本文選題：拉帕醇 + 1��； 參考：《蘭州大學(xué)》2017年碩士論文

【摘要】：與正常細(xì)胞相比,腫瘤細(xì)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(guò)加劇細(xì)胞的氧化應(yīng)激狀態(tài)來(lái)殺死癌細(xì)胞。更重要的是,由于正常細(xì)胞具有強(qiáng)大的抗氧化防御系統(tǒng),所以可以抵御外來(lái)的ROS應(yīng)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(lèi)化合物可以增加細(xì)胞的ROS水平,進(jìn)而殺死腫瘤細(xì)胞。本論文以拉帕醇為先導(dǎo)化合物,設(shè)計(jì)合成了一系列5,7-二甲氧基-1,4-萘醌衍1.目標(biāo)化合物的設(shè)計(jì):在文獻(xiàn)調(diào)研的基礎(chǔ)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(guò)改變側(cè)鏈長(zhǎng)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(zhǎng)度以及體積對(duì)抗細(xì)胞增值活性的影響;將相同的策略應(yīng)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(duì)設(shè)計(jì)的目標(biāo)化合物進(jìn)行初篩,發(fā)現(xiàn)基本滿(mǎn)足成藥5規(guī)則的要求。2.目標(biāo)化合物的合成:根據(jù)目標(biāo)化合物設(shè)計(jì)合成路線(xiàn),對(duì)關(guān)鍵反應(yīng)步驟:傅克�；磻�(yīng)和2-氯-1,4-萘醌系列合成的反應(yīng)條件進(jìn)行優(yōu)化,最終獲得最優(yōu)的合成路線(xiàn)。3.目標(biāo)化合物抗細(xì)胞增殖活性機(jī)制研究:通過(guò)MTT方法檢測(cè)目標(biāo)化合物對(duì)于六種腫瘤細(xì)胞A549(人非小細(xì)胞肺癌)、Hela(人宮頸癌細(xì)胞)、Hep-G2(人類(lèi)肝癌細(xì)胞)、NCI-H460(人大細(xì)胞肺癌細(xì)胞)、HL60(急性白血病細(xì)胞)、K562(人慢性骨髓性白血病細(xì)胞)和兩種人正常細(xì)胞WI-38(人胚胎肺成纖維細(xì)胞)、HEK 293(人類(lèi)胚胎腎細(xì)胞)的抗細(xì)胞增殖活性。其中,化合物9e對(duì)HL60細(xì)胞的半抑制濃度IC50為3.80μM。相對(duì)于正常細(xì)胞WI-38細(xì)胞,其選擇性指數(shù)為10.7,說(shuō)明化合物在殺死癌細(xì)胞的同時(shí),幾乎不影響正常細(xì)胞。然后我們發(fā)現(xiàn)化合物9e可以誘導(dǎo)HL-60細(xì)胞凋亡,阻滯細(xì)胞周期在G2/M期,以及誘導(dǎo)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(xì)胞的過(guò)程。4.構(gòu)效關(guān)系分析:隨著烷基側(cè)鏈變長(zhǎng),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(tuán)的化合物7j-7n表現(xiàn)出更好的抗增殖活性�；衔�9e具有最好的抗增殖活性,表明C-2位置氯取代對(duì)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(xué)位授予單位】：蘭州大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類(lèi)號(hào)】：R914;R96

【參考文獻(xiàn)】

相關(guān)期刊論文 前3條

1 Showkat A Ganie;Asima Jan;Sabeera Muzaffar;Bilal A Zargar;Rabia Hamid;M Afzal Zargar;;Radical scavenging and antibacterial activity of Arnebia benthamii methanol extract[J];Asian Pacific Journal of Tropical Medicine;2012年10期

2 Philip Jacob P;Madhumitha G;Mary Saral A;;Free radical scavenging and reducing power of Lawsonia inermis L.seeds[J];Asian Pacific Journal of Tropical Medicine;2011年06期

3 張明曉;李學(xué)剛;;乙酸酐、H_2O_2和1,5二-羥基萘酚一鍋合成胡桃醌[J];應(yīng)用化學(xué);2007年12期

，

本文編號(hào)：2025927