3 -Azido-3 -deoxythymidine, conversion

A similar approach started with (45)-(2 )-5-acetoxy-4-formyloxy-2-pentenal (11) or the de-formylated (4S)-(2 )-5-acetoxy-4-hydroxy-2-pentenal (12), which were prepared from tri-O-acetyl-D-glucal55. Both aldehydes added hydrazoic acid to afford, after acidic cyclization and alkylation, an almost 1 1 mixture of the 3-azido-2,3-dideoxypentoses 13 in 79% total yield from 12 and 31 % total yield from 11. The structures of the products are confirmed by their NMR spectra and by further conversion to 3 -azido-3 -deoxythymidine (AZT) and its stereoisomers, the absolute configurations of which are known. 

However, equivalent potency of enzyme inhibition has been reported for the triphosphates of 3 -deoxythymidine and 3 -amino-3 -deoxythymidine despite the weak antiviral activity of the parent nucleosides (163) and (90) in vitro, both of which are poor substrates for phosphorylation [213, 214]. These observations suggest that the antiviral aetivity of 2, 3 -dideoxynucleo-sides may depend less on the relative inhibitory activities of the triphosphates against isolated RT, but rather reflects the affinity of the parent nucleosides for the cellular kinase enzymes effecting triphosphorylation. Nevertheless, other studies of RT inhibition by nucleoside triphosphates have demonstrated a defined SAR for modifications at the 3 -position [215], and it is likely that the azido substituent of AZT contributes both to the requisite substrate activity for the cellular phosphorylating enzymes, and the specificity of RT inhibition following conversion to the triphosphate. 

Azathymidine, 3 -azido-3 -deoxythymidine (AZT), after conversion to the corresponding 5 -triphosphate, inhibits viral reverse transcriptase. Hence, AZT is used in the treatment of AIDS (Chapter 25). 

Nucleoside analogues are widely used as antiviral agents in the treatment in AIDS and AIDS-related complex. The only clinical agent approved in the United States for the treatment of AIDS is 3 -azido-3 -deoxythymidine (AZT) [54,55]. The molecular mechanism of action for this nucleoside includes conversion into its corresponding 5 -monophosphate by the action of cellular nucleoside kinase, followed by stepwise phosphorylation catalyzed by cellular nucleoside kinase to the corresponding 5 -triphosphate. These inhibit proviral DNA synthesis [55-57], catalyzed by HIV reverse transcriptase (RT), and incorporation to the 3 end of the growing DNA chain [55,58]. 

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