Influencing Epigenetic Information with a Hydrolytically Stable Carbocyclic 5-Aza-2'-deoxycytidine.
Animals
Aza Compounds
/ chemistry
Cell Line
DNA Methylation
/ drug effects
DNA Modification Methylases
/ antagonists & inhibitors
Deoxycytidine
/ analogs & derivatives
Enzyme Inhibitors
/ chemistry
Epigenesis, Genetic
/ drug effects
Hydrolysis
Mice
Models, Molecular
Mouse Embryonic Stem Cells
/ drug effects
5-methyl-2′-deoxycytidine
DNA modification
epigenetics
methylation
nucleoside analogues
Journal
Angewandte Chemie (International ed. in English)
ISSN: 1521-3773
Titre abrégé: Angew Chem Int Ed Engl
Pays: Germany
ID NLM: 0370543
Informations de publication
Date de publication:
09 09 2019
09 09 2019
Historique:
received:
17
04
2019
revised:
31
05
2019
pubmed:
18
6
2019
medline:
20
9
2020
entrez:
18
6
2019
Statut:
ppublish
Résumé
5-Aza-2'-deoxycytidine (AzadC) is an antimetabolite in clinical use, which reduces the level of the epigenetic modification 5-methyl-2'-deoxycytidine (mdC). AzadC is incorporated into the genome of proliferating cells, where it inhibits DNA methyltransferases (DNMTs), leading to a reduction of mdC. The loss of mdC, which is a transcriptional silencer in the promoter region found upstream of genes, leads to the reactivation of the corresponding gene, including tumor-suppressor genes, which elicits a beneficial effect. The problem associated with AzadC is that the compound is hydrolytically unstable. It decomposes during treatment to a variety of poorly characterized hydrolysis products. After its incorporation into the genome, this hydrolytic instability generates abasic sites. It is consequently difficult to dissect whether the activity of the compound is caused by DNMT inhibition or more generally by DNA lesion formation. We now discovered that a disarmed version of AzadC, in which the ribose oxygen was replaced by a CH
Identifiants
pubmed: 31206985
doi: 10.1002/anie.201904794
doi:
Substances chimiques
Aza Compounds
0
Enzyme Inhibitors
0
Deoxycytidine
0W860991D6
DNA Modification Methylases
EC 2.1.1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
12984-12987Subventions
Organisme : Deutsche Forschungsgemeinschaft
ID : SFB1309-TP-A4
Pays : International
Organisme : Deutsche Forschungsgemeinschaft
ID : SPP1784
Pays : International
Organisme : Deutsche Forschungsgemeinschaft
ID : GRK2338/1-P12
Pays : International
Organisme : Deutsche Forschungsgemeinschaft
ID : SFB1361-TP-02
Pays : International
Organisme : H2020 European Research Council (EPIR)
ID : 741912
Pays : International
Organisme : Boehringer Ingelheim Fonds
ID : Fellowship
Pays : International
Informations de copyright
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
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