State Key Laboratory of Fine Chemicals, and Department of Pharmaceutical Science, Dalian University of Technology, 2 Linggong Road, 116024, Dalian, China.
Angew Chem Int Ed Engl. 2022 Nov 21;61(47):e202210249. doi: 10.1002/anie.202210249. Epub 2022 Oct 7.
Singlet oxygen can be generated by thermal cycloreversion of aromatic endoperoxides. However, for any practical potential of chemically generated singlet oxygen within a therapeutic context, the time and place of the release of this cytotoxic species must be tightly regulated. We now show that using a bimodular design with a hypoxia responsive unit and fluoride-triggered endoperoxide unit, a bioorthogonal metabolic shunt can be established, where an enzymatically generated submicromolar fluoride signal plays a crucial role. Thus, cellular nitroreductase is repurposed in a bioorthogonal enzymatic activity, where it releases fluoride ions upon the reduction of a targeted compound. The fluoride ions released in the initial reaction remove the silyl stopper, yielding a highly accelerated release of singlet oxygen. The result is a remarkable difference in cytotoxicity between hypoxic and normoxic conditions as evidenced by microscopy, viability assays and the use of control compounds.
单线态氧可以通过芳香内过氧化物的热环反转产生。然而，对于任何在治疗背景下通过化学方法产生的单线态氧的实际潜力，这种细胞毒性物质的释放时间和地点必须严格控制。我们现在表明，使用具有缺氧反应单元和氟化物触发内过氧化物单元的双模设计，可以建立一个生物正交代谢旁路，其中酶产生的亚毫摩尔氟化物信号发挥关键作用。因此，细胞硝基还原酶被重新用于生物正交酶活性，在这种活性中，当靶化合物被还原时，它会释放氟离子。在初始反应中释放的氟离子去除了硅基封端基，从而加速了单线态氧的释放。显微镜检查、活力测定和对照化合物的使用证明了这一点，这导致在缺氧和正常氧条件下细胞毒性有显著差异。
