Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 61, Issue 47, Pages -Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.202210249
Keywords
Apoptosis; Bioorthogonal; Endoperoxide; Hypoxia; Singlet Oxygen
Categories
Funding
- LiaoNing Revitalization Talents Program [XLYC1902001, XLYC1907021]
- National Natural Science Foundation of China [22178048, 22007008]
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By utilizing a dual-module design with a hypoxia responsive unit and fluoride-triggered endoperoxide unit, we have established a bioorthogonal metabolic shunt that enables controlled generation of singlet oxygen in cells, resulting in significantly different cytotoxicity under hypoxic and normoxic conditions.
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.
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