發(fā)布時間：2018-05-12 02:11

  本文選題：茅蒼術(shù) + 化學(xué)成分�。� 參考：《北京協(xié)和醫(yī)學(xué)院》2017年博士論文

【摘要】：茅蒼術(shù)(Atractylodeslancea)為中醫(yī)臨床常用中藥。為進(jìn)一步闡明其藥效物質(zhì)基礎(chǔ),本文采用體外活性與紫外導(dǎo)向的方法對有效部位進(jìn)行系統(tǒng)分離。采用多種柱色譜技術(shù)從正丁醇部位30%亞部位中共分離得到126個單體化合物,通過UV,IR,HRESIMS,1D和2DNMR等譜學(xué)技術(shù)鑒定出74個新化合物與52個已知化合物,并借助實驗和理論ECD、Mo2(OAc)4和Rh2(OCOCF3)4誘導(dǎo)ECD以及X-ray等手段對新化合物的立體構(gòu)型進(jìn)行了確定。74個新化合物包括8個香根螺烷型倍半萜(1-8)、10個桉葉烷型倍半萜(9-18)、3個愈創(chuàng)木烷型倍半萜(19-21)、2個艾里莫酚烷型倍半萜(22,23)、11個鏈狀C10-烯炔(24-34)、21個鏈狀C13-烯炔(35-55)、6個鏈狀C14-烯炔(56-61)、2個呋喃環(huán)多烯炔(62.63)、5個噻吩環(huán)多烯炔(64-68)、2個雙四氫呋喃類木脂素(69,70)、2個酚苷(71,72)、1個吡嗪類生物堿(73)以及1個苯并四氫呋喃類衍生物(74)。解析出的已知化合物(75-126)主要包括木脂素、多烯炔、倍半萜以及香豆素等類型化合物。在化學(xué)成分研究的基礎(chǔ)上,對得到的81個單體化合物進(jìn)行了多方面的體外藥理活性篩選�；�合物2,4,22,24,27,71,72.73,84,109,122在10μM濃度下與撲熱息痛合用時,對后者引起的肝細(xì)胞損傷有較好的保護(hù)作用,與模型組相比有統(tǒng)計學(xué)差異。化合物3,4,9,47,90,120,122,123在10μM濃度下對脂多糖誘導(dǎo)小膠質(zhì)細(xì)胞釋放的NO具有較好的抑制作用。本課題在開展過程中,還建立了一種能夠簡便、快速測定具有鏈狀鄰二醇片段的多烯炔苷相對構(gòu)型(赤或蘇)的1H NMR方法。選擇氘代醋酸和重水作為測試溶劑,當(dāng)鏈狀鄰二醇片段的3JHH偶合常數(shù)約為7.0 Hz時,則該化合物可歸屬為蘇式構(gòu)型,而當(dāng)3JHH偶合常數(shù)約為3.5 Hz時,則該化合物可歸屬為赤式構(gòu)型。溶液中氘代醋酸的比例可根據(jù)待測樣品的實際溶解度進(jìn)行微調(diào)。此種方法不需要對烯炔苷類化合物進(jìn)行水解,極大縮減了實驗的工作量,繼而促進(jìn)了類似化合物絕對構(gòu)型的確定。此外,在確定香根螺烷倍半萜(1-5)絕對構(gòu)型的過程中,還發(fā)現(xiàn)苷元中具有1個手性中心的化合物(1,2)與苷元中具有2個手性中心的化合物(3-5)呈現(xiàn)出相似的ECD譜圖。借助計算ECD與X-單晶衍射技術(shù),進(jìn)一步研究發(fā)現(xiàn)此類結(jié)構(gòu)中遠(yuǎn)離共軛體系的C-7位在240～260nm附近呈現(xiàn)較強的Cotton效應(yīng)且強于C-5位的Cotton效應(yīng);化合物3-5在250 nm附近的Cotton效應(yīng)可能為C-7與C-5位發(fā)色團(tuán)Cotton效應(yīng)的加權(quán)疊加。相關(guān)結(jié)果為香根螺烷型倍半萜立體構(gòu)型的研究提供了參考。
[Abstract]:Atractylodeslancea (Atractylodeslancea) is a traditional Chinese medicine. In order to further elucidate the substance basis of its pharmacodynamics, the active parts were systematically separated by in vitro activity and UV-guided method. A total of 126 monomers were isolated from the 30% subfraction of n-butanol by various column chromatography techniques. 74 new compounds and 52 known compounds were identified by UVX IR HRESIMS1D and 2DNMR techniques. The stereotypes of the new compounds were determined by means of experimental and theoretical methods such as ECD-Mo2OAc4, Rh2(OCOCF3)4 induced ECD and X-ray. 74 new compounds include 8 Gyabgon spiroalkyl sesquiterpenes 1-8, 10 eucalyptane sesquiterpenes 9-18, and 3 guaiacane-type ploidy. Sesquiterpenoids 19-21, 2 alimohexane sesquiterpenes 2223C, 11 chain C10-enyne 24-34, 21 chain C13-enyne 35-55, 6 chain C14-enyne 56-61, 2 furancyclic polyenyne 62.63, 5 thiophene polyenyne 64-68, 2 dihydrofuran 697070, 2 pyrazine 71- 72o, 1 pyrazine Alkaloid 73) and one benzo-tetrahydrofuran derivative. The known compounds include lignin, polyenyne, sesquiterpene and coumarin. Based on the study of chemical constituents, 81 monomers were screened for their pharmacological activities in vitro. When compound 2H _ 4N _ 2H _ (22) O _ (22) C _ (27) 71C _ (72.73N) ~ (84) 109122 was combined with paracetamol at a concentration of 10 渭 M, it had a better protective effect on hepatocyte injury induced by paracetamol, which was significantly different from that in the model group. Compound 3H _ 4H _ 4N _ (47) C _ (901) 201 22123 had a good inhibitory effect on no release from microglia induced by lipopolysaccharide at a concentration of 10 渭 M. In the course of this study, a 1H NMR method was developed for the rapid determination of the relative configuration of polyenylethynine with chain O-diol fragments. Deuterated acetic acid and heavy water were selected as the test solvent. When the 3JHH coupling constant of the chain O-diol fragment was about 7.0Hz, the compound could be classified as a Soviet configuration, and if the 3JHH coupling constant was about 3.5Hz, the compound could be classified as a red-type configuration. The ratio of deuterated acetic acid in the solution can be fine-tuned according to the actual solubility of the sample to be tested. This method does not need to hydrolyze the alkynylate compounds, which greatly reduces the experimental workload and promotes the determination of the absolute configuration of similar compounds. In addition, during the determination of the absolute configuration of Gyabgon spirosine sesquiterpene 1-5), it was also found that the ECD spectra of the compounds with one chiral center in the glycoside and two chiral centers in the glycogen were similar to those in the glycogen. By calculating the ECD and X- single crystal diffraction technique, it is found that the C-7 position, which is far away from the conjugated system, has a strong Cotton effect near 240~260nm and is stronger than the Cotton effect at C-5 position. The Cotton effect of compound 3-5 near 250nm may be a weighted superposition of the Cotton effect of C-7 and C-5 chromophore. The results provide a reference for the study of Gyabgon spiroid sesquiterpene stereotype.
【學(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【學(xué)位級別】：博士
【學(xué)位授予年份】：2017
【分類號】：R284;R285
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本文編號：1876645