Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 57, Issue 21, Pages 6141-6145Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201801058
Keywords
1,2-dithiolane; cancer; prodrugs; redox regulation; thioredoxin reductase
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Funding
- National Natural Science Foundation of China [21572093, 21778028]
- Lanzhou University (Fundamental Research Funds for the Central Universities) [lzujbky-2017-ot02, lzujbky-2017-sp06]
- 111 project
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Elevated reactive oxygen species and antioxidant defense systems have been recognized as one of the hallmarks of cancer cells. As a major regulator of the cellular redox homeostasis, the selenoprotein thioredoxin reductase (TrxR) is increasingly considered as a promising target for anticancer drug development. The current approach to inhibit TrxR predominantly relies on the modification of the selenocysteine residue in the C-terminal active site of the enzyme, in which it is hard to avoid the off-target effects. By conjugating the anticancer drug gemcitabine with a 1,2-dithiolane scaffold, an unprecedented prodrug strategy is disclosed that achieves a specific release of gemcitabine by TrxR in cells. As overexpression of TrxR is frequently found in different types of tumors, the TrxR-dependent prodrugs are promising for further development as cancer chemotherapeutic agents.
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