New cytosine derivatives as inhibitors of DNA methylation

DNA cytosine methylation catalyzed by DNA methyltransferase 1 (DNMT1) is an epigenetic method of gene expression regulation and development. Changes in methylation pattern lead to carcinogenesis. Inhibition of DNMT1 activity could be a good strategy of safe and efficient epigenetic therapy. In this work, we present a novel group of cytosine analogs as inhibitors of DNA methylation. We show new methods of synthesis and their effect on in vitro reaction of DNA methylation. Almost all of analyzed compounds inhibit DNA methyltransferase activity in the competitive manner. Ki values for the most potent compound 4-N-furfuryl-5,6-dihydroazacytosines is 0.7 μM. These compounds cause also a decrease of 5-methylcytosine (m5C) level in DNA of mammalian HeLa and HEK293 cells.

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► New derivative of cytosine was synthesized.
► New conditions of reaction with aldehydes leading to Schiff base formation are presented.
► New approach allows to skip N1 of cytosine protection and exclude pyridine.
► Obtained compounds are potent inhibitors of DNMT1.
► These inhibitors can be used in anti-cancer therapy.