Poster Open Access

Metabolization and Optimization of Carbocyclic 5-Aza-2′-Deoxycytidine

Peev, Elsa; Heiss, Matthias; Aumer, Tina; Sommermann, Corinna; Carell, Thomas

Acute myeloblastic leukaemia (AML) is a type of cancer affecting the cells of the bone marrow, preventing the normal production of blood cells. When a person is affected, the prognosis is poor. Whether due to late diagnosis or lack of more specific treatments, the cure rate is low.1 5-Aza-2′-Deoxycytidine (Decitabine, AzadC or DAC) is one of this drug, and like most of them it has important drawbacks. This molecule is a nucleoside analogue drug. When incorporated into DNA, it inhibits DNA methyltransferases (DNMTs) and causes the level of DNA methylation to fall, leading to the reactivation of tumour suppressor genes.2,3 However, AzadC is used as a remedy of last resort due to significant side effects, probably because of spontaneous hydrolysis of the molecule and yet we achieved to obtain a stable derivative of this epigenetic medicine. By modifying the ribose of the base into a carbocycle (cAzadC or cDAC), we preserved the original mode of action in cellulo while obtaining a hydrolytically stable compound.4 The current work contributes to map the overall the metabolization pathway of cAzadC in diverse cell lines and organs. The investigation of the proteins interacting with our compound allows its progressive structural optimisation to overcome potential resistance and obtain a drug for AML that is both, specific and stable.

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