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

Although 2'-deoxy-beta -D-5-azacytidine (Decitabine) and beta -D-5-azacytid ine display potent antileukemic properties, their therapeutic use is hamper ed by their sensitivity to nucleophiles and to deamination catalysed by cyt idine deaminase. As shown earlier [Shafiee M., Griffon J.-F., Gosselin G., Cambi A., Vincenzetti S., Vita A., Erikson S., Imbach J.-L., Maury G., Bioc hem. Pharmacol. 56 (1998) 1237-1242], beta -L-enantiomers of cytidine deriv atives are resistant to cytidine deaminase. We thus synthesized several 5-a zacytosine beta -L-nucleoside analogues to evaluate their enzymatic and bio logical properties. 2'-Deoxy-beta -L-5-azacytidine (L-Decitabine), beta -L- 5-azacytidine, 1-(beta -L-xylo-furanosyl)5-azacytosine, and 1-(2-deoxy-beta -L-threo-pentofuranosyl)5-azacytosine were stereospecifically prepared sta rting from L-ribose and L-xylose. D- and L-enantiomers of 2'-deoxy-beta -5- azacytidine were weak substrates of human recombinant deoxycytidine kinase (dCK) compared to beta -D-deoxycytidine, whereas both enantiomers of beta - 5-azacytidine or the L-xylo-analogues were not substrates of the enzyme. As expected, none of the presently reported derivatives of beta -L-5-azacytid ine was a substrate of human recombinant cytidine deaminase (CDA). The prep ared 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-Dec itabine, this suggests that the enantioselectivities of concerned enzymes o ther than dCK and CDA might not be favourable. (C) 2000 Editions scientifiq ues et medicales Elsevier SAS.