论文总字数：21651字

摘 要

目前随着人类社会的发展和科技的进步，人类寿命的期望也在增长，但是肿瘤和癌症等疾病问题是阻碍这一进程的一块绊脚石。目前普遍应用的临床抗肿瘤药物（如硼替佐米）对肿瘤症状的针对性不够高，虽然对肿瘤病灶组织细胞有一定得效果，但是同时也会对周围机体正常的组织细胞产生影响造成损害。所以着手开发新的高效且低毒的抗肿瘤药物在生物医药领域有着重大意义。在类泛素化NEDD8信号通路中的限速酶是NAE，它决定着整个CRLs卡林蛋白质的活性，而CRLs又是控制泛素化过程的关键节点，所以通过抑制NAE的活性，可以达到间接控制泛素化过程的活性的目的。目前有一种比较优良的NAE抑制剂叫MLN4924，已经进入临床实验I期。但是几大类NAE抑制剂来说，这几类都或多或少地存在着各种各样的实际问题。有人利用高通量虚拟筛选技术来从众多的有潜力的化合物中挑选出了最优选择即NAE酶的可逆抑制剂M22。M22化合物中的苄基结构能与ATP腺嘌呤竞争，当嘧啶并吡啶酮环结构取代苄基之后，与ATP亲和力得到提高。实验室设计出了一系列基于M22化合物和嘧啶并吡啶酮类结合起来的化合物。通过实验路径设计，我们通过四大步来合成关键化合物M。

关键词： 肿瘤 Neddylation 抑制剂 M22

Design and synthesis of antitumor drugs targeting ubiquitin-like enzyme NAE

Abstract

At this decade , as the phenomenon of population aging is becoming more and more obvious, and the expectation of human life expectancy is also increasing. But diseases such as oncology and cancer are a stumbling block to this process. At present, the widely used clinical antineoplastic drugs (such as bortezomib) are not specific enough for tumor symptoms, although they have a certain effect on the tissue cells of tumor foci, but at the same time, they will also affect the normal tissues and cells of the surrounding body and cause damage. Therefore, it is of great significance to develop new anti-tumor drugs with high efficiency and low toxicity in the field of biomedicine. The rate-limiting enzyme in the ubiquitin-like NEDD8 signal pathway is NAE, which determines the activity of the whole CRLs Kulin ring protein, and CRLs is the key node to control the ubiquitination process, so by inhibiting the activity of NAE, we can indirectly control the activity of the ubiquitination process. At present, a relatively good NAE inhibitor called MLN4924, has entered the first phase of clinical trials. However, for several categories of NAE inhibitors, these categories have a variety of practical problems more or less. Some people use high-throughput virtual screening technology to select the optimal choice, the reversible inhibitor M22 of NAE enzyme, from many potential compounds. The benzyl structure of M22 compound can compete with ATP adenine, and the affinity with ATP is improved when benzyl is replaced by pyrimidinopyridone ring structure. A series of compounds based on the combination of M22 compounds and pyrimidinopyridinones were designed in the laboratory. Through the experimental path design, we take four steps to synthesize the key compound M.

Keywords: Tumor, Neddylation, inhibitor, M22

目录

摘要 I

Abstract II

第一章 文献综述 1

1.1研究背景与数据统计 1

1.2肿瘤及泛素与类泛素通路（Neddylation） 2

1.2.1 肿瘤及其成因 2

1.2.2泛素-蛋白酶体通路系统 3

1.2.3类泛素-蛋白酶体系统和NEDD8 5

1.2.4蛋白质Neddylation的生物学生物学效应 6

1.3.NAE抑制剂 6

1.3.1 MLN4924 6

1.3.2 M22和其他类型的NAE抑制剂 8

1.4小结 9

第二章 NAE酶抑制剂的中间化合物的合成 10

2.1关于M22先导化合物构效优化的分析 10

2.2实验仪器与试剂准备 11

2.3关键中间体化合物M的合成实验步骤 11

2.3.1化合物1→化合物2的合成步骤 11

2.3.2化合物2→化合物3的合成实验步骤 13

2.3.3化合物3→化合物4的合成实验步骤 14

2.3.4化合物4→化合物M 的合成实验步骤 15

第三章 总结与未来展望 17

3.1总结 17

3.2展望 17

参考文献 18

致谢 22

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