HepG2 cell). Chapter 2 Canthin-6-one was isolated from higher fungi Russula virescens with anti-HIV and anti-cancer activity. Canthin-6-one and 5 Canthin-6-one analogues with modification at cycle A and cycle D were synthesized and their anti-HIV/anti-cancer activity evalution are in progress. Chapter 3 Vulpinic acid was isolated from higher fungi Pulverobletus ravenelii with anti-HIV activity. Vulpinic acid, 6 pulvinic acid analogues, 6 vulpinic lactone analogues and 5 vulpinic acid analogues were synthesized by modification at position-4 of benzene cycle, and anti-HIV activity evalution of them are in progress. Chapter 4 Physical data for compounds described from Chapter 1 to Chapter 3. Chapter 5 Review of β-carboline alkiolds.
语种: 中文
内容类型: 学位论文
URI标识: http://ir.kib.ac.cn/handle/151853/162
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:
高等真菌生物碱 Flazin 的全合成、结构修饰及其抗HIV和抗肿瘤活性.汤建国[d].中国科学院昆明植物研究所,2007.20-25
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