本文選題：紫蘇醇 + 紫蘇醇衍生物��； 參考：《沈陽藥科大學(xué)》2014年博士論文

【摘要】：紫蘇醇是來源于植物的異戊二烯萜類揮發(fā)油,是為數(shù)不多的既有癌癥預(yù)防又有癌癥治療作用的天然產(chǎn)物之一。紫蘇醇具有良好的抗腫瘤作用,而且毒性小、不易產(chǎn)生耐藥性。但紫蘇醇在體內(nèi)代謝迅速,口服給藥生物利用度低,因而限制了其臨床應(yīng)用。本實驗室對檸檬烯和欖香烯衍生物的研究發(fā)現(xiàn),增加化合物的極性有利于抗腫瘤活性的提高。因此,本論文擬在紫蘇醇結(jié)構(gòu)中引入含氮基團,希望能獲得抗腫瘤活性強,毒副作用小的新穎化合物。 本文以紫蘇醇為先導(dǎo)化合物,在保持其分子骨架的前提下,以紫蘇醛為起始原料,首先合成了紫蘇醇、7-乙基紫蘇醇、7-甲基紫蘇醇和紫蘇酸甲酯四個母核,再以各種取代的胺基對其進行結(jié)構(gòu)修飾,共設(shè)計合成了5個系列61個化合物,包括14個紫蘇醇類衍生物(Al-A14)、11個7-乙基紫蘇醇類衍生物(B1-B11)、10個7-甲基紫蘇醇類衍生物(C1-C10)、18個紫蘇酸甲酯類衍生物(Dl-D18)和8個紫蘇胺類衍生物(E1-E8),其中59個未見文獻報道。所有目標化合物的結(jié)構(gòu)均經(jīng)MS和1H-NMR確證。 用MTT法對所合成的61個目標化合物進行了體外抗腫瘤活性篩選。以HeLa、MCF-7、HepG2、HCT116、A549、A375-S2、HT-1080、U937、HL-60和K562為測試細胞株,以5-氟尿嘧啶為陽性對照藥,結(jié)果顯示,所合成的大部分化合物對10種腫瘤細胞均表現(xiàn)出不同程度的抑制作用。說明含氮基團的引入確實有利于抗癌活性的提高,由此充分驗證了本文的設(shè)計思想。 對目標化合物構(gòu)效關(guān)系進行初步探討,結(jié)果如下：在紫蘇醇以及7-甲基或乙基取代的紫蘇醇含氮衍生物(A,B和C系列)中,取代基為伯胺的目標化合物的抗腫瘤活性強于仲胺；在紫蘇酸甲酯的含氮衍生物(D系列)中,引入的不同的含氮取代基團對化合物的抗腫瘤活性并無顯著的影響；紫蘇醇結(jié)構(gòu)中的羥基被氨基替換的紫蘇胺類衍生物(E系列)中,引入金剛烷胺基的目標化合物E5抗腫瘤活性強于其他目標化合物。 選取E5對其抗腫瘤作用機制進行了進一步研究。研究結(jié)果表明E5可以呈濃度依賴性、時間依賴性抑制A549細胞的增殖。用相差顯微鏡、熒光染色及流式細胞術(shù)檢測表明,E5可引起A549細胞發(fā)生凋亡。免疫印跡分析結(jié)果證實了E5誘導(dǎo)A549細胞發(fā)生凋亡的作用,對法尼基轉(zhuǎn)移酶有抑制作用,對Ras下游Raf/MEK/ERK信號通路有抑制作用。研究結(jié)果表明：E5通過抑制法尼基轉(zhuǎn)移酶,從而抑制Raf/MEK/ERK信號通路而誘導(dǎo)細胞凋亡。
[Abstract]:Perilla alcohol is a volatile oil of isoprene terpenoids from plants. It is one of the few natural products which can prevent and cure cancer.Perilla alcohol has good anti-tumor effect, and it is not easy to produce drug resistance because of its small toxicity.However, the rapid metabolism of perilla alcohol in vivo and low bioavailability of oral administration limit its clinical application.Our laboratory studies on limonene and elemene derivatives show that increasing the polarity of the compounds is beneficial to the increase of anti-tumor activity.Therefore, in this paper, nitrogen-containing groups were introduced into the perilla alcohol structure in order to obtain novel compounds with strong anti-tumor activity and less toxic side effects.In this paper, under the premise of keeping the molecular skeleton of perilla alcohol as the leading compound, four parent nuclei of perilla alcohol 7-ethyl perilla alcohol 7-methyl perilla alcohol and methyl perilla acid were synthesized with perilla aldehyde as the starting material.Five series of 61 compounds were designed and synthesized by modifying them with various substituted amino groups.It consists of 14 perilla alcohols, 11 7-ethylperilla derivatives B1-B11, 10 7-methylperilla derivatives, C1-C10, 18 methyl perilla derivatives, Dl-D18) and 8 perilla derivatives, E1-E8, among which 59 have not been reported in the literature.The structures of all the target compounds were confirmed by MS and 1H-NMR.The anti-tumor activity of 61 target compounds was screened by MTT method in vitro.The HL-60 and K562 cell lines of HL-60 and K562 were tested with HCT116A549-A375-S2HT-1080 and 5-fluorouracil as positive control. The results showed that most of the synthesized compounds showed different inhibitory effects on 10 kinds of tumor cells.It shows that the introduction of nitrogen-containing groups is beneficial to the improvement of anticancer activity, which fully validates the design idea of this paper.The structure-activity relationship of the target compounds was preliminarily discussed. The results were as follows: the antitumor activity of the target compounds with primary amine was stronger than that of secondary amines in perilla alcohol and nitrogen-containing derivatives of 7-methyl-or ethyl-substituted perilla alcohol.In D series of nitrogen-containing derivatives of methyl perilla, the different nitrogen-containing substituents had no significant effect on the antitumor activity of the compounds.The anti-tumor activity of target compound E 5 was stronger than that of other target compounds.E5 was selected to further study the mechanism of its anti-tumor effect.The results showed that E5 could inhibit the proliferation of A549 cells in a concentration-dependent and time dependent manner.Phase contrast microscopy, fluorescence staining and flow cytometry showed that E5 could induce apoptosis of A549 cells.Western blot analysis confirmed that E5 induced apoptosis in A549 cells, inhibited farinotransferase and inhibited Raf/MEK/ERK signaling pathway downstream of Ras.The results showed that the cell apoptosis was induced by inhibiting the Raf/MEK/ERK signaling pathway by inhibiting farinotransferase.
【學(xué)位授予單位】：沈陽藥科大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2014
【分類號】：R914.5;R96

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