本文選題：拉帕醇 + 1��； 參考：《蘭州大學》2017年碩士論文

【摘要】：與正常細胞相比,腫瘤細胞具有較高的活性氧(ROS)水平和受損的抗氧化防御系統(tǒng),因此,促ROS生成的藥物可以通過加劇細胞的氧化應激狀態(tài)來殺死癌細胞。更重要的是,由于正常細胞具有強大的抗氧化防御系統(tǒng),所以可以抵御外來的ROS應激損傷。所以,促ROS生成的腫瘤藥物,可以降低藥物治療的副作用。研究表明:1,4-萘醌類化合物可以增加細胞的ROS水平,進而殺死腫瘤細胞。本論文以拉帕醇為先導化合物,設計合成了一系列5,7-二甲氧基-1,4-萘醌衍1.目標化合物的設計:在文獻調(diào)研的基礎上,我們以2-羥基-1,4-萘醌為母核,將甲氧基引入芳環(huán)旨在增加醌環(huán)的親電性和降低氧化還原電位;通過改變側(cè)鏈長度和空間結(jié)構(gòu),旨在增加化合物的脂溶性和研究碳鏈的長度以及體積對抗細胞增值活性的影響;將相同的策略應用于2-甲氧基-1,4-萘醌和2-氯-1,4-萘醌系列。最后,我們利用成藥5規(guī)則對設計的目標化合物進行初篩,發(fā)現(xiàn)基本滿足成藥5規(guī)則的要求。2.目標化合物的合成:根據(jù)目標化合物設計合成路線,對關鍵反應步驟:傅克�；磻�2-氯-1,4-萘醌系列合成的反應條件進行優(yōu)化,最終獲得最優(yōu)的合成路線。3.目標化合物抗細胞增殖活性機制研究:通過MTT方法檢測目標化合物對于六種腫瘤細胞A549(人非小細胞肺癌)、Hela(人宮頸癌細胞)、Hep-G2(人類肝癌細胞)、NCI-H460(人大細胞肺癌細胞)、HL60(急性白血病細胞)、K562(人慢性骨髓性白血病細胞)和兩種人正常細胞WI-38(人胚胎肺成纖維細胞)、HEK 293(人類胚胎腎細胞)的抗細胞增殖活性。其中,化合物9e對HL60細胞的半抑制濃度IC50為3.80μM。相對于正常細胞WI-38細胞,其選擇性指數(shù)為10.7,說明化合物在殺死癌細胞的同時,幾乎不影響正常細胞。然后我們發(fā)現(xiàn)化合物9e可以誘導HL-60細胞凋亡,阻滯細胞周期在G2/M期,以及誘導ROS水平升高。加入抗氧化劑N-乙酰半胱氨酸(NAC),可以抑制凋亡,周期阻滯和ROS生成,表明ROS參與殺死細胞的過程。4.構(gòu)效關系分析:隨著烷基側(cè)鏈變長,化合物7a-7i的抗增殖活性逐漸增加。具有環(huán)己烷或取代苯基團的化合物7j-7n表現(xiàn)出更好的抗增殖活性。化合物9e具有最好的抗增殖活性,表明C-2位置氯取代對其抗增殖活性非常有利。
[Abstract]:Compared with normal cells, tumor cells have higher reactive oxygen species (Ros) level and damaged antioxidant defense system. Therefore, Ros-promoting drugs can kill cancer cells by exacerbating oxidative stress. More importantly, normal cells have a strong antioxidant defense system, so they can resist external Ros stress damage. Therefore, tumor drugs that promote Ros production can reduce the side effects of drug therapy. It is shown that the Ros level of the cells can be increased by 1: 1 and 4-naphthoquinone compounds, which can kill the tumor cells. In this paper, a series of 5-dimethoxy-1-methoxy 4-naphthoquinone derivatives were designed and synthesized by using lappa alcohol as a leading compound. Design of target compounds: on the basis of literature review, we introduced methoxy into aromatic ring to increase the electrophilicity of quinone ring and reduce the redox potential by changing the length and spatial structure of the side chain. The aim of this study was to increase the liposolubility of the compounds and to study the effects of the length and volume of the carbon chain on the cell proliferation activity. The same strategy was applied to the series of 2-methoxy -1o 4-naphthoquinone and 2-chloro-1-butadiene 4-naphthoquinone. Finally, we use the 5 rule of patent medicine to screen the designed target compound, and find that it basically meets the requirement of the 5 rule of patent medicine. 2. Synthesis of target compounds: according to the design of synthesis route of the target compound, the key reaction steps: Fourier acylation reaction and the reaction conditions of 2-chloro-1n 4-naphthoquinone series synthesis were optimized, and the optimal synthesis route was obtained. Study on the mechanism of anti-proliferation activity of the target compound: MTT assay was used to detect the effect of the target compound on six kinds of tumor cells, A549 (human non-small cell lung cancer) Hela (human cervical cancer cell line Hep-G2) (human hepatocellular carcinoma cell line NCI-H460) Anti-proliferative activities of K562 (human chronic myeloid leukemia cell) and WI-38 (human embryonic lung fibroblast) and two human normal cells (human embryonic kidney cells). The IC50 of compound 9e on HL60 cells was 3.80 渭 M. The selectivity index of WI-38 cells was 10.7 compared with that of normal WI-38 cells, indicating that the compounds killed cancer cells and almost did not affect normal cells at the same time. Then we found that compound 9e could induce HL-60 cell apoptosis, block cell cycle at G _ 2 / M phase, and increase Ros level. The addition of the antioxidant N-acetylcysteine can inhibit apoptosis, cycle arrest and Ros production, suggesting that Ros is involved in the cell killing process. Structure-activity relationship analysis: as the alkyl side chain became longer, the antiproliferative activity of compound 7a-7i increased gradually. The compound 7j-7n with cyclohexane or substituted phenyl group showed better antiproliferative activity. Compound 9e has the best antiproliferative activity, indicating that the substitution of C-2 position chlorine is very beneficial to its anti-proliferation activity.
【學位授予單位】：蘭州大學
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：R914;R96

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本文編號：2025927