Raf-1抑制剂的设计、合成与生物活性研究和奥拉帕尼结构修饰
发布时间：2018-08-13 20:41
【摘要】：寻求新颖高效的抗癌药物是当今癌症治疗的重要的任务之一，基于靶向药物治疗方式对新型Raf-1激酶抑制剂的设计，合成以及生物活性的评估进行了研究。 恶性肿瘤也称为癌症，是一类以细胞异常快速增殖和转移为特点的疾病，已经严重威胁人类的健康。当前肿瘤治疗主要有三种方式：放射治疗、外科手术治疗和化学药物治疗。近年来，随着对于癌症分子基础的认识，肿瘤的治疗产生了针对抑制涉及在细胞内的信号转导的蛋白激酶的靶向药物治疗的方式。在众多信号通路中，Raf激酶介导Ras/Raf/MEK/ERK信号通路由于在人类癌症的发生与形成中起到非常重要作用，特别是那些与Raf-1激酶有关的作用。因此Raf-1激酶为靶点进行抗癌药物的研发成为当今研究的热点。为了得到结构新颖、具有自主知识产权的Raf-1激酶抑制剂，通过以Bayer公司开发报道的Raf激酶抑制剂索拉非尼（Sorafenib）作为先导化合物，根据构效关系以及当前芳基脲类Raf-1激酶抑制剂的研究进展等条件，运用传统药物设计方法设计与合成了一系列化合物，共合成10个目标化合物，中间体和目标化合物的结构经过1H NMR、ESI-MS和HR-MS证实，均为新化合物。通过ADP-Glo激酶检测试剂盒对目标化合物进行Raf-1激酶的抑制活性测试实验，结果表明，所有的目标化合物对Raf-1激酶具有一定程度的抑制作用。其中9个目标化合物对Raf-1激酶的抑制活性（IC50）低于1μM。此外，用人类肝癌细胞HepG-2和人肺腺癌细胞A549细胞株对目标化合物进行体外细胞活性筛选试验，结果显示，目标化合物对人肝癌细胞系HepG2的生长表现出了非常显著的抑制作用，其中有7个化合物高于阳性对照物索拉非尼。而对人肺腺癌细胞株A549的生长则表现出了一般的抑制作用。化合物30f的抑制活性最好，对HepG2细胞系的抑制活性是索拉非尼的6倍。而且表现出了非常显著的选择性，值得研究。另外，对目标化合物进行初步的构效关系讨论，为进一步寻找作用于Raf-1激酶的高效、低毒、特异性强的新型抗癌药物的研究具有一定的指导意义。 此外，对于已知化合物的结构修饰是发现新药的重要手段与途径。因此，对全新作用机制的新药奥帕拉尼（Olaparib，AZD2281）的结构修饰进行了研究。主要研究结果如下：通过以Olaparib为原料对其进行化学修饰，重铬酸钾在酸性的条件下将其氧化成Olaparib酮，其活性较好于Olaparib。在此基础上，进一步对其酮基进行修饰还原，，得到一种含有羟基的Olaparib衍生物，也是一个重要的中间体。研究得到的终产物经MS和1H NMR确认。在此基础上，可以合成一系列新型的Olaparib衍生物，对于新药的创制具有重要意义。
[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.
【学位授予单位】：东北农业大学
【学位级别】：硕士
【学位授予年份】：2013
【分类号】：TQ463
本文编号：2182123
[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.
【学位授予单位】：东北农业大学
【学位级别】：硕士
【学位授予年份】：2013
【分类号】：TQ463
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