Bioorthogonal chemistry offers powerful tools to study and manipulate biological systems without interfering with the biological processes. Of paramount interest is the possibility to exploit bioorthogonal tools to deliver novel therapeutic applications. Bioorthogonal prodrug activation is one of the most exciting areas of research and is currently progressing toward phase I clinical trials. Despite their limitations in biological media, transition-metal catalysts have been engineered to enact abiotic cofactors and trigger bond-breaking reactions widely employed for the release of small molecules from masking groups. Here, we highlight the challenges and opportunities of metal-mediated bioorthogonal cleavage reactions for the release of cargo molecules and other emerging applications such as protein activation and RNA degradation.

生物正交化学提供了强大的工具来研究和操纵生物系统，而不会干扰生物过程。最令人感兴趣的是利用生物正交工具来提供新的治疗应用的可能性。生物正交前药激活是最令人兴奋的研究领域之一，目前正朝着 I 期临床试验的方向发展。尽管它们在生物介质中存在局限性，但过渡金属催化剂已被设计成能够产生非生物辅助因子并触发广泛用于从掩蔽基团中释放小分子的断键反应。在这里，我们强调了金属介导的生物正交切割反应在释放货物分子和其他新兴应用（如蛋白质活化和 RNA 降解）方面的挑战和机遇。