分子多样性类天然杂环化合物的设计合成及生物活性研究
发布时间：2018-08-05 17:53
【摘要】：多环吡啶、多环吲哚等天然杂环化合物具有优良的抗菌、抗肿瘤、抗HIV等生物活性。以天然药物分子为先导,采用多样性导向合成策略,简捷高效地设计合成具有分子多样性的类天然杂环化合物并进行生物活性研究,对研究开发自主知识产权的药物具有重要意义。 本文以杂环烯酮缩胺及硝基葡烯糖为主要合成砌块,设计合成三大类共十二类类天然杂环化合物,总计353个化合物。对部分化合物进行了抗菌、抗肿瘤、荧光及细胞成像等生物活性的研究。 一、多环毗啶类化合物的合成及性质 茚并喹啉类化合物：通过串联反应一步法合成分子多样性多环茚并喹啉化合物。产物经体外抗瘤活性筛选,其中10c和10r具有较好细胞毒活性(Scheme1)。 多环咕吨酮及双环吡啶类化合物：构建多环咕吨酮化合物库及双环吡啶化合物库并对其进行荧光光谱性质及细胞成像的研究。部分化合物具有较好的pH荧光探针性能及较好的生物相容性和细胞穿透性(Scheme2)。 吡啶并香豆素类化合物：构建吡啶并香豆素化合物库(Scheme3)。咪唑并吡啶类化合物：构建了咪唑并吡啶类化合物库(Scheme4)。 嘧啶/苯并二氮杂(?)类化合物：合成手性侧链嘧啶/苯并二氮杂(?)类化合物库(Scheme5)。 二、多环吲哚类化合物：螺环吲哚酮化合物和多卤代吲哚化合物的合成 螺环吲哚酮化合物：高立体/区域选择性合成螺环吲哚酮化合物库(Scheme6)。 多卤代吲哚化合物：构建了多卤代吲哚化合物库(Scheme7)。 三、α-位取代杂环烯酮缩胺的合成 2-亚磷酸二乙酯基杂环烯酮缩胺：发展了一种以Mn(OAc)2/KMnO4复合催化体系代替Mn(OAc)3合成2-亚磷酸二乙酯基二甲缩硫醚的方法(Scheme8)。 Z构型杂环烯酮缩胺化合物：构建了2-吡唑啉酮基杂环烯酮缩胺化合物库及2-香豆素基杂环烯酮缩胺化合物库(Scheme9)。 2-亚硝基杂环烯酮缩胺类化合物：发展了一种新型有机亚硝基化试剂并构建了2-亚硝基杂环烯酮缩胺化合物库(Scheme10)。
[Abstract]:Polycyclic pyridine, polycyclic indole and other natural heterocyclic compounds have excellent antibacterial, anti-tumor, anti-HIV and other biological activities. Taking the natural drug molecule as the leader and adopting the strategy of diversity oriented synthesis, the natural heterocyclic compounds with molecular diversity were designed and synthesized in a simple and efficient manner and their biological activities were studied. It is of great significance for the research and development of drugs with independent intellectual property rights. In this paper, twelve kinds of natural heterocyclic compounds were designed and synthesized with heterocyclic ketenamine and nitroglutene as main synthetic blocks, with a total of 353 compounds. The biological activities of some compounds such as antibacterial, anti-tumor, fluorescence and cell imaging were studied. Synthesis and properties of first, polycyclic pyridine compounds; Indenoquinoline compounds: synthesis of polycyclic ninhydrin quinoline compounds by a one-step series reaction. The antitumor activity of the product was screened in vitro, of which 10c and 10r had good cytotoxic activity (Scheme1). Polycyclic ton-one and bicyclic pyridine compounds: the polycyclic ton-one library and the bicyclic pyridine compound library were constructed and their fluorescence spectra and cellular imaging were studied. Some of the compounds have better pH fluorescence probe properties, better biocompatibility and cell penetration (Scheme2). Pyridine coumarin compounds: a pyridine coumarin compound library (Scheme3) was constructed. Imidazolidopyridine compounds: a library of imidazolidopyridine compounds (Scheme4) was constructed. Pyrimidine / benzodiazide (?) Synthesis of chiral side chain pyrimidine / benzodiazide (?) Like compound library (Scheme5). Synthesis of polycyclic indole compounds: spirocyclic indole compounds and polyhalogenated indole compounds: high stereoselective synthesis of spirocyclic indole compounds (Scheme6). Polyhalogenated indole compounds: a polyhalogenated indole compound library (Scheme7) was constructed. Synthesis of tri-position substituted heterocyclic ketene amine; diethyl 2-phosphate heterocyclic ketene amine: a method for synthesis of 2-diethyl 2-phosphate diethyl ester dimethyl sulfides by using Mn (OAc) 2/KMnO4 complex catalyst system instead of Mn (OAc) _ 3 has been developed (Scheme8). Z configuration heterocyclic ketene ketenamine compound: 2-pyrazoline keto-heterocyclic ketene condensate compound library and 2-coumarin heterocyclic ketene condensate compound library (Scheme9). Amines: a new organic nitrite reagent was developed and a 2-nitroso-heterocyclic ketene condensate compound library (Scheme10) was constructed.
【学位授予单位】：云南大学
【学位级别】：博士
【学位授予年份】：2013
【分类号】：O626
本文编号：2166542
[Abstract]:Polycyclic pyridine, polycyclic indole and other natural heterocyclic compounds have excellent antibacterial, anti-tumor, anti-HIV and other biological activities. Taking the natural drug molecule as the leader and adopting the strategy of diversity oriented synthesis, the natural heterocyclic compounds with molecular diversity were designed and synthesized in a simple and efficient manner and their biological activities were studied. It is of great significance for the research and development of drugs with independent intellectual property rights. In this paper, twelve kinds of natural heterocyclic compounds were designed and synthesized with heterocyclic ketenamine and nitroglutene as main synthetic blocks, with a total of 353 compounds. The biological activities of some compounds such as antibacterial, anti-tumor, fluorescence and cell imaging were studied. Synthesis and properties of first, polycyclic pyridine compounds; Indenoquinoline compounds: synthesis of polycyclic ninhydrin quinoline compounds by a one-step series reaction. The antitumor activity of the product was screened in vitro, of which 10c and 10r had good cytotoxic activity (Scheme1). Polycyclic ton-one and bicyclic pyridine compounds: the polycyclic ton-one library and the bicyclic pyridine compound library were constructed and their fluorescence spectra and cellular imaging were studied. Some of the compounds have better pH fluorescence probe properties, better biocompatibility and cell penetration (Scheme2). Pyridine coumarin compounds: a pyridine coumarin compound library (Scheme3) was constructed. Imidazolidopyridine compounds: a library of imidazolidopyridine compounds (Scheme4) was constructed. Pyrimidine / benzodiazide (?) Synthesis of chiral side chain pyrimidine / benzodiazide (?) Like compound library (Scheme5). Synthesis of polycyclic indole compounds: spirocyclic indole compounds and polyhalogenated indole compounds: high stereoselective synthesis of spirocyclic indole compounds (Scheme6). Polyhalogenated indole compounds: a polyhalogenated indole compound library (Scheme7) was constructed. Synthesis of tri-position substituted heterocyclic ketene amine; diethyl 2-phosphate heterocyclic ketene amine: a method for synthesis of 2-diethyl 2-phosphate diethyl ester dimethyl sulfides by using Mn (OAc) 2/KMnO4 complex catalyst system instead of Mn (OAc) _ 3 has been developed (Scheme8). Z configuration heterocyclic ketene ketenamine compound: 2-pyrazoline keto-heterocyclic ketene condensate compound library and 2-coumarin heterocyclic ketene condensate compound library (Scheme9). Amines: a new organic nitrite reagent was developed and a 2-nitroso-heterocyclic ketene condensate compound library (Scheme10) was constructed.
【学位授予单位】：云南大学
【学位级别】：博士
【学位授予年份】：2013
【分类号】：O626
【参考文献】
相关期刊论文 前10条
1 蔡雄,王国俊,瞿瑶,樊成辉,张瑞祺,徐文胜;苦参素注射液治疗慢性乙型肝炎临床疗效分析[J];第二军医大学学报;1997年01期
2 王普善;;天然产物在新药发现中的地位与机会(Ⅱ)——天然产物仍是发现新药的一个重要领域[J];中国医药导刊;2006年02期
3 王普善;;天然产物在新药发现中的地位与机会(Ⅲ)——有机合成化学扩大了天然产物作为药物先导化合物的可能性[J];中国医药导刊;2006年03期
4 慈云祥;贾欣;;荧光量子效率的简化测量方法[J];分析化学;1986年08期
5 张宁;陈蓁蓁;唐波;;荧光成像在生物分析中的应用[J];分析化学;2006年07期
6 李华,许禄,苏锵;咪唑并吡啶类化合物结构及PDE抑制活性的三维构效关系研究[J];高等学校化学学报;1998年01期
7 ;The Development of Modern Pesticides[J];Chemical Research in Chinese Universities;2002年04期
8 王树清,高崇;1-苯基-3-甲基-5-吡唑啉酮的合成工艺研究[J];染料与染色;2004年02期
9 孙汉董;;植物资源、植物化学与新药开发[J];国外医药(植物药分册);1999年06期
10 赵剑锋;徐利敏;雷玉平;郭文勇;;1-苯基-3-甲基-2-吡唑啉-5-酮衍生物的合成[J];化学与生物工程;2007年07期
，本文编号：2166542
本文链接：https://www.wllwen.com/falvlunwen/zhishichanquanfa/2166542.html
