【摘要】：尋求新穎高效的抗癌藥物是當(dāng)今癌癥治療的重要的任務(wù)之一，基于靶向藥物治療方式對(duì)新型Raf-1激酶抑制劑的設(shè)計(jì)，合成以及生物活性的評(píng)估進(jìn)行了研究。 惡性腫瘤也稱(chēng)為癌癥，是一類(lèi)以細(xì)胞異�？焖僭鲋澈娃D(zhuǎn)移為特點(diǎn)的疾病，已經(jīng)嚴(yán)重威脅人類(lèi)的健康。當(dāng)前腫瘤治療主要有三種方式：放射治療、外科手術(shù)治療和化學(xué)藥物治療。近年來(lái)，隨著對(duì)于癌癥分子基礎(chǔ)的認(rèn)識(shí)，腫瘤的治療產(chǎn)生了針對(duì)抑制涉及在細(xì)胞內(nèi)的信號(hào)轉(zhuǎn)導(dǎo)的蛋白激酶的靶向藥物治療的方式。在眾多信號(hào)通路中，Raf激酶介導(dǎo)Ras/Raf/MEK/ERK信號(hào)通路由于在人類(lèi)癌癥的發(fā)生與形成中起到非常重要作用，特別是那些與Raf-1激酶有關(guān)的作用。因此Raf-1激酶為靶點(diǎn)進(jìn)行抗癌藥物的研發(fā)成為當(dāng)今研究的熱點(diǎn)。為了得到結(jié)構(gòu)新穎、具有自主知識(shí)產(chǎn)權(quán)的Raf-1激酶抑制劑，通過(guò)以Bayer公司開(kāi)發(fā)報(bào)道的Raf激酶抑制劑索拉非尼（Sorafenib）作為先導(dǎo)化合物，根據(jù)構(gòu)效關(guān)系以及當(dāng)前芳基脲類(lèi)Raf-1激酶抑制劑的研究進(jìn)展等條件，運(yùn)用傳統(tǒng)藥物設(shè)計(jì)方法設(shè)計(jì)與合成了一系列化合物，共合成10個(gè)目標(biāo)化合物，中間體和目標(biāo)化合物的結(jié)構(gòu)經(jīng)過(guò)1H NMR、ESI-MS和HR-MS證實(shí)，均為新化合物。通過(guò)ADP-Glo激酶檢測(cè)試劑盒對(duì)目標(biāo)化合物進(jìn)行Raf-1激酶的抑制活性測(cè)試實(shí)驗(yàn)，結(jié)果表明，所有的目標(biāo)化合物對(duì)Raf-1激酶具有一定程度的抑制作用。其中9個(gè)目標(biāo)化合物對(duì)Raf-1激酶的抑制活性（IC50）低于1μM。此外，用人類(lèi)肝癌細(xì)胞HepG-2和人肺腺癌細(xì)胞A549細(xì)胞株對(duì)目標(biāo)化合物進(jìn)行體外細(xì)胞活性篩選試驗(yàn)，結(jié)果顯示，目標(biāo)化合物對(duì)人肝癌細(xì)胞系HepG2的生長(zhǎng)表現(xiàn)出了非常顯著的抑制作用，其中有7個(gè)化合物高于陽(yáng)性對(duì)照物索拉非尼。而對(duì)人肺腺癌細(xì)胞株A549的生長(zhǎng)則表現(xiàn)出了一般的抑制作用�；衔�30f的抑制活性最好，對(duì)HepG2細(xì)胞系的抑制活性是索拉非尼的6倍。而且表現(xiàn)出了非常顯著的選擇性，值得研究。另外，對(duì)目標(biāo)化合物進(jìn)行初步的構(gòu)效關(guān)系討論，為進(jìn)一步尋找作用于Raf-1激酶的高效、低毒、特異性強(qiáng)的新型抗癌藥物的研究具有一定的指導(dǎo)意義。 此外，對(duì)于已知化合物的結(jié)構(gòu)修飾是發(fā)現(xiàn)新藥的重要手段與途徑。因此，對(duì)全新作用機(jī)制的新藥奧帕拉尼（Olaparib，AZD2281）的結(jié)構(gòu)修飾進(jìn)行了研究。主要研究結(jié)果如下：通過(guò)以O(shè)laparib為原料對(duì)其進(jìn)行化學(xué)修飾，重鉻酸鉀在酸性的條件下將其氧化成Olaparib酮，其活性較好于Olaparib。在此基礎(chǔ)上，進(jìn)一步對(duì)其酮基進(jìn)行修飾還原，，得到一種含有羥基的Olaparib衍生物，也是一個(gè)重要的中間體。研究得到的終產(chǎn)物經(jīng)MS和1H NMR確認(rèn)。在此基礎(chǔ)上，可以合成一系列新型的Olaparib衍生物，對(duì)于新藥的創(chuàng)制具有重要意義。
[Abstract]:Searching for novel and effective anticancer drugs is one of the most important tasks in cancer treatment. The design, synthesis and bioactivity evaluation of novel Raf-1 kinase inhibitors are studied based on targeted drug therapy. Malignant tumor, also known as cancer, is a disease characterized by abnormal rapid cell proliferation and metastasis, which has seriously threatened human health. At present, there are three main methods of cancer treatment: radiotherapy, surgical treatment and chemotherapeutic therapy. In recent years, with the understanding of the molecular basis of cancer, tumor therapy has produced targeted drug therapy for inhibiting protein kinase involved in intracellular signal transduction. Raf kinase-mediated Ras/Raf/MEK/ERK signaling pathway plays a very important role in the development and development of human cancer, especially those related to Raf-1 kinase. Therefore, the development of anticancer drugs targeting Raf-1 kinases has become a hot topic. In order to obtain novel Raf-1 kinase inhibitors with independent intellectual property rights, Solafini (Sorafenib), a novel Raf kinase inhibitor developed by Bayer, was used as a lead compound. According to the structure-activity relationship and the current research progress of aryl ureas Raf-1 kinase inhibitors, a series of compounds were designed and synthesized using traditional drug design methods, and a total of 10 target compounds were synthesized. The structures of the intermediates and the target compounds were confirmed by 1H NMRE ESI-MS and HR-MS. ADP-Glo kinase assay kit was used to test the inhibitory activity of Raf-1 kinase on the target compounds. The results showed that all the target compounds had a certain degree of inhibition on Raf-1 kinase. The inhibitory activity (IC50) of 9 target compounds to Raf-1 kinase was less than 1 渭 M. In addition, the target compounds were screened by human hepatoma cell line HepG-2 and human lung adenocarcinoma cell line A549 in vitro. The results showed that the target compound could inhibit the growth of human hepatoma cell line HepG2 significantly. Seven of the compounds were higher than the positive control solafinil. The growth of human lung adenocarcinoma cell line A549 showed a general inhibitory effect. The inhibitory activity of compound 30 f was the best, and the inhibitory activity of compound 30 f on HepG2 cell line was 6 times higher than that on Solafenib cell line. And it shows very remarkable selectivity, which is worth studying. In addition, the preliminary structure-activity relationship of the target compounds is discussed, which has a certain guiding significance for the further study of novel anticancer drugs acting on Raf-1 kinase with high efficiency, low toxicity and strong specificity. In addition, structural modification of known compounds is an important means and pathway for the discovery of new drugs. Therefore, the structural modification of Olaparibn AZD 2281, a novel mechanism, was studied. The main results are as follows: by chemical modification of Olaparib, potassium dichromate was oxidized to Olaparib ketone under acidic conditions, and its activity was better than that of Olaparib. On this basis, the ketone group was further modified and reduced to obtain a hydroxyl Olaparib derivative, which is also an important intermediate. The final product was confirmed by MS and 1H NMR. On this basis, a series of new Olaparib derivatives can be synthesized, which is of great significance for the creation of new drugs.
【學(xué)位授予單位】：東北農(nóng)業(yè)大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2013
【分類(lèi)號(hào)】：TQ463

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