论文总字数：26704字

摘 要

胰腺癌是一种侵袭性的恶性肿瘤，具有有限的有效治疗选择和极高的死亡率。患有胰腺癌的人群中有97.7%的人的KRAS突变。KRAS属于RAS族系中的一员， KRAS突变是胰腺癌发生的主要因素，其明显促进肿瘤细胞的增殖分化。但是目前临床上还没有有效的KRAS抑制剂。对于KRAS基因突变的抑制途径包括直接靶向KRAS信号传导，这一策略取得巨大成功但是仍未批准为临床药物。第二种策略，竞争抑制KRAS-PDE6δ蛋白与蛋白的相互作用，从而降低KRAS的质膜定位，从而降低肿瘤增殖的信号传导。

在本文中我们将研究重点集中在抑制KRAS膜定位上。通过与KRAS竞争性的结合PDE6δ的位点导致KRAS重定位到广泛的内膜表面，最终抑制KRAS的信号传导。

本课题在前期研究中通过虚拟筛选，设计合成，体外评价等系列研究，发现了对胰腺癌细胞具有显著抑制活性的KRAS-PDE6δ抑制剂先导化合物A。在此基础上进行结构修饰优化，采用CCK8,Western Blot，免疫荧光等技术检测其药理活性，找到可用于药物开发的苗头化合物。结合活性数据分析，指导今后药物结构优化，提高药物活性。

关键词：KRAS-PDE6δ抑制剂 胰腺癌 计算机辅助药物设计

Design, synthesis and antitumor activity studies of novel KRAS-PDE6δ

Abstract

Pancreatic cancer is an aggressive malignancy with limited effective therapeutic options and exceedingly high mortality rates. The study found that 97.7% of people with pancreatic cancer had mutations in the KRAS. KRAS belongs to a member of the RAS family whose mutation is a major factor in the development of pancreatic cancer. KRAS significantly promotes the proliferation and differentiation of tumor cells. However, there are currently no effective KRAS inhibitors in the clinic. Inhibition pathways for KRAS gene mutations include direct targeting of KRAS signaling, a strategy that has been highly successful but has not yet been approved as a clinical drug. The second strategy, competition, inhibits the interaction of KRAS-PDE6δ protein with proteins, thereby reducing the plasma membrane localization of KRAS and reducing the signal transduction of tumor proliferation.

In this paper we focus our research on the inhibition of KRAS membrane localization. The competitive binding of PDE6δ to KRAS results in the relocation of KRAS to a broad endometrial surface, ultimately inhibiting KRAS signaling.

In the previous study, we found a lead compound A of KRAS-PDE6δ inhibitor with significant inhibitory activity against pancreatic cancer cells through a series of studies including virtual screening, design synthesis, and in vitro evaluation. On this basis, structural modification optimization was carried out, and its pharmacological activity was detected by CCK8, Western Blot, immunofluorescence and other techniques to find a seed compound that can be used for drug development. Combined with activity data analysis, it will guide the optimization of drug structure in the future and improve drug activity.

Keywords: KRAS-PDE6δ inhibitor；pancreatic cancer； computer-aided drug design

目 录

摘 要 I

Abstract II

第一章 文献综述 1

1.1 引言 1

1.2 KRAS-PDE6δ相互作用的生物学功能和结构基础 1

1.2.1 KRAS蛋白及功能 1

1.2.2 KRAS-PDE6δ蛋白与蛋白相互作用 1

1.3 现有的KRAS-PDE6δ的小分子抑制剂 4

1.3.1苯并咪唑类 4

1.3.2 哒嗪酮类 5

1.3.3 苯二磺胺类衍生物 6

1.3.4 二氢喹唑啉酮类 7

第二章 基于“拼接原理”合成新型KRAS-PDE6δ小分子抑制剂的设计思想及活性分析 12

2.1 设计思想-先导化合物的发现 12

2.2先导化合物的活性分析 12

第三章 实验方法 17

3.1 先导化合物的结构修饰与筛选 17

3.2 先导化合物活性测试方法 17

第四章 实验部分 18

4.1 仪器设备 18

4.2 合成实验 18

4.2.1总合成路线 18

4.3 实验结果 21

4.3.1 化合物数据 21

4.3.2主要化合物1H and 13C-NMR Spectra 23

4.3.3药理活性数据 29

第五章 总结 32

参考文献 33

附录 化合物活性测试方法 37

致谢 39

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