【作者】 李小妹；

【导师】 林茂；

【作者基本信息】 中国协和医科大学 ， 药物化学， 2003， 博士

【摘要】 天然低聚芪类化合物是由二苯乙烯单体(如白藜芦醇、异丹叶大黄素、氧化白藜芦醇等)以不同方式、不同聚合度聚合而成的一类结构复杂、具有多种生物活性的化合物。近年，该类化合物已被发现具有抗菌、抗炎免疫、抗氧化、抗肿瘤、抗癌以及抗HIV等多种生物活性，日益引起国内外学者的广泛关注。本文对近年该类化合物的化学研究进展、仿生合成中的氧化偶合反应进行了综述，并对两种国产买麻藤属植物的化学成分进行了研究。同时对低聚芪类化合物进行了结构的修饰(异种单体的氧化偶合以及单体的异戊烯化、异戊烯化单体的聚合反应)，并对天然的低聚芪及仿生合成得到的化合物进行了药效筛选，初步归纳了二苯乙烯及其聚合物的构效关系。从两种买麻藤属植物，垂子买麻藤(Gnetum pendulum C．Y Cheng)和大子买麻藤(Gnetum montanum Markgr．f．megalocarpum Markgr．)中共分得32个化合物，其中8个为新化合物(包括4个新颖化合物)。从垂子买麻藤茎60％乙醇提取物的乙酸乙酯部分中总共分离得到了11种化合物，其中4个为新化合物。分别鉴定为：gnetupendins A-D(1-4)，isorhapontigenin(5)、resveratrol (6)、daucosterol (7)、shegansu B (8)、gnetulin (9)、gnetin D(10)、isorhapontigenin-3-D-β-D-glucoside (11)。其中，gnetupendins A，B是具有新颖骨架的芪类化合物，为3，5-二羟基取代苯环中多一个苄基取代的芪类化合物，这类骨架的化合物过去文献未曾报道。Gnetupendin C为首次从天然界得到的由白藜芦醇和氧化白藜芦醇构成的顺式苯骈二氢呋喃类二聚体(即Ⅳ-A类)：gnetupendin D为首次从天然界中分得的异丹叶大黄素聚合体的糖苷。从大子买麻藤茎中经过系统成分分离得到了21个化合物，鉴定了20个化合物，其中4个为新化合物，分别命名为gnetumontanins A-D(1-4)，已知化合物的结构分别鉴定为：pinosylvin (5)、洋芹素(apigenin，6)、gnetifolin A (7)、p-coumaric acid (8)、isorhapontigenin (9)、resveratrol (10)、gnetol (11)、gnetupendinB (12)、daucosterol (13)、shegansu B (14)、(-)-ε-vinifefin (15)、gnetulin (16)、gnetin D (17)、gnetuhainin M (18)、isorhapontigenin-3-O-β-D-glucoside (19)、isorhapontigenin-12-O-β-D-glucoside(20)。其中，gnetumontanin A为首次从天然界分得的由两个氧化白藜芦醇为单元形成的苯骈二氢呋喃类二聚体；gnetumontanin B为由两个氧化白藜芦醇和一个白藜芦醇单元通过两个苯骈二氢呋喃环形成的三聚体；gnetumontanins C和D为具有新颖骨架的含有苯骈δ-内酯环部分的新化合物及其糖苷。从海南买麻藤中曾获得许多异种二苯乙烯聚合的低聚芪，为了研究仿生聚合反应及进一步寻找有特殊作用的化合物，对具有不同活性的异种单体，白藜芦醇和异丹叶大黄素进行了氧化偶联聚合反应，经分离，共鉴定了9个化合物，8个为新化合物。它们的结构分别鉴定为：Fe-2为由白藜芦醇自身聚合的已知二聚体ε-viniferin；Fe-3，Fe-4为由白藜芦醇和异丹叶大黄素的二聚体；Fe-6为由两个异丹叶大黄素形成的具有对称结构的二聚体；Fe-5、Fe-7、Fe-8和Fe-9均为由异丹叶大黄素和白藜芦醇的形成的三聚体，Fe-10为异丹叶大黄素自身聚合的三聚体。所得化合物中，Fe-3～Fe-10均为新化合物，其中Fe-7的结构中含ampelopsin骨架(五员呋喃环骈七员脂环部分)，Fe-8～Fe-10的结构中含有较为对称的两个苯骈二氢呋喃环部分，这些骨架在仿生合成中首次报道。根据文献报道异戊烯基具有多方面的生物活性，为了合成带有异戊烯基的低聚芪，分别以白藜芦醇和异丹叶大黄素为母体合成了一系列异戊烯化的中间体：以白藜芦醇为母体，在碱性条件下，引入异戊烯基，合成了白藜芦醇带异戊烯基系列化合物。通过柱层析共分得12个衍生物，并鉴定了它们的结构，确定其中11个为新化合物，1个为已从天然界分得的已知化合物，初步搞清了白藜芦醇引入异戊烯基的规律；以异丹叶大黄素为母体，在路易斯酸催化下，引入异戊烯基，分离得到3个新化合物。对产率较高的中间体进行了聚合反应的实验，获得2个带有两个异戊烯基的低聚芪类二聚体。为了评估结构与活性关系，又合成了5个射干素B系列化合物。对以甲酸为催化剂的二苯乙烯聚合反应进行了深入研究，发现Diels-Alder反应过程中，能丢失两个苯环等的新型反应。在仿生合成实验中，共得到32个化合物。对所得天然产物及人工合成样品(包括中间体)分别进行了抗氧化、抗炎、抗HIV及抗肿瘤活性筛选，获得了有意义的构效关系数据。更多还原

【Abstract】 Naturally occurring oligostilbene is a type of compounds with complex structures and muti-faceted bioactivities, polymerized by resveratrol or its derivatives (such as isorhapontigenin, oxyresveratrol, etc.) with different polymeric type or degree. In recent years, oligostilbenes have been found to have various biological activities, including anti-fungal, anti-inflammatory, anti-oxidant, anti-tumour, anti-cancer and anti-HIV, which have attracted more and more attention from worldwide researchers.The chemical studies on the progress in naturally occurring oligostilbenes have been reviewed in this thesis, as well as the oxidative-coupling in biomimetic synthesis. Mainly introduced in details, the chemical constituents from two Chinese Gnetaceae species, and the structure modification of oligostilbenes, the oxidative coupling reactions between different monomers, the prenylation of stilbene monomer and their polymerization. The pharmacological activities were tested on the obtained compounds, and the Structure-Activity relationships of stilbenes were discussed.From the lianas of two species of plants, Gnetum pendulum and G. montanum f. megalocarpum, 32 compounds were obtained altogether, among them, 8 were new including 4 novel compounds.From the EtOAc soluble fraction of 60% EtOH extract of the lianas of G. pendulum, 11 compounds were isolated, and 4 of them were new ones. The structures were identified as: gnetupendins A-D (1-4), isorhapontigenin (5)、resveratrol (6)、daucosterol (7)、shegansu B (8)、gnetulin (9)、gnetin D (10)、isorhapontigenin -3-O-β-D-glucoside (11). Their structures were characterized unambiguously on the basis of chemical and spectroscopic evidence. Gnetupendins A and B were new stilbenes with novel skeletons, with the 3, 5-dihydroxyl- benzene ring substituted by a benzyl group, this skeleton has never been reported before. Gnetupendin C was a new stilbene dimer coupled by a resveratrol and an oxyresveratrol with a cis dihydrobenzofuran obtained from nature for the first time, gnetupendin D was the first isorhapontigenin dimer glucoside obtained from nature.From the lianas of G. montanum f. megalocarpum, 21 compounds were obtained by systematic isolation, 20 of them were identified, 4 of them were new compounds named as gnetumontanins A-D (1-4), and the known compounds were determined to be: pinosylvin (5)、apigenin (6)、gnetifolin A (7)、p-coumaric acid (8), isorhapontigenin (9)、resveratrol (10)、gnetol (11)、gnetupendin B (12)、daucosterol (13)、shegansu B (14)、(-)-ε-viniferin (15)、gnetulin (16)、gnetin D (17)、gnetuhainin M (18)、isorhapontigenin-3-O-β-D-glucoside (19)、isorhapontigenin-12-O-β-D-glucoside (20) . Gnetumontanin A is the first oligostilbene dimerized by two oxyresveratrol units with dihydrobenofuran ring; gnetumontanin B is a new stilbene trimer polymerized by two oxyresveratrol and one resveratrol units with two dihydrobenofuran rings; gnetumontanin C is a new stilbenoid with a novel skeleton including aδ-lactone portion and gnetumontanin D is a glucoside of it.From the lianas of G. hainansene, some oligostilbenes polymerized by different monomer were obtained, in order to study biomimetic synthesis and seek for more leading compounds, oxidative coupling reaction were performed by the different bioactive monomer resveratrol and isorhapontigenin. After separation and purification, 9 compounds were obtained and 8 of them were new. The structures were determined as: Fe-2,ε-viniferin, a known compound, is a dimer of resveratrol. Fe-3 and Fe-4 are both new dimers of resveratrol and isorhapontigenin. Fe-5, Fe-7, Fe-8, Fe-9 are new trimers polymerized by isorhapontigenin and resveratrol units. Fe-6 is a new symmetrical dimer of isorhapontigenin. Fe-3～Fe-10 are all new compounds. The structure of Fe-7 has the ampelopsinic skeleton, and the structures of Fe-8～Fe-10 has two dihydrobenzofuran rings with symmetry. These skeletons were reported for the first time in the biomimetic synthesis.From the literatures, prenyl group is reported to be a group with muti-faceted bioactivity, in order to polymerize oligomeric stilbenes with prenylated groups, a series of prenylated stilbene monomers were semi-synthesized from resveratrol and isorhapontigenin respectively. Under the basic conditions, prenyl group was inducted to the structure of resveratrol, and a series of prenylated derivatives were obtained. After isolation by silica gel column chromatography, 12 compounds were determined, among them, 11 were new and 1 was a known naturally occurring compound. The regular of prenyl group induction to resveratrol was concluded. Catalyzed by Lewis acid, prenyl group was inducted to the structure of isorhapontigenin. Alter separation, 3 new compounds were determined. Polymerization experiment of the high-yielded compound was executed to obtain 2 stilbene dimers with two prenyle groups.In order to evaluate the Structure-Activity relationship, a series of shegansu B derivatives were semi-synthesized.Meanwhile, a comprehensive investigation on formic acid catalyzed polymerization of oligostilbene was studied. A special reaction losing two substituted benzene rings and a methoxyl group successively during Diels-Alder reaction was found.32 compounds were produced by the biomimetic experiment.For the obtained naturally occurring and semi-synthesized oligostilbenes (including the intermediate compounds), the pharmacological activities were evaluated on anti-oxidative, anti-inflammatory, anti-HIV and anti-tumour activities, respectively and valuable experimental data were obtained about the Structure-Activity relationship.更多还原