Unnatural enantiomers of 5-azacytidine analogues : Syntheses and enzymatic properties

Abstract Although 2′-deoxy-β- d -5-azacytidine (Decitabine) and β- d -5-azacytidine display potent antileukemic properties, their therapeutic use is hampered by their sensitivity to nucleophiles and to deamination catalysed by cytidine deaminase. As shown earlier [Shafiee M., Griffon J.-F., Gosselin G., Cambi A., Vincenzetti S., Vita A., Erikson S., Imbach J.-L., Maury G., Biochem. Pharmacol. 56 (1998) 1237–1242], β- l -enantiomers of cytidine derivatives are resistant to cytidine deaminase. We thus synthesized several 5-azacytosine β- l -nucleoside analogues to evaluate their enzymatic and biological properties. 2′-Deoxy-β- l -5-azacytidine ( l -Decitabine), β- l -5-azacytidine, 1-(β- l - xylo -furanosyl)5-azacytosine, and 1-(2-deoxy-β- l - threo -pentofuranosyl)5-azacytosine were stereospecifically prepared starting from l -ribose and l -xylose. d - and l -enantiomers of 2′-deoxy-β-5-azacytidine were weak substrates of human recombinant deoxycytidine kinase (dCK) compared to β- d -deoxycytidine, whereas both enantiomers of β-5-azacytidine or the l - xylo -analogues were not substrates of the enzyme. As expected, none of the presently reported derivatives of β- l -5-azacytidine was a substrate of human recombinant cytidine deaminase (CDA). The prepared compounds were tested for their activity against HIV and HBV and they did not show any significant activity or cytotoxicity. In the case of l -Decitabine, this suggests that the enantioselectivities of concerned enzymes other than dCK and CDA might not be favourable.