Cyclic Dichalcogenides Extend the Reach of Bioreductive Prodrugs to Harness Thiol/Disulfide Oxidoreductases: Applications to
Journal
ACS central science
ISSN: 2374-7943
Titre abrégé: ACS Cent Sci
Pays: United States
ID NLM: 101660035
Informations de publication
Date de publication:
26 Apr 2023
26 Apr 2023
Historique:
received:
08
12
2022
medline:
1
5
2023
pubmed:
1
5
2023
entrez:
1
5
2023
Statut:
epublish
Résumé
Small-molecule prodrug approaches that can activate cancer therapeutics selectively in tumors are urgently needed. Here, we developed the first antitumor prodrugs designed for activation by thiol-manifold oxidoreductases, targeting the thioredoxin (Trx) system. The Trx system is a critical cellular redox axis that is tightly linked to dysregulated redox/metabolic states in cancer, yet it cannot be addressed by current bioreductive prodrugs, which mainly cluster around oxidized nitrogen species. We instead harnessed Trx/TrxR-specific artificial dichalcogenides to gate the bioactivity of 10 "off-to-on" reduction-activated duocarmycin prodrugs. The prodrugs were tested for cell-free and cellular reductase-dependent activity in 177 cell lines, establishing broad trends for redox-based cellular bioactivity of the dichalcogenides. They were well tolerated
Identifiants
pubmed: 37122469
doi: 10.1021/acscentsci.2c01465
pmc: PMC10141580
doi:
Types de publication
Journal Article
Langues
eng
Pagination
763-776Informations de copyright
© 2023 The Authors. Published by American Chemical Society.
Déclaration de conflit d'intérêts
The authors declare the following competing financial interest(s): J.G.F., L.Z., J.T.-S. and O.T.-S. are inventors on patent applications PCT/EP2022/057483 and PCT/EP2022/059280 filed by the Ludwig-Maximilians-University (LMU) Munich in 2021, covering compound structures reported in this paper.
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