FIGURE 10.13 Mechanism of DNMT inhibition by 5-azacytidine and decitabine.

also being studied in patients with chronic myelogenous leukemia resistant to imatinib. 7

5-Fluoro-2'-deoxycytidine is another DNA demethylating agent that is currently underogoing Phase I studies in association with tetrahydrouridine.58 Its mechanism of action involves incorporation into DNA as nucleotide 10.17, followed by methylation at C-5 mediated by nucleophilic attack of a cysteine residue in the active pocket of DNMT to give intermediate 10.18, which is methylated by S-adenosylmethionine to 10.19. The absence of a proton at C-5 prevents the elimination reaction necessary for liberating the free enzyme (Fig. 10.14).

5-Azacytidine, decitabine, and 5-fluoro-2'-deoxycytidine suffer from low in vitro and in vivo stabilities. The in vitro stability can be improved by suppression of the N5=C6 imine function by either suppression of the double bond or the nitrogen atom, in order to prevent the addition of nucleophiles. Two examples are DHAC and zebularine. Sometimes these compounds are associated with tetrahy-drouridine, an inhibitor of cytosine deaminase that behaves as a transition state nh2

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