2 ,5 -Phosphodiester antiviral activity

Mode of action AZT must be converted to the corresponding nucleoside triphosphate by mammalian thymidine kinase in order for it to exert its antiviral activity. AZT-triphosphate is then incorporated into the growing chain of viral (but not mammalian nuclear) DNA by reverse transcriptase1. Because AZT lacks a hydroxyl at the 3 position, another 5 -3 phosphodiester linkage cannot be formed. Thus, synthesis of the DNA chain is terminated, and replication of the virus cannot take place. The relative lack of discrimination of the viral reverse transcriptase is believed to favor the introduction of the AZT into the viral-catalyzed process the cellular DNA polymerase is more selective. In addition, the phosphory-... 

A structure-related disadvantage of the duplex drugs is that upon enzymatic cleavage of the phosphodiester bonds, a 1-to-l ratio of nucleoside to nucleotide is obtained (see Figure 7.7-6). Thus, the desired 5 -phosphorylated nucleotide is only formed at maximally 50%. Additionally, one of the two nucleosides has to be transformed into a lipophilic derivative without loss of antitumor or antiviral activity. On the other hand, it was shown that the lipophilic derivatization of nucleosides can result in enhanced activity and modulation of cell specificity [106]. 

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