1、,点击化学和生物正交反应 在生物分子标记中的前所未有的选择性,导师:熊博 报告人:吴蔚 学号：2010111924,Outline 文献背景“点击化学”、正交实验的定义及特征在药物开发中的应用生物正交反应标记生物分子成像展望,文献背景,“点击化学”正交设计实验,点击化学的提出者,Barry Sharpless,点击化学:选用易得原料，通过可靠，高效而又具选择性的化学反应来实现碳杂原子连接(C-X-C)，低成本快速合成大量新化合物的一套强大的，实用的合成方法,点击化学定义,连接方式(C-X-C)： Generate substances by joining small units togeth
2、er with heteroatom links； 热力学驱动力：high thermodynamic driving force (20 kcal/mol)过程标准: Modular, wide in scope, give very high yields, generate only inoffensive byproducts that can be removed by non chromatographic methods, stereo-specific, simple reaction conditions, readily available starting materia
3、ls and reagents, use of no solvent or a solvent that is benign or easily removed, and simple product isolation;,定义及特征,点击化学是指选用易得原料，通过可靠，高效而又具选择性的化学反应来实现碳杂原子连接(C-X-C)，低成本快速合成大量新化合物的一套强大的，实用的合成方法。,点击化学的特征,连接方式(C-X-C)： Generate substances by joining small units together with heteroatom links 热力学驱动力： hi
4、gh thermodynamic driving force (20 kcal/mol),过程标准: Modular, wide in scope, give very high yields, generate only inoffensive byproducts that can be removed by non hromatographic methods, stereo-specific, simple reaction conditions, readily available starting materials and reagents, use of no solvent
5、or a solvent that is benign or easily removed, and simple product isolation,点击化学反应特征,点击化学的优点,high yields easy to perform,wide scope faster synthesis,product isolation must besimple insensitive to oxygen or water,readily available reagents highly selective reactions,thermodynamic driving force 20 kca
6、l/mol,正交试验设计：研究多因素多水平的又一种设计方法，它是根据正交性从全面试验中挑选出部分有代表性的点进行试验 特点：“均匀分散，齐整可比”，高效率、快速、经济,用正交法设计测试用例正交表的构成,点击化学反应类型1. STRATEGY OF CLICK CHEMISTRY AND BIOORTHOGONAL REACTIVITY1.1.叠氮，炔烃环加成反应Azide-Alkyne Cycloaddition.1.2.自由铜叠氮，炔烃环加成反应Copper-Free Azide-Alkyne Cycloaddition.1.3. 道丁格连接反应Staudinger Ligation.1.4
7、.其他反应 Other Reactions.1.5.比较生物正交反应条件Comparison of Bioorthogonal Reactions and Conditions.,2. IMPACTS OF CLICK CHEMISTRY ON DRUG DEVELOPMENT,Derivatization of Lipid Probes. Modification. Labeling of Nucleotides for Imaging DNA and RNA.,Introduction of Unnatural Amino Acids Bearing Reactive Tags into
8、Proteins. Labeling of Viral Surfaces.,Incorporation of Labeled Probes onto Proteins via PostTranslational Activity-BasedProtein Profiling,3.1,3.2,3.3,3. LABELING AND IMAGING OF BIOMOLECULES USING BIOORTHOGONAL REACTIONS,FIGURE 2: In situ combinatorial drug development. (A) General schematic for temp
9、lated inhibitor development. Binding of reactants by the target enzyme leads to catalytic formation of the optimal inhibitor.(B) Application of this approach to the development of a potent bisubstrate inhibitor of acetylcholinesterase.,FIGURE 4: Incorporation of unnatural amino acids into proteins.
10、(A) Noncanonical amino acids that have been introduced into proteins. (B) Schematic for unnatural amino acid mutagenesis using a genetically engineered tRNA synthetase.,FIGURE 5: Metabolic labeling of cell-surface glycans using bioorthogonal chemistry. (A) Azide and alkyne-derivatized sugars that su
11、ccessfully infiltrate biosynthetic pathways. (B) Schematic for the incorporation of simple sugar derivatives onto glycoproteins via metabolic pathways,followed by selective labeling through bioorthogonal chemistry.,展 望,链接化学是一种简单的合成方式，其目的是加速新功能物质和材料的发现，目前尚处于初步发展阶段，但自提出以来，由于其具有反应易得，条件温和，产率高，反应具有选择性且几乎定量等优点，已开始由基础理论研究阶段逐步转入实际应用阶段，在药物化学，生物科学，高分子等领域均有广泛的应用。可以预计，将来会发现更多快速，高效，可靠且有高选择性的反应，链接化学将在医药，农业等各个方面获得更加广泛的应用。,Thanks for your attention,
