Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW, Cambridge, UK.
Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Avenida Professor Egas Moniz, 1649-028, Lisboa, Portugal.
Chembiochem. 2019 Jun 14;20(12):1541-1546. doi: 10.1002/cbic.201900098. Epub 2019 Apr 29.
In addition to its use for the study of biomolecules in living systems, bioorthogonal chemistry has emerged as a promising strategy to enable protein or drug activation in a spatially and temporally controlled manner. This study demonstrates the application of a bioorthogonal inverse electron-demand Diels-Alder (iEDDA) reaction to cleave trans-cyclooctene (TCO) and vinyl protecting groups from carboxylic acid-containing molecules. The tetrazine-mediated decaging reaction proceeded under biocompatible conditions with fast reaction kinetics (<2 min). The anti-inflammatory activity of ketoprofen was successfully reinstated after decaging of the nontoxic TCOprodrug in live macrophages. Overall, this work expands the scope of functional groups and the application of decaging reactions to a new class of drugs.
除了用于研究活系统中的生物分子外，生物正交化学还成为一种有前途的策略，可以实现蛋白质或药物的时空控制激活。本研究展示了生物正交逆电子需求 Diels-Alder(iEDDA)反应在从含羧酸分子中裂解反式环辛烯(TCO)和乙烯基保护基中的应用。四嗪介导的脱笼反应在生物相容条件下进行，反应动力学快(<2 min)。在活巨噬细胞中脱笼非毒性 TCO 前药后，酮洛芬的抗炎活性得以成功恢复。总的来说，这项工作扩展了功能基团的范围，并将脱笼反应应用于一类新的药物。
