千层塔近缘植物的生物活性成分及石杉碱甲的结构修饰研究
其他题名STUDY ON THE BIOACTIVE CONSTITUENTS OF HUPERZIA SERRATA RELATED PLANTS AND SYNTHESIS OF DERIVATIVE OF HUPERZINE A
颜健
学位类型博士
导师邱明华
2007-05-30
学位授予单位中国科学院昆明植物研究所
学位授予地点昆明植物研究所
学位专业植物学
关键词石松科 石杉科 千层塔三萜 石松生物碱 石杉碱甲 抗乙酰胆碱酯酶
摘要石杉碱甲是从传统中要千层塔中分离得到的一个具有高效、可逆地抑制乙酰胆碱酯酶(AChE)活性的生物碱。药理研究表明:石杉碱甲的选择性、生物利用度和改善记忆障碍的作用均高于他克林和毒扁豆碱,是临床治疗早老年痴呆症(Alzheimer’s Disease,AD)和重症肌无力很有前途的药物。目前作为新药已在国内批准上市。鉴于石杉碱甲的特殊的药理特性,我们课题组开展了千层塔的近缘植物—石松科、石杉科植物生物活性成分及石杉碱甲的结构修饰研究,希望能够找到具有良好乙酰胆碱酯酶抑制活性或者其他生物活性的物质。 本论文主要研究石杉科和石松科五种植物的次生代谢产物及生物活性成分,抗老年痴呆症药物石杉碱甲的结构修饰以及千层塔三萜综述,由四章组成。第一章主要论述石松科4种植物化学成分及其抗肿瘤、乙酰胆碱酯酶抑制剂生物活性的研究,我们从石松属两个不同产地的石松(Lycopodium japonicum Thunb)中分别分离得到20个和12个化合物;从扁枝石松属两个不同产地的扁枝石松(Diphasiastrum complanatum(L.)Holub)中分别分离得到20个和9个次化合物;从灯笼草属锡金灯笼草变种(Palhinhaea cernua var. sikkimensis)中分离得到25个化合物;从藤石松属藤石松(Lycopodiastrum casuarinoides(Spring)Holub)中分离得到18个化合物。第二章主要对石杉科马尾杉属粗糙马尾杉(Phlegmariurus squarrosus(Forst.)Love et D. Love)的化学成分及生物活性进行了研究,从中分离得到16个化合物;然后对石杉科马尾杉属粗糙马尾杉(P. squarrosus)、马尾杉(P. phlegmarius)的初提物进行活性测试。在这两章的植物化学研究中,共从五种植物中分离得到120个化合物(不重复80个化合物),其化合物的类型涉及三萜、生物碱、黄酮、香豆素、甾体等,其中新化合物26个,包括5个结构新颖的重排化合物,我们并对其中的部分化合物进行乙酰胆碱酯酶抑制剂、抗肿瘤、组织蛋白酶B的抑制剂的生物活性的研究。发现大量成分化合物-onocerin具有乙酰胆碱酯酶抑制剂生物活性;化合物lycoclavanol,lycoclavanin,3, 20, 21, 24-tetrahydroxyserrat-14-en-29-yl-p-coumarate,3, 13, 14, 20, 21, 24, 29-hexahydroxy-14(1312)abeo-12H-serratane,3, 13, 14, 21, 24-pentahydroxy-14(1312)abeo-12H-serratan-29-yl p-coumarate,serrat-14-en-3, 21, 24, 29 tetraol,serrat-14-en-3, 21, 24, 30 tetraol具有一定的抗肿瘤生物活性,其中新颖结构化合物3, 13, 14, 21, 24-pentahydroxy-14(1312)abeo-12H-serratan-29-yl p-coumarate对肿瘤细胞的敏感株和耐药株的IC50无明显差距,提示可抵抗耐药细胞的作用;发现粗糙马尾杉、马尾杉初提物对组织蛋白酶B具有一定的抑制作用。第三章是治疗老年痴呆症药物石杉碱甲的结构修饰及生物活性研究,主要通过席夫碱反应合成一系列的石杉碱甲衍生物,其中新化合物10个,并测试其抗乙酰胆碱酯酶生物活性,绝大多数化合物都表现很好的生理活性,其中4个化合物IC50值比阳性对照物(乙酰水杨酸毒扁豆碱)和石杉碱甲本身强1000倍。第四章为千层塔三萜的研究进展,主要从千层塔三萜的来源、结构分类、波谱学特征、生物活性、生源合成途径等方面对其进行整理、归纳。千层塔三萜(serratane)又称锯齿石松烷三萜,具有丰富的结构类型和多种多样的生物活性,是石松科,石杉科,松科的松属、云杉属植物的特征性成分,在其它科属的植物中也有零散报道,但目前为止还没有关于千层塔三萜的综述,因此本章从多个方面对其进行详细归纳和整理。
其他摘要Huperzine A (Hup.A), an alkaloid isolated from Chinese Folk Herb Huperzia serrata (Thunb.) by Chinese scientists, is a potent, selective and reversible inhibitor of AChE. Its clinical studies have shown that its specificity, biological availability and ability to ameliorate memory impairment are superior to that of Tacrine and Physostigmine. Its superiority makes Huperzine A become a particularly promising AChE inhibitor and have resulted in the approval of Huperzine A for the drug treatment of AD in China. Because of the pharmacological characterization of Huperzine A, our group is working on the bioactive constituents of Huperzia serrata kindred plants and synthesis of derivative of Huperzine A. We hope to find bioactive constituents for anti- acetylcholinesterase and some other sides. Our job covered the secondary metabolites and bioactive constituents of five species belonging to family Huperziaceae and Lycopodiaceae, and synthesis of derivative of Huperzine A, and serratane review. The thesis was composed of four chapters. The first chapter expounded the chemical composition of four species belonging to family Lycopodiaceae, and tested anti-cancer and anti-acetylcholinesterase activities. We respectively separated and identified 20 and 12 compounds from Lycopodium japonicum Thunb in two different habitats, 20 and 9 compounds from Diphasiastrum complanatum (L.) Holub in two different habitats, 25 compounds from Palhinhaea cernua var. sikkimensis, and 18 compounds from Lycopodiastrum casuarinoides (Spring) Holub. The second chapter was about the study on the chemical constituents of Phlegmariurus squarrosus belonged to family Huperziaceae, from which we got 18 compounds. Subsequently we tested the bioactivities of those compounds and the crude extract of P. squarrosus and P. phlegmarius. There were 120 compounds separated and identified from five plants. The compounds included triterpenoid, alkaloid, flavone, coumarin and steroid. Among them 26 compounds were new, and included 5 novel compounds. In the bioactive test, we tested some compounds for anti-acetylcholinesterase and anti-cancer activities. The results showed that -onocerin had the anti-acetylcholinesterase activity in the high content; lycoclavanol, lycoclavanin, 3, 20, 21, 24-tetrahydroxyserrat-14-en-29-yl-p-coumarate, 3, 13, 14, 20, 21, 24, 29-hexahydroxy-14(1312)abeo-12H-serratane, 3, 13, 14, 21, 24-pentahydroxy-14(1312)abeo-12H-serratan-29-yl p-coumarate, serrat-14-en-3, 21, 24, 29 tetraol, serrat-14-en-3, 21, 24, 30 tetraol exhibited anti-cancer acitivity. Especially, the novelty compound 3, 13, 14, 21, 24-pentahydroxy-14(1312) abeo-12H-serratan-29-yl p-coumarate was worthy of research. The third chapter was about my work on the synthesis and anti-acetylcholinesterase bioactivity of derivative of Huperzine A. We synthesized a series of derivatives of Huperzine A by Schiff reaction and tested their bioactivities. 10 compounds were new. Most of them showed good bioactivities, and among them, four compounds of anti-acetylcholinesterase bioactivities showed potential effect. The fourth chapter was a review about serratane-type triterpenoid, which included the resource, structure classification, spectroscopic character, bioactivity and biogenetic route of serratane triterpene. Serratane triterpene had affluent structure and diverse bioactivities, and was also the characteristic constituent of family Huperziaceae, Lycopodiaceae, Pinus genus and Spruce genus. So we reported serratane-type triterpenoid from five aspects in the chapter.
页数175
语种中文
文献类型学位论文
条目标识符http://ir.kib.ac.cn/handle/151853/284
专题昆明植物所硕博研究生毕业学位论文
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颜健. 千层塔近缘植物的生物活性成分及石杉碱甲的结构修饰研究[D]. 昆明植物研究所. 中国科学院昆明植物研究所,2007.
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