论文总字数：16567字

摘 要

动态组合化学作为近年来产生的一门新兴学科，它集组合化学与高通量筛选优势于一体，在先导化合物的发现与优化方面有着常规方法难以企及的优势。微反应器也是近些年发展起来的一项化学工艺技术，与大反应器相比，其微管既可以作为混合器，又可以作为反应器，有着极高的混合效率与反应转化率。本论文试图通过将动态组合化学和微反应器结合起来，组成一套基于微尺度效应下的动态组合化合物的构建及分析的模式，为化合物的合成与筛选探索新方法。

本论文用四种酸和两种醇通过微反应器的酯化反应产物构成化合物库，并在其中加入来牛血清白蛋白筛选出它的竞争性抑制剂。我们首先通过测定温度，时间，pH对牛血清白蛋白的活性的影响来确定反应条件，然后利用高分辨质谱的检测发现其抑制剂。同时我们用常规反应瓶进行对照实验，通过两者的比较，对微反应下的动态组合化学与常规反应的优劣进行了深入的探讨。行了深入的探讨。

关键词：动态组合化学 微反应器 抑制剂

Construction and Analysis of Dynamic Combination Compound Library Based on Microscale Effect

Abstract

Dynamic combination of chemistry as a new discipline in recent years, after 20 years of research and development, is now in drug research and development, materials, chemical and other fields have a wide range of applications. Dynamic combination of chemical assemblage and screening in one of the advantages of the construction of the dynamic combination of compound library for the effective search for substrates, inhibitors, new receptors, catalysts and carriers to provide a new way of thinking. Microreactor is also a chemical process developed in recent years, compared with the large reactor, the micro-tube can be used as a mixer, but also as a reactor, has a very high mixing efficiency and reaction conversion rate. In this paper, we try to combine the dynamic combination chemistry and microreactor to form a set of dynamic combination compounds based on micro-scale effect, and explore a new method for the synthesis and screening of compounds.

  In this paper, four acid and two alcohols were used to form a library of compounds by the esterification reaction product of the microreactor, and bovine serum albumin was added to screen for its competitive inhibitor. We first determined the reaction time by measuring the effect of temperature, time, and pH on the activity of bovine serum albumin, and then found the inhibitor by the detection of the reaction product by column chromatography and mass spectrometry. At the same time, we use the conventional reaction bottle to set the control, through the comparison of the two, under the micro-reaction of the combination of chemical and conventional reaction of the pros and cons of in-depth discussion.

Keywords：Dynamic combination chemistry；Microreactor；Inhibitors

目 录

摘 要 I

Abstract II

第一章 文献综述 1

1.1微反应技术的研究进展 1

1.1.1 微反应器的定义 1

1.1.2微反应器的特性 2

1.1.3微反应器的优点 2

1.1.4 微反应器的发展现状与展望 2

1.2动态组合化学的研究进展 3

1.2.1 动态组合化学产生的背景 3

1.2.2 动态组合化学的原理和方法 3

1.2.3 动态组合化学的发展现状与展望 4

1.3 本课题的研究内容和意义 5

第二章 实验材料与方法 7

2.1 药品与仪器 7

2.1.1实验仪器 7

2.1.2实验试剂 7

2.2实验原理与方法 8

2.3微尺度效应下的动态组合化学库的构建过程 8

2.3.1.反应溶液的配制 8

2.3.2.连续法BSA抑制剂的筛选 9

2.3.3.结果检测 9

2.3.4.间歇法BSA抑制剂的筛选 9

第三章 结果与讨论 11

3.1 牛血清白蛋白的活性测定 11

3.1.1 牛血清白蛋白活性的温度—时间曲线测定 11

3.1.2 牛血清白蛋白对pH的耐受性试验 13

3.2 基于微反应器的动态组合化学库的构建与分析 14

3.3 基于反应瓶的动态组合化学库的构建与分析 16

第四章 结论与展望 20

参考文献 21

致谢 24

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