七种高等真菌化学成分研究和Pulverolide合成研究
杨婉秋
学位类型博士
导师刘吉开
2010-01
学位授予单位中国科学院研究生院
学位专业药物化学
摘要高等真菌活性成分Pulverolide是从黄粉末牛肝菌(Pulveroboletus ravenelii)中分离得到的结构新颖的黄色色素,该分子具有极罕见的2氢-呋喃[3,2-并]苯并吡喃-2-酮骨架。初步活性研究发现,Pulverolide对谷氨酸受体亚型之一的a-氨基-3-羟基-5-甲基-异恶唑丙酸受体(AMPA受体)有很好的激动作用,能提高突触传递,改善脑神经电信号传递,为治疗老年痴呆及其它记忆障碍神经系统性疾病提供了新思路。合成Pulverolide及其类似物对进一步研究其药理活性,发现新型治疗该类疾病的药物具有十分重要的意义。本论文第一章对Pulverolide及其类似物进行了合成研究,并综述了目标分子的前体类似物Pulvinic acid的合成进展。尝试了以异香草醛和苯乙酸为起始原料的三种不同合成思路。第一种思路是以Michael加成反应为关键反应获得关键中间体2,5-二苯基取代的戊酸酯的合成方法,该路线为查尔酮类似物的合成提供了一条新思路;第二种思路是以苯并吡喃取代物为关键中间体来合成目标分子;第三种思路是以Aldol反应生成关键中间体5-羟基(苯基)甲基-3-苯-季酮酸,再在微波条件下构建目标分子骨架的合成方法。最终我们通过第三种思路首次合成了目标分子Pulverolide,并且修正了原结构。该路线中使用微波加热的技术将关键中间体直接芳香化生成目标分子骨架的方法,大大缩短了合成路线,为合成大量Pulverolide类似物提供了便捷的合成途径。鉴于高等真菌次生代谢产物的多样性,本论文二至四章对七种云南野生高等真菌子实体和发酵液进行了系统的化学成分研究,它们分别是:牛肝菌科的美味牛肝菌(Boletus edulis)、铜色牛肝菌(B. aereus)和黄皮疣柄牛肝菌(Leccinum crocipodium);多孔菌科的黄鳞多孔菌(Polyporus Ellisii)和多年生集毛菌(Coltricia perennis);伞菌科的梭柄松苞菇(Catathelasma ventricosum)和黑盖蜡伞(Hygrophorus camarophyllus)。利用多种层析材料和分离技术以及借助现代波谱学方法共分离鉴定了90个化合物,包括61个不同化合物,其中新化合物2个((1S)-(4-Acetylphenyl)-1,2-ethanediol和(1S)-(3-Ethenylphenyl)-1,2-ethanediol)。化合物结构类型包括神经酰胺、鞘糖脂、环肽、甾类、萜类、对联三苯类、脂肪酸类、核苷等化合物。从美味牛肝菌发酵液中分离得到的四个苯乙二醇类化合物和一个有机铝环六肽化合物首次发现存在于高等真菌中。第五章综述了牛肝菌科(Boletaceae)的化学成分研究进展。该科真菌多为食用,部分具有很好的药用价值,但化学成分研究的报道不多,本章提供了1975-2009年间报道的化学成分184个,参考文献51篇。
资助项目Pulverolide, a new butenolide-type fungal pigment with a rare 2H-furo[3,2-b]chromen-2-one skeleton isolated from Pulveroboltus ravenelii, showed potentiating α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor activity. Therefore, it was considered to be a promising candidate treating Alzheimer’s and dysmnesia disease. Total synthesis of pulverolide together with its analogues and further investigations on its pharmacological activity are important to find new medicines for treatment of Alzhermeri’s disease.Chapter 1 elaborated the study on total synthesis of pulverolide. Three different approaches for the synthesis with same starting materials isovanillin and phenylacetic acid have been investigated. In the first synthetic route, 2,5-diphenyl-pentanoate was designed as a key intermediate via Michael addition reaction for the synthesis. In the second method, similar structure of chromene was used as an intermediate material to synthesize the target molecule. In the third approach, there are two key steps included to synthesize pulverolide. One is the development of 5-(hydroxyl(phenyl)methyl)-3-phenyl-tetromic acid aldol reaction and another is an aromatization reaction step with microwave. As a result, the first total synthesis of pulverolide has been successfully achieved through the third route, and the original proposed structure was revised. Microwave heating enhanced aromatization was the highlight. The original synthesis route has been shortened and several analogues were obtained through this manner.In Chapters 2-4, chemical constituents of seven higher fungi were studied. There are including Boletus edulis, B. aereus, Leccinum crocipodium, Polyporus ellisii, Coltricia perennis, Catathelasma ventricosum and Hygrophorus camarophyllus collected from Yunnan Province, P. R. China. More than 60 different compounds, including two news, (1S)-(4-acetylphenyl)-1,2-ethanediol and (1S)-(3-ethenylphenyl)-1,2-ethanediol, were isolated and identified. Four phenyl-1,2-ethanediols and one Al(Ⅲ) complex desferriferricrocin were isolated from B. edulis for the first time.Chapter 5 is a review on chemical constituents of Boletaceae. The paper provides 184 structurally diverse compounds published between 1975-2009, and 51 references.
语种中文
文献类型学位论文
条目标识符http://ir.kib.ac.cn/handle/151853/16038
专题昆明植物所硕博研究生毕业学位论文
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杨婉秋. 七种高等真菌化学成分研究和Pulverolide合成研究[D]. 中国科学院研究生院,2010.
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