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

项目摘要/摘要 恶氮杂环类化合物通过N-转移与甲硫氨酸侧链反应的独特活性已被证实. 成功地被用来制造强大的生物偶联试剂，被许多研究小组使用。 然而，这种试剂的使用受到加入二次反应的困难的限制。 手柄和狭窄的货物范围，由于合成条件苛刻和敏感的恶唑烷。 硝酮的光异构化提供了一种温和的恶氮杂环类化合物的合成方法。这条路线通向 恶氮杂环类化合物允许加入用当前合成方法无法获得的货物和 介绍了一种有效的用光控制恶氮杂环丙啶反应性的方法。这项提议旨在澄清 硝酮化学结构与异构化能力的定量关系 恶氮杂环丙烷和由此产生的恶氮杂环丙烷生物结合反应性。硝酮的光异构化将是 用于合成结合了其他常用点击手柄的二价试剂。最后， 由光异构化提供的对恶氮杂环丙啶反应性的精细控制将被用于 用于蛋白质修饰的原位恶唑烷反应性。这些研究将极大地扩大 这类有价值的生物偶联试剂的用途。

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.