Bioorthogonal reactions have become essential tools for Chemical Biology and Drug Discovery. Despite recent advances in the development of bioorthogonal reactions, there still exists a need for reactions with improved kinetics and selectivities. Alkenes have been exploited in the context of site-specific protein modification and labelling, for example in cross-metathesis, photochemical 1,3-dipolar cycloaddition and tetrazine Diels-Alder cycloaddition strategies. Pericyclic reactions are a class of reactions where alkenes are suitable partners to achieve selectivity. These reactions are particularly attractive for applications in biological systems because their often-accelerated rate in polar media and their concerted mechanisms reduce undesired reactivity with biological nucleophiles and electrophiles. This project aims to 1) explore the reactivity of alkenes in benign aqueous conditions for site-specific ligand/protein labelling using a photoinduced [2+2] cycloaddition strategy, 2) site-specific incorporation of bioorthogonal group norbornadiene via genetic code expansion for directed site-specific cellular protein labeling, 3) the design and synthesis of ligands of ligands of oncogenic IL7R in T-cell acute lymphoblastic leukaemia (T-ALL) and 4) the use of a bioorthogonal approach for live cell imaging of oncogenic IL7R in T-ALL.
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