5-Azacytidine53 and its 2'-deoxy analog decitabine incorporate into DNA as false nucleotides 10.14, which are complexed by the DNMT enzyme similar to its natural substrates. Attack of the mercapto group in the active site gives adduct 10.15, and its methylation at the N-5 position takes place normally to give 10.16, but the lack of a hydrogen atom at N-5 after methylation prevents the elimination reaction necessary to restore the enzyme, which is thus inactivated (Fig. 10.13).

Although Phase II clinical studies of 5-azacytidine as an antitumor drug took place in 1972, its ability to inhibit DNA methylation was established in 1980. Beginning in 1993, a number of studies proved its efficacy in the treatment of MDS, leading to its approval by FDA for this indication.54 Because of the poor oral absorption of nucleosides, administration has to be by injection.55

Decitabine is also a long-known anticancer drug that was tested in the clinic in the 1970s using the maximum tolerated doses, with myelosuppression as its main side effect. It was not until 2004 that it was shown to have higher efficacy at much lower doses, with a correlation with DNA demethylation being observed.56 In 2003, decitabine received orphan drug status for treatment of MDS, and it is nh2 I 2 N^N

dR Decitabine

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