Serhan Mariam, Josephson Jason D, Masoud Shadi Sedghi, Nakajima Masaya, Pezacki John Paul
Department of Chemistry and Biomolecular Sciences, University of Ottawa, 150 Louis-Pasteur, Ottawa, Ontario, K1N 6N5, Canada.
Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8675, Japan.
Chemistry. 2024 Apr 16;30(22):e202303699. doi: 10.1002/chem.202303699. Epub 2024 Mar 12.
3-oxidopyridinium ions are water stable and soluble heteroaromatic betaines that behave as latent dipoles and undergo a wide variety of cycloadditions. Research into the cycloaddition reactions of 3-oxidopyridiniums was spearheaded by Alan R. Katritzky and collaborators from the early 1970s until the late 1980s, but they have yet to be used for bioorthogonal applications. Herein we report that 3-oxidopyridiniums can readily react with 4-dibenzocyclooctynol (DIBO), a common bioorthogonal handle, in a [3+2] cycloaddition. The mechanism was investigated by altering the electronics of the reaction by changing the substituent on the 5 position of the pyridinium. Electron-donating 5-substituents have been shown to significantly increase the rate of the reaction, with bimolecular rate constants ranging from 3.3×10 s with 5-trifluoromethyl-N-methyl-3-oxidopyridinium to 1.07 M s with 5-amino-N-methyl-3-oxidopyridinium. 3-oxidopyridiniums' appreciable cycloaddition rates and compatibility with bioorthogonally relevant environments give them the potential to be used in a variety of bioconjugation applications.
3-氧化吡啶鎓离子是水稳定且可溶的杂芳基甜菜碱，其表现为潜在偶极并能发生多种环加成反应。对3-氧化吡啶鎓环加成反应的研究由艾伦·R·卡特里茨基及其合作者于20世纪70年代初至80年代末率先开展，但它们尚未用于生物正交应用。在此我们报告，3-氧化吡啶鎓能在[3+2]环加成反应中与常见的生物正交手柄4-二苯并环辛炔醇（DIBO）轻松反应。通过改变吡啶鎓5位上的取代基来改变反应的电子性质，从而对反应机理进行了研究。已表明给电子的5-取代基能显著提高反应速率，双分子速率常数范围从5-三氟甲基-N-甲基-3-氧化吡啶鎓的3.3×10 s到5-氨基-N-甲基-3-氧化吡啶鎓的1.07 M s。3-氧化吡啶鎓可观的环加成速率以及与生物正交相关环境的兼容性使其有潜力用于多种生物共轭应用。
