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结构多样的二萜类成分的发现及活性研究

发布时间:2018-03-19 16:24

  本文选题:鸡骨香 切入点:半枝莲 出处:《中国科学院大学(中国科学院上海药物研究所)》2017年博士论文 论文类型:学位论文


【摘要】:天然产物往往有着结构新颖多变、生物活性广泛等特点,是创新药物、药物候选物和药物先导物的重要来源。在众多类型的天然产物中,二萜类成分是其中结构类型最丰富和最重要的活性成分之一。许多著名的二萜类化合物如紫杉醇、关附甲素、银杏内酯类以及穿心莲内酯类均表现出较好的生物活性,这些活性化合物的发现使得二萜类化合物成为当今天然药物研究领域的热点。本文对四种富含二萜类成分的药用植物鸡骨香(Croton crassifolius Geisel.)、半枝莲(Scutellaria barbata D.Don)、腺梗宧莶(Sigesbeckia pubescens L.)和蔓荆子(Vitex rotundifolia L.)进行了系统的化学成分研究,运用Chromatorex C18、Chromatorex C8、MCI gel CHP-20P、TSK gel Toyopearl HW-40F、Sephadex LH-20、硅胶柱色谱及半制备高效液相色谱等分离手段对上述四种植物的提取物进行系统的分离纯化,通过波谱学技术、X-射线单晶衍射以及水解反应等方法鉴定了108个化合物,包括86个二萜类化合物,其中新化合物33个。所发现的新化合物类型包括克罗烷型二萜、贝壳杉烷型二萜、海松烷型二萜、半日花烷型二萜、倍半萜糖苷、木脂素及黄酮等。根据药用植物的民间用法结合多种药理活性筛选模型,发现了部分具有良好生物活性的化合物。从鸡骨香(Croton crassifolius Geisel.)根的丙酮提取物中分离鉴定了57个化合物,包括42个二萜(1-42),12个倍半萜(43-54)及木脂素等成分(55-57),其中化合物1-18为新的二萜,化合物1-4是B环或A环发生重排的二萜,化合物18是自然界中比较少见的绰奇烷型二萜。化合物43是一个新的倍半萜糖苷类化合物,是首次报道该植物含有倍半萜糖苷类成分。从半枝莲(Scutellaria barbata D.Don)全草的丙酮提取物中分离鉴定了10个化合物,全部为新克罗烷型二萜(58-67),其中化合物scubatins A-F(58-63)为新化合物,化合物61-63为含有螺环的新克罗烷型二萜。从腺梗宧莶(Sigesbeckia pubescens L.)全草的丙酮提取物中分离鉴定了25个化合物,包括18个贝壳杉烷型及海松烷型二萜(68-85),4个倍半萜(86-89)及木脂素、黄酮等成分(90-92)。新化合物有5个,其中有2个对映贝壳杉烷型二萜(68-69),1个对映海松烷型二萜(79),1个木脂素(91)和1个黄酮二聚体(92),3个新的二萜类化合物均通过铜靶X-射线单晶衍射技术确定了绝对构型。从蔓荆子(Vitex rotundifolia L.)果实的乙醇提取物中分离鉴定了16个化合物,全部为二萜类化合物,其中化合物93/94为新的含有螺环结构的半日花烷型二萜,化合物96为新的含有对羟基苯甲酸取代的半日花烷型二萜。对所分离到的二萜类化合物进行进一步的药理活性研究。细胞毒活性测试结果表明化合物9/10、20、22、63、66和74显示出不同程度的细胞毒活性,IC50为5.2-32.7μM。Di I-LDL细胞吞噬实验表明化合物19和39表现出中等程度的降脂活性。
[Abstract]:Natural products are often characterized by novel structure and wide biological activity. They are important sources of innovative drugs, drug candidates and drug precursors. The diterpenoids are one of the most abundant and important active components in which many famous diterpenoids such as paclitaxel Ginkgolide ginkgolide and andrographolide have good bioactivity. The discovery of these active compounds has made diterpenoids a hot spot in the field of natural medicine research. In this paper, four medicinal plants, Croton crassifolius Geisel.Or, Scutellaria barbata D. Dondonia, Sigesbeckia pubescens L., are studied. The chemical constituents of Vitex rotundifolia L. were systematically studied. The extracts of the four plants were systematically separated and purified by means of Chromatorex C18, Chromatorex C8, MCI gel CHP-20P, TSK gel Toyopearl HW-40F Sephadex LH-20, silica gel column chromatography and semi-preparative high performance liquid chromatography. A total of 108 compounds, including 86 diterpenoids, were identified by spectroscopic techniques such as X-ray single crystal diffraction and hydrolysis. The diterpenoids of kauricotaxane, diterpene, diterpene, sesquiterpene glycoside, lignin and flavonoids were selected according to the folk usage of medicinal plants and various pharmacological activity screening models. 57 compounds, including 42 diterpenoids 1-42, 12 sesquiterpenes 43-54) and lignin, were isolated and identified from the acetone extract from the roots of Croton crassifolius Geisel.Of them, compounds 1-18 were new diterpenes. Compound 1-4 is a diterpene that rearranges B or A ring, compound 18 is a rare deterpene in nature. Compound 43 is a new sesquiterpene glycoside compound. It is the first time that the plant contains sesquiterpenoid glycosides. Ten compounds were isolated from the acetone extract of Scutellaria barbata D. Don. all of them were neocoroalkane diterpenoids 58-67, among which scubatins A-F 58-63) were new compounds. Compound 61-63 was a neocoroane diterpene containing snails. 25 compounds were isolated and identified from acetone extract of Sigesbeckia pubescens L., including 18 diterpenes of kapurane and kapodine, and 4 sesquiterpenes, 86-89) and lignin, respectively. Flavonoids, etc., from 90 to 92. There are 5 new compounds. Among them, there are two enantiotaxane diterpenoids 68-69, one enantiosporine diterpene 79, one lignin 91) and one flavonoid dimer, and three new diterpenoids have been determined by copper target X-ray single crystal diffraction technique. Sixteen compounds were isolated and identified from the ethanol extract of Vitex rotundifolia L. All of them are diterpenoids, of which compound 93/94 is a new type of diterpenoid with spiroid structure. Compound 96 is a new diterpenoid containing substituted p-hydroxybenzoic acid. Further pharmacological activity of the isolated diterpenoid compounds was studied. The cytotoxic activity of IC50 was 5.2-32.7 渭 M.Di I-LDL cells phagocytosis assay showed that compounds 19 and 39 showed moderate lipid-lowering activity.
【学位授予单位】:中国科学院大学(中国科学院上海药物研究所)
【学位级别】:博士
【学位授予年份】:2017
【分类号】:R284

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