Unnatural enantiomers of 5-azacytidine analogues: syntheses and enzymatic properties.
Although 2'-deoxy-beta-D-5-azacytidine (Decitabine) and beta-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], beta-L-enantiomers of cytidine derivatives are resistant to cytidine deaminase. We thus synthesized several 5-azacytosine beta-L-nucleoside analogues to evaluate their enzymatic and biological 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 starting 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-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.
Gaubert
G
G
UMR 5625 du CNRS, Département de Chimie, Université Montpellier II, Place Bataillon, 34095 5, Montpellier Cedex, France.
Mathé
C
C
Imbach
J
J
Eriksson
S
S
Vincenzetti
S
S
Salvatori
D
D
Vita
A
A
Maury
G
G
D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001374:Azacitidine / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D003842:Deoxycytidine Kinase / Q000378:metabolism; D006518:Hepatitis Viruses / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D013057:Spectrum Analysis; D013237:Stereoisomerism
D000998:Antiviral Agents; D003842:Deoxycytidine Kinase; D001374:Azacitidine