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题名: 四种百合群植物的甾体皂甙研究
作者: 张影
学位类别: 博士
答辩日期: 2007-01-08
授予单位: 中国科学院昆明植物研究所
授予地点: 昆明植物研究所
导师: 杨崇仁
关键词: 百合群 ; 高大鹿药 ; 康定玉竹 ; 象腿丝兰 ; 穿山龙 ; 甾体皂甙 ; 抗真菌活性 ; 质量标准 ; 黄精属化学分类 ; 分子多样性
学位专业: 植物学
中文摘要: 深部真菌感染的主要病原菌以念珠菌(Candida),隐球菌(Cryptococcus),曲霉菌(Aspergillus)最常见,严重威胁患有恶性肿瘤、艾滋病、糖尿病及器官移植严重烧伤等免疫受损人群的生命安全。目前,临床上抗深部真菌感染药主要有五类:天然的大环菌素,全合成的恶唑,烯氨和抗代谢5-氟胞嘧啶,以及半合成的echinocandins。代表药分别为两性霉素B(amphotericin B),氟康唑(fluconazole),特比萘芬(terbinafine),5-氟胞嘧啶(flucytosine),卡泊芬净(caspofungin)。现有的抗真菌药以合成药为主,各类药物都有不可回避的缺点,例如:两性霉素B对肾脏有很强的毒性,氟康唑类极易产生耐药性,特比萘芬的疗效仅限于指趾部皮肤菌,卡泊芬净对隐球菌无效。因此,从天然产物中寻找新型、高效低毒、选择性好、作用机制新颖的抗真菌活性化合物,是深部真菌感染药物研究和开发的发展趋势。 甾体皂甙是天然产物中一类重要的化学成分,是甾体药物工业的重要原料。研究表明,从百合群植物中分离得到的甾体皂甙类成分显示出较好的抗常见病原真菌的活性。为寻找抗真菌活性的先导化合物,本论文对富含甾体皂甙的四种百合群植物:高大鹿药 [Smilacina atropurpurea (Franch) Wang et Tang],康定玉竹(Polygonatum prattii Baker),象腿丝兰(Yucca elephantipes Regel)和穿山龙(Dioscorea nipponica Makino),进行了系统的化学成分研究,从中共分离鉴定了42个化合物。其中,19个为新的甾体配糖体,包括7个A环多羟基取代及7个A/B环为顺式稠合的结构复杂而不常见的甾体配糖体 (第一章至第四章)。 在植物化学研究的基础上,结合制药企业生产的需求,本论文对穿山龙水溶性甾体皂甙冻干粉的制备工艺及其质量标准进行了研究,并通过指纹图谱研究,对穿山龙注射液的现行质量标准进行了修订 (第四章)。 同时,对从本论文以及龙舌兰 (Agave Americana L.),晚香玉 (Polianthes tuberosa L.),湖北黄精 (Polygonatum zanlanscianense Pamp.)和小花盾叶薯蓣 (Dioscorea parviflora Ting.)四种植物中分离得到的51个甾体皂甙进行了抗真菌活性研究,供试菌株包括白色念珠菌(Candida albicans),光滑念珠菌(C. glabrata),克柔念珠菌(C. krusei),新型隐球菌(Cryptococcus neoformans) 及烟曲菌(Aspergillus fumigatus)等5种常见致病真菌。研究结果发现,替告皂甙元(tigogenin)配糖体有显著的抑制和杀灭新型隐球菌和烟曲菌的作用,其活性与两性霉素B(amphotericin B)相当,而细胞毒性则明显低于阿霉素(doxorubicin),具有广泛的开发应用前景。构效关系分析结果表明,甙元的氧化水平以及糖基的性质对抗真菌活性有显著影响 (第五章)。 甾体皂甙为黄精属植物的主要次生代谢产物,也是该属药用植物的主要生理活性物质。在上述植物化学研究的基础上,本论文对黄精属植物甾体皂甙的分子多样性研究结果进行了综合分析,并结合甙元的氧化水平和糖基的性质讨论了甾体皂甙的分子进化规律,同时参考黄精植物的形态特征,以及染色体和核型分析等研究结果,探讨了甾体皂甙成分与系统分类的相关性,为黄精属的系统进化提供植物化学方面的信息与证据 (第六章)。 最后,本论文综述了抗病原真菌药物研究现状及其发展趋势 (第七章)。 以上研究结果,已发表SCI论文两篇(累积影响因子6.553,2005年),待发表文章五篇,并已申请专利两项。
英文摘要: Opportunistic fungal infection, mainly resulting from Candida, Cryptococcus, and Aspergillus, are life-threatening in immunocompromised patients with cancer, AIDS, diabetes, or organ transplant, etc. The current antifungal armamentarium include five major drug classes, polyenes, azoles, allylamines, echinocandins and flucytosine. Representatives from the five classes are amphotericin B (AMB), fluconazole (FLU), terbinafine, caspofungin, and flucytosine, respectively. However, these synthesized antifungal drugs suffers one or more major shortcomings. For example, significant dose-limiting toxicities to kidney for AMB, rapid development of resistance for the azole drugs, limitation of the use to dermatophytoses for terbinafine, and lack of effectiveness in cryptococcosis for caspofungin. This has highlighted the need to discover new antifungal agents from natural products, preferably with new modes of action. C-27 steroidal saponins are an important class of natural products which used widely as starting materials for the synthesis of steroidal hormones. Previous researches on steroidal saponins from Liliales plant display significant antifungal activity. To search for new antifungal agents, the phytochemical studies on Smilacina atropurpurea (Franch) Wang et Tang, Polygonatum prattii Baker, Yucca elephantipes Regel and Dioscorea nipponica Makino were carried out which led to the isolation of forty-two constituents including nineteen new steroidal glycosides. Of them, seven polyhydroxylated in A-ring and seven cis-fused A/B ring uncommon steroidal compounds were involved (Chapters 1-4). To meet the need of pharmacy, the preparation methods and quality control of freeze-dried powder containing water-soluble steroidal saponins from D. nipponica were established on the bases of phytochemical studies. The current standard of "Chuan-Shan-Long Injection" was also revised through chemical fingerprint research (Chapter 4). Fifty-one steroidal sapogenins and saponins obtained from this thesis and other four plants: Agave americana L., Polianthes tuberosa L., Polygonatum zanlanscianense Pamp., and Dioscorea parviflora Ting., were tested for their antifungal activity against the opportunistic pathogens Candida albicans, C. glabrata, C. krusei, Cryptococcus neoformans and Aspergillus fumigatus. The results showed that four tigogenin saponins exhibited significant activity against C. neoformans and A. fumigatus, comparable to the positive control amphotericin B with low cytotoxicity to mammalian cells which could be used widely for development and application. The analytic results of structure-activity relationships (SAR) of the tested steroids presented that both the oxidated level of the aglycone and the characteristic of sugar moiety worked significantly on antifungal activity (Chapter 5). C-27 steroidal saponins, as important secondary metabolites, are abundant in genus Polygonatum. We comprehensively analyzed the chemical diversity of steroidal glycosides in Polygonatum plants and through which the evolution rules of these compounds have discussed based on the oxidated level of aglycone and the properties of sugar moiety. The relativity between steroidal saponins and systematic taxonomy was also discussed in this thesis together with the morphologic characteristic, chromosome and karyotype analysis, etc. And the study provided chemical information and proofs for the systematic evolution of Polygonatum species (Chapter 6). In addition, the progress and the development tendency on research of antifungal drugs were reviewed in the thesis (Chapter 7). These researches in this paper led to the publication of two SCI articles [totle IF (2005), 6.553], five papers prepared and two patents appled.
语种: 中文
内容类型: 学位论文
URI标识: http://ir.kib.ac.cn/handle/151853/156
Appears in Collections:昆明植物所硕博研究生毕业学位论文_学位论文

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四种百合群植物的甾体皂甙研究.张影[d].中国科学院昆明植物研究所,2007.20-25
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