Influencing Epigenetic Information with a Hydrolytically Stable Carbocyclic 5‐Aza‐2′‐deoxycytidine
2019-06-17
M. Sc. Thomas M. Wildenhof, M. Sc. Sarah Schiffers, M. Sc. Franziska R. Traube, Dr. Peter Mayer, Prof. Dr. Thomas Carell
Angew. Chem. Int. Ed., 2019, 58 (37), 12984
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 CH2 group, is surprisingly stable under a variety of pH values while keeping activity against the DNMTs.
Speaker: Prof. Dr. Thomas Carell
Ludwig-Maximilians-Universität München
Institut für Chemische Epigenetik (ICEM)
Department of Chemistry
Office:
Würmtalstrasse 201
81377 Munich
Germany
Mailing address:
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Management: Dr. Nada Raddaoui
Institute for Chemical Epigenetics Munich (ICEM)
Office:
Würmtalstrasse 201, Building L, Room 03.004
81377 Munich
Germany
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Butenandtstr. 5 - 13
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Secretary: Birgit Carell
Institute for Chemical Epigenetics Munich (ICEM)
Office:
Würmtalstrasse 201, Building L, Room 00.007
81377 Munich
Germany
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Butenandtstr. 5 - 13
81377 Munich
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website support: Martina Schuster
Prof. Dr. Lena Daumann
LMU Munich
Department of Chemistry
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Dr. Sabine Schneider
LMU Munich
Institute for Chemical Epigenetics
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House L
81377 Munich, Germany
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Dr. Martin Sumser (Coordinator)
LMU Munich
Institute for Chemical Epigenetics
Butenandtstr. 5 - 13
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81377 Munich, Germany
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