【作者】 杨曦亮；

【导师】 吴继洲； 杨希雄；

【作者基本信息】 华中科技大学 ， 天然药物化学， 2006， 硕士

【摘要】 中药贝母系百合科（Liliaceae）贝母属（Fritillaria）多种植物的干燥鳞茎,湖北贝母Fritillaria hupehensis Hsiao et K.C.Hsia原野生于鄂西自治州,现已收载于《中华人民共和国药典》（2000年版,2005版）。本实验以酸提碱沉法从湖北贝母中分离提取了共十七种生物碱,经理化常数鉴定及IR、EI-MS、FAB-MS、1H-NMR、13C-NMR、DEPT、1H-1HCOSY、HMQC、HMBC、NOSEY等波谱技术分析,并与标准品对照,鉴定了它们的结构。其中四种为新的微量生物碱,十三种为已知生物碱。这四种生物碱的结构分别是:（20R, 25S） 5α, 14α-cevanine -3β-actyl -6-one （乙酰化浙贝乙素,C1）, （20R, 25S） 5α, 14α-cevanine -3β-actyl -6β-ol （乙酰化浙贝甲素, C3 ）, 5α,17α-17,23-seco-7,12-dien-jervanine-3β,23β-dihydroxy-6-one （ C8 ）, 5α,17α-17,23-seco-7,12-dien-jervanine-3β,13α,23β-trihydroxy-6-one（C9）。并修正了已知生物碱湖贝乙素（hupehenirine） （20S, 25S） 5α, 14α,17β-cevanine-6β-hydroxy-3-one的C₅及C₁₇碳的归属。其中乙酰化浙贝乙素、乙酰化浙贝甲素是从湖北贝母中提取的新生物碱;C8和C9是两种新的介藜芦碱类异甾生物碱,它们的结构中具有的两个烯键与六元环酮共轭的骨架,在天然产物中尚属首次发现。浙贝丙素、鄂贝乙素为首次从湖北贝母中分离得到。由于浙贝乙素是湖北贝母中的主要生物碱,且药效学实验表明浙贝乙素具有优良的镇咳、祛痰、平喘之功效的结论,整体效果明显。本课题以浙贝乙素为先导化合物,进行结构改造和结构修饰,合成了乙酰化浙贝乙素,经理化常数测定及FAB-MS、DEPT、1H-NMR等波谱技术分析,鉴定了它的结构。在结构改造的基础上,在药效研究的前提下,我们测定了浙贝乙素及其五种衍生物（乙酰化物、丙酰化物、丁酰化物、氧化物、苯甲酰化物）的LD50值。取昆明种小白鼠,随机分组,腹腔注射给药,以动物急性死亡率为指标,按Bliss法求其量-毒关系的LD50和LD50 95%可信限。结果表明:浙乙乙酰化物、丙酰化物、丁酰化物、苯甲酰化物和氧化物毒性分别为14.39 mg·kg^-1、14.47 mg·kg^-1、18.41 mg·kg^-1、23.21 mg·kg^-1、9.98 mg·kg^-1 ,均小于浙贝乙素。由此可以得出结论:浙贝乙素的这五种衍生物毒性小,有希望从中得到一高效、低毒的镇咳药物。更多还原

【Abstract】 Beimu, Bulbus Fritillariae, is derived from the bulbs of many species of the genus Fritillaria of the Liliaceae. Fritillaria hupehensis Hsiao et K.C. Hsia is a plant growing in the southwest district of Hubei Province, China. And it has been involved in the China Pharmacopoeia.In our study, we got the extraction isolated by alcohol, then with the acid-base method we gain crude alkaloid. Isolating the ointment further by gel column chromatography,we got four new microcrystalline alkaloids and thirteen known alkaloids, among which there are two alkaloids founded from Hubeibeimu firstly. C8 and C9 are new C-nor-D-homo-steroid-Alkaloids of Jervine groups, and their frames of conjugation have been found by the first time in natural products. By spectroscopic analysis （IR、EI-MS、FAB -MS、1H-NMR、13C-NMR、DEPT、1H-1H COSY、HMQC、HMBC、NOESY）, the structures of new alkaloids have been established respectively to be （20R, 25S） 5α, 14α-cevanine -3β-actyl -6-one （C1）and （20R, 25S） 5α, 14α-cevanine -3β-actyl -6β-ol （ C3 ） , 5α,17α-17,23-seco-7,12-dien-jervanine-3β,23β-dihydroxy-6-one （ C8 ）, 5α,17α-17,23-seco-7,12-dien-jervanine-3β,13α,23β-trihydroxy-6-one（C9）. What’s more, we rectified the fifth and seventeenth carbon places Of hupehenirine （20S, 25S） 5α,14α,17β-cevanine-6β-hydroxy-3-one.Peminine is the main alkaloid of Fritillaria hupehensis Hsiao et K.C. Hsia, and many Phamacological studies indicate that peminine’s antitussive, expectorant and antiasthmatic activity is all very good. We took peminine as a leading compoud, synthetized the （20R, 25S） 5α, 14α-cevanine -3β-actyl -6-one. The structure of it has been established by spectroscopic analysis （FAB -MS、1H-NMR、DEPT and etc. ） On the basis of the pharmacodynamics experiments of Peminine and its five derivatives, we examined the acute dosing toxicity of them. The animals were randomly divided into groups, which were given medicine through ip. Calculate their LD50 and 95% confidence interval by Bliss methods referring to animals’acute morality. The Results are that their LD50 were 14.39, 14.47, 18.41, 23.21, 9.98 mg·kg^-1 in mice respectively, and their toxicities were all lower than peiminine. Therefore, we can drew the conclusion that the five derivatives of peiminine have low toxicity and it is hopeful to find an effective and low-toxicity medicine from those.更多还原