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Bioorthogonal Bond Cleavage Reactions for Traceless Activation of Drugs and Proteins

用于药物和蛋白质无痕激活的生物正交键断裂反应

基本信息

批准号：
1800475
负责人：
金额：
--
依托单位：
University of Cambridge
依托单位国家：
英国
项目类别：
Studentship
财政年份：
2016
资助国家：
英国
起止时间：
2016 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=studentship-1800475
关键词：
Bioorthogonal Bond Cleavage Reactions Traceless

项目摘要

Bioorthogonal reactions are an attractive area of research in chemical biology. Bond cleavage reactions are being studied as a way to deprotect and therefore activate a protein or a drug with spatiotemporal control. Methods for the release of primary and secondary amines have been established, however strategies for release of tertiary amines need to be developed. There are many examples of drugs that contain a tertiary amine including anticancer (auristatin or tubulysin) and antibiotic (rifabutin or clindamycin) drugs. During this project we will develop a new bioorthogonal method for the traceless release of tertiary amines which can be used to achieve spatiotemporal deprotection of these drugs. This new tool will be invaluable in chemical biology and molecular medicine.1-(vinyloxy)butyl will be used as a new handle that, when reacted with a tetrazine, will trigger an intramolecular cascade reaction and lead to the release of the tertiary amine. The handle will be installed onto a simple amine (N,N-dimethylbenzylamine) to form a model system which can be used to study the stability of the handle and the kinetics of the tetrazine decaging reaction. The handle will then be attached to several drugs and the stability and release of these prodrugs will be studied in vitro. We will apply the tetrazine decagine methodology that has been developed in the Bernardes group.

生物正交反应是化学生物学研究的一个热点。键裂解反应被研究作为一种解除保护的方法，从而激活具有时空控制的蛋白质或药物。伯胺和仲胺的释放方法已经建立，但叔胺的释放策略还有待开发。含有叔胺的药物有许多例子，包括抗癌药物（耳抑素或微管溶素）和抗生素（利福布汀或克林霉素）药物。在本项目中，我们将开发一种新的生物正交法，用于叔胺的无痕迹释放，可用于实现这些药物的时空去保护。这种新工具将在化学生物学和分子医学中发挥不可估量的作用。1-（乙烯氧基）丁基将被用作一个新的手柄，当与四嗪反应时，将触发分子内级联反应并导致叔胺的释放。将手柄安装在简单的胺（N，N-二甲基苄胺）上，形成一个模型系统，可用于研究手柄的稳定性和四嗪降解反应的动力学。然后将手柄附着在几种药物上，并在体外研究这些前药的稳定性和释放。我们将采用贝尔纳德斯小组开发的四嗪十agine方法。