Design and Synthesis of Modular Reagents for Chemical Biology

• Main Author: Mehari, Bereketab Tesfayesus
• Other Authors: Jewett, John C.
• Language: en_US
• Published: The University of Arizona. 2018
• Online Access: http://hdl.handle.net/10150/626654; http://arizona.openrepository.com/arizona/handle/10150/626654

Bioconjugation strategies for chemical modification of biomolecules play an important role in gaining greater understanding of biological processes. A number of chemical reactions have been developed for labeling biomolecules in biologically relevant conditions. In an effort to expand the chemical tools available for biological studies, the Jewett group is working towards developing new and improving current bioconjugation strategies to address questions in chemical biology. The traceless Bertozzi-Staudinger reaction is one of the most selective bioconjugation reactions. However, its utility is limited due to poor solubility in aqueous conditions and challenges in the synthesis of functionalized variations of the reagent. A modular one-pot synthetic strategy has been developed. It was also demonstrated that this method can be used to introduce aldehyde and azide functionalities as chemical handles for modification of these reagents. In addition, the design and synthesis of a traceless Bertozzi-Staudinger reagent that has been functionalized with a triazabutadiene probe is described. The orthogonal nature of the traceless Bertozzi-Staudinger and triazabutadiene moieties was established. The utility of the bifunctionalized reagent as a tool for attaching a cargo onto the traceless Bertozzi-Staudinger reagent by utilizing the reactivity of the triazabutadiene moiety and vice versa was demonstrated using a model compound. It was also shown that the reagents that have been modified using this strategy retained their chemical reactivity. In conclusion, this work describes the design and synthesis of bioconjugation reagents that can expand the toolbox of reagents available for the study of biological process.