Bioorthogonal Bond Cleavage Reactions for Traceless Activation of Drugs and Proteins

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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.