Institute of Applied Synthetic Chemistry, TU Wien, 1060, Vienna, Austria.
Center for Anatomy and Cell Biology, Medical University of Vienna, 1090, Vienna, Austria.
Chembiochem. 2022 Oct 19;23(20):e202200363. doi: 10.1002/cbic.202200363. Epub 2022 Aug 30.
Bond-cleavage reactions triggered by bioorthogonal tetrazine ligation have emerged as strategies to chemically control the function of (bio)molecules and achieve activation of prodrugs in living systems. While most of these approaches make use of caged amines, current methods for the release of phenols are limited by unfavorable reaction kinetics or insufficient stability of the Tz-responsive reactants. To address this issue, we have implemented a self-immolative linker that enables the connection of cleavable trans-cyclooctenes (TCO) and phenols via carbamate linkages. Based on detailed investigation of the reaction mechanism with several Tz, revealing up to 96 % elimination after 2 hours, we have developed a TCO-caged prodrug with 750-fold reduced cytotoxicity compared to the parent drug and achieved in situ activation upon Tz/TCO click-to-release.
生物正交的四嗪连接引发的键断裂反应已成为一种化学控制（生物）分子功能的策略，并实现了在活体内原药的激活。虽然这些方法大多利用了被笼蔽的胺，但目前用于释放酚类的方法受到不利反应动力学或 Tz 响应反应物稳定性不足的限制。为了解决这个问题，我们设计了一种自耗性连接物，它可以通过氨基甲酸酯键将可断裂的反式环辛烯（TCO）和酚连接起来。通过对几种 Tz 的反应机制进行详细研究，我们发现反应 2 小时后可达到高达 96%的消除率，我们开发了一种 TCO 笼原药，与母体药物相比其细胞毒性降低了 750 倍，并在 Tz/TCO 点击释放时实现了原位激活。
