Bioorthogonal Bond Cleavage Reactions for Traceless Activation of Drugs and Proteins

生物正交反应是化学生物学研究的一个热点领域。人们正在研究键断裂反应，以此作为一种去保护并激活具有时空控制的蛋白质或药物的方法。已经建立了伯胺和仲胺的释放方法，但需要制定叔胺的释放战略。有许多含有叔胺的药物，包括抗癌药物(金黄色葡萄糖素或管溶素)和抗生素(利福布汀或克林霉素)药物。在这个项目中，我们将开发一种新的生物正交法来实现叔胺的无痕迹释放，该方法可以用来实现这些药物的时空去保护。这种新的工具在化学生物学和分子医学中将是非常有价值的。1-(乙烯氧基)丁基将被用作一种新的手柄，当它与四嗪反应时，将引发分子内的级联反应，并导致叔胺的释放。将手柄安装在一个简单的胺(N，N-二甲基苄胺)上，形成一个模型系统，用于研究手柄的稳定性和四嗪降解反应的动力学。然后将手柄连接到几种药物上，并将在体外研究这些前药的稳定性和释放。我们将采用Bernardes小组开发的四嗪去甲肾上腺素方法。

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.