Design and synthesis of bioreductive prodrugs of class I histone deacetylase inhibitors and their biological evaluation in virally transfected acute myeloid leukemia cells.
HDACs
epigenetics
hypoxia
nitroreductases
prodrugs
Journal
Archiv der Pharmazie
ISSN: 1521-4184
Titre abrégé: Arch Pharm (Weinheim)
Pays: Germany
ID NLM: 0330167
Informations de publication
Date de publication:
06 Nov 2023
06 Nov 2023
Historique:
revised:
19
10
2023
received:
25
09
2023
accepted:
20
10
2023
medline:
7
11
2023
pubmed:
7
11
2023
entrez:
6
11
2023
Statut:
aheadofprint
Résumé
Although histone deacetylase (HDAC) inhibitors show promise in treating various types of hematologic malignancies, they have some limitations, including poor pharmacokinetics and off-target side effects. Prodrug design has shown promise as an approach to improve pharmacokinetic properties and to improve target tissue specificity. In this work, several bioreductive prodrugs for class I HDACs were designed based on known selective HDAC inhibitors. The zinc-binding group of the HDAC inhibitors was masked with various nitroarylmethyl residues to make them substrates of nitroreductase (NTR). The developed prodrugs showed weak HDAC inhibitory activity compared to their parent inhibitors. The prodrugs were tested against wild-type and NTR-transfected THP1 cells. Cellular assays showed that both 2-nitroimidazole-based prodrugs 5 and 6 were best activated by the NTR and exhibited potent activity against NTR-THP1 cells. Compound 6 showed the highest cellular activity (GI
Identifiants
pubmed: 37932028
doi: 10.1002/ardp.202300536
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e2300536Subventions
Organisme : Excellence Strategy of the German Federal and State Governments
ID : CIBSS-EXC 2189
Organisme : Deutsche Forschungsgemeinschaft (DFG)
ID : 278002225/RTG 2202
Organisme : Deutsche Forschungsgemeinschaft (DFG)
ID : 469954457
Organisme : Deutsche Forschungsgemeinschaft (DFG)
ID : 471614207
Organisme : Alexander von Humboldt Foundation Project
ID : EGY 1191187
Informations de copyright
© 2023 The Authors. Archiv der Pharmazie published by Wiley-VCH GmbH on behalf of Deutsche Pharmazeutische Gesellschaft.
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