Development of Bifunctional and Light Activated ReACT Bioconjugation Reagents via Nitrone Photoisomerization

点击翻译按钮获取中文摘要

PROJECT SUMMARY/ABSTRACT The unique reactivity of oxaziridines towards methionine sidechains via N-transfer has been successfully leveraged to make powerful bioconjugation reagents used by numerous research groups. However, the utility of this reagent is limited by the difficulty of incorporating secondary reactive handles and a narrow cargo scope due to the harsh synthesis conditions and sensitivity of oxaziridines. Photoisomerization of nitrones provides a mild method of oxaziridine synthesis. This route to oxaziridines allows for incorporation of cargo not accessible with current synthetic methods and presents a powerful way of controlling oxaziridine reactivity using light. This proposal aims to elucidate quantitative relationships between nitrone chemical structure and its ability to isomerize to oxaziridines and the resulting oxaziridine bioconjugation reactivity. Nitrone photoisomerization will be leveraged to synthesize bivalent reagents that incorporate other commonly used click handles. Finally, the exquisite control over oxaziridine reactivity provided by the photoisomerization will be used to uncage oxaziridine reactivity in situ for protein modifications. These studies will greatly expand the utility of this valuable class of bioconjugation reagents.