三尖杉属植物生物碱成分研究和活性酯碱资源评价

	三尖杉属植物生物碱成分研究和活性酯碱资源评价
	余光兴
导师	蔡祥海
关键词	三尖杉属,种子,三尖杉生物碱,分离鉴定,酯碱资源评价 Cephalotaxus,Seeds,Cephalotaxine alkaloids,Isolation and identification,Ester alkaloids resources evaluation
摘要	裸子植物三尖杉科三尖杉属植物（Cephalotaxus Sieb. et Zucc）是我国首创的抗白血病新药高三尖杉酯碱、三尖杉酯碱的唯一药源。该属植物资源稀缺、酯碱含量低的特点，曾一度成为活性酯碱获得FDA新药批准的主要障碍，因此寻找资源成为重要的课题。自上世纪70年代以来，人们对整个三尖杉属植物资源（茎、叶和根）中生物碱类成分进行了研究，为新药开发奠定了基础。异三尖杉酯碱、脱氧三尖杉酯碱也有显著的抗白血病药理活性，由于在所调查植物中含量较低，资源匮乏，并未进行深入的药理临床研究。本论文旨在继续探讨三尖杉属植物种子中生物碱的结构多样性、丰富三尖杉酯碱的资源分布规律。篦子三尖杉（Cephalotaxus oliveri Mast.）和高山三尖杉（C. fortunei var. alpina Li）中生物碱成分的报道都集中于茎、叶部位，未见其种子中化学成分研究的报道。同时我们对高山三尖杉、篦子三尖杉、三尖杉（C. fortunei）、贡山三尖杉（C. lanceolata）、西双版纳粗榧（C. mannii）、粗榧（C. sinensis）六种植物的种子、假种皮、茎、叶四个部位进行了四种主要酯碱的含量测定，以期拓展三尖杉属植物酯碱资源分布规律，为三尖杉酯碱类成分的新功能开发奠定基础。本论文由两章组成，第一章为篦子三尖杉和高山三尖杉种子中生物碱类成分的结构与活性研究。从篦子三尖杉种子中分离鉴定生物碱39个，其中12个新化合物，部分生物碱为骨架新颖的四氢异喹啉生物碱，可能是该属植物中已知三尖杉碱、高绿刺桐碱的平行类型，进一步支持和完善了三尖杉生物碱的生源假设。从高山三尖杉种子中分离得到化合物40个，包含生物碱28个，其中2个为新生物碱。对分离得到的非酯碱类化合物进行神经保护活性评价，发现化合物3-epicomosine能显著增强了HEI-OC1细胞活力，拓展了三尖杉生物碱的生物活性，为听力保护提供潜在的先导分子。第二章为三尖杉属植物四种活性酯碱的资源评价。通过对六种三尖杉属植物不同部位总生物碱的提取、富集和含量测定，确定了四种主要酯碱总含量分布情况（种子>茎>叶>假种皮）。发现三尖杉酯碱在西双版纳粗榧种子中含量最高，异三尖杉酯碱在篦子三尖杉种子中含量最高，高三尖杉酯碱在高山三尖杉茎中含量最高，去氧三尖杉酯碱在三尖杉种子中含量最高。种子中总酯碱含量和种子可再生程度均优于茎，四种酯碱的最高含量均高于目前应用于制药的三尖杉茎中的相应含量，为酯碱的开发和三尖杉属植物资源的合理利用提供了重要参考价值; Plants of the genus Cephalotaxus (Gymnospermae, Cephalotaxaceae) are the only source of homoharringtonine and harringtonine, the antileukemia drugs developed by China. Scarce plant resources and low content of active ester alkaloids were main obstacles to FDA approval of ester-type alkaloids. So finding resources has become an important subject. Since the 1970s, extensive chemical studies have been carried out on the alkaloids of Cephalotaxus (containing steams, leaves and roots), which laid a foundation for the drug development of harringtonine and homoharringtonine. Isoharringtonine and deoxyharringtonine also have significant anti leukemia pharmacological activities. Due to the low content in the investigated plants, no in-depth pharmacological clinical research has been carried out. The purpose of this paper is to continue to explore the structural diversity of alkaloids in the seeds of Cephalotaxus and enrich the distribution of ester-type alkaloids. The reports on the alkaloid components of Cephalotaxus oliveri and Cephalotaxus fortunei var. alpina Li were concentrated in the stems and leaves, and the chemical components in the seeds have not been reported now. At the same time, we collected six kinds of plants, including C. fortune var. alpina, C. oliveri, C. fortunei, C. lanceolata, C. mannii and C. sinensis, which were divided into four parts: seed, aril, stem and leaf, to test the contents of four antitumor active ester-type alkaloids, hoping to expand the evaluation of ester alkaloids resources in Cephalotaxus plants, providing some reference for the new function development and utilization of ester-type alkaloids.This paper consists of two chapters. The first chapter is the study on the structure and activity of alkaloids in the seeds of Cephalotaxus oliveri and Cephalotaxus fortunei var. alpina Li. Thirty-nine alkaloids were isolated from the seeds of Cephalotaxus oliveri, including twelve new compounds. Some were tetrahydroisoquinoline alkaloids with novel skeleton and may parallel to cephalotaxine-, and homoerythrina-type alkaloids. The discovery of these compounds further supported and improved the biogenic inference of Cephalotaxus alkaloids. Fourty compounds were isolated from the seeds of Cephalotaxus fortunei var. alpina Li, including twenty-eight alkaloids, two of which were new. The neuroprotective activity was evaluated for the isolated non-ester-type alkaloids. Compound 3-epicomosine which can significantly enhance the activity of HEI-OC1 cells was found. This study expanded the biological activity of Cephalotaxus alkaloids and provided a potential lead molecule for hearing protection.The second chapter is the resource evaluation of four active ester alkaloids. Through the extraction, analysis and content determination of total alkaloids in different parts of six species of Cephalotaxus, we determined the distribution of the total content of four ester alkaloids (seed > stem > leaf > aril) and the highest content of each ester alkaloid (harringtonine: the seeds of C. mannii; isoharringtonine: the seeds of C.oliveri ; homoharringtonine: the stems of C. fortune var. alpina; deoxyharringtonine: the seeds of C. fortunei). The content of total ester alkaloids and the degree of regeneration in seeds is higher than that of stems. The highest contents of the four ester alkaloids are higher than the corresponding contents in the stems of C. fortune, which is used for drug productions now. This study may provide important reference value for the development of ester alkaloids and reasonably utilization Cephalotaxus resources.
语种	中文
	2022-06
学位授予单位	中国科学院大学
文献类型	学位论文
条目标识符	http://ir.kib.ac.cn/handle/151853/75085
专题	昆明植物所硕博研究生毕业学位论文
推荐引用方式 GB/T 7714	余光兴. 三尖杉属植物生物碱成分研究和活性酯碱资源评价[D]. 中国科学院大学,2022.

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