Deoxycytidine triphosphate deaminase

The 2 -azido group of cytarazid renders the nucleoside more resistant to deamination to the 2 -azidouridine derivative (153) by deoxycytidine deaminase, but was also observed to reduce substrate affinity for the deoxycytidine kinase necessary for anabolic phosphorylation to the active cytarazid 5 -triphosphate [180]. Conversely, cytarazid was a more potent inhibitor of the target DNA polymerases a and K = 0.6 and 0.7 //M, respectively) than the parent ara-C (.A = 10 and 17 fiM, respectively), and the dissimilar spectrum of antitumour activity exhibited by the two compounds was attributed to differences in stability, metabolic activation and inhibitory potency [180, 181]. Interestingly, the instability of cytarazid to thiols present in the assay media, was commented on but not pursued [180]. In view of previous discussions concerning the bioreduction of AZT... 

Replacement of the uracil moiety of the 3 -azido nucleoside analogue 1 with the cytosine to form 7 did not affect its antiviral activity however, when the substituent on carbon-5 of the cytosine moiety was either fluoro 8 or methyl 9, the antiviral activity was markedly reduced. This could be explained if these 3 -azido-2, 3 -dideoxycytidine analogues were required to be deaminated by deoxycytidine deaminase for which the 5-methyl or 5-fluoro analogues are not substrates. Other possibilities include differences in metabolic conversion to the di- and triphosphates analogues, as well as the relative affinities of the triphosphate analogues for the reverse transcriptase. 

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