Deoxycytidine triphosphate deamination

P-D-Arabinofuranosylcytosine [147-94-4] (ara-C, 16), C H N O, reportedly has had significant therapeutic effects in patients with localized herpes zoster, herpes eye infections, and herpes encephaUtis (33), although several negative results have also been reported (34) (Fig. 2). Ara-C, also known as cytarabine, is quite toxic and is only recommended for very severe viral infections. It is rapidly deaminated in humans to the relatively inactive ara-U Ara-C is converted in the cell to the 5 -monophosphate by deoxycytidine kinase, followed by formation of the corresponding di- and triphosphate. The triphosphate has been shown to inhibit DNA polymerase. 

Sources of deoxyuridine in DNA include the presence of dUTP because dUMP (the substrate for thymidylate synthase) or dUDP (from ribonucleotide reductase action on UDP) are phosphorylated to the triphosphate. DNA polymerase recognizes these compounds as substrates. Another source is the deamination of deoxycytidine in DNA, promoted by a variety of compounds. If deoxyuridine is on a template strand of the DNA, it will direct the incorporation of an A in the newly made strand of DNA. This will convert a G-C pair to an A-T pair. 

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... 

Fludarabine phosphate, a fluorinated deamination-resistant nucleotide analog of the antiviral agent vidarabine (9-P-D-arabinofuranosyl-adenine), is active in CLL and low-grade lymphomas. After rapid extracellular dephosphorylation to the nucleoside fludarabine, it is rephosphorylated intracellularly by deoxycytidine kinase to the active triphosphate derivative. This antimetabolite inhibits DNA polymerase, DNA primase DNA ligase, and ribonucleotide reductase, and is incorporated into DNA and RNA. The triphosphate nucleotide is an effective chain terminator when incorporated into DNA, and the incorporation of fludarabine into RNA inhibits RNA function, RNA processing, and mRNA translation. 

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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