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Its mode of action is unusual because the compound is one of the few drugs that act at the epigenetic level of the genetic code. AzadC is incorporated as an antimetabolite into the genome and creates covalent, inhibitory links to DNA methyltransferases (DNMTs) that methylate 2\u2019\u2010deoxycytidine (dC) to 5\u2010methyl\u2010dC (mdC). Consequently, AzadC treatment leads to a global loss of mdC, which presumably results in a reactivation of silenced genes, among them tumor suppressor and DNA damage response genes. Because AzadC suffers from severe instability, which limits its use in the clinic, a more sophisticated AzadC derivative would be highly valuable. Here, we report that a recently developed carbocyclic AzadC analogue (cAzadC) blocks DNMT1 in the AML cell line MOLM\u201013 as efficient as AzadC. Moreover, cAzadC has a surprisingly strong anti\u2010proliferative effect and leads to a significantly higher number of double strand breaks compared to AzadC, while showing less off\u2010target toxicity. These results show that cAzadC triggers more deleterious repair and apoptotic pathways in cancer cells than AzadC, which makes cAzadC a promising next generation epigenetic drug.<\/jats:p>","DOI":"10.1002\/chem.202200640","type":"journal-article","created":{"date-parts":[[2022,3,14]],"date-time":"2022-03-14T05:05:09Z","timestamp":1647234309000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Epigenetic Anti\u2010Cancer Treatment With a Stabilized Carbocyclic Decitabine Analogue"],"prefix":"10.1002","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5691-1941","authenticated-orcid":false,"given":"Franziska R.","family":"Traube","sequence":"first","affiliation":[{"name":"Department of Chemistry Ludwig-Maximilians-Universit\u00e4t M\u00fcnchen  Butenandtstr. 5\u201313 81377 Munich Germany"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3130-9807","authenticated-orcid":false,"given":"Nat\u00e9rcia 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