4 -Cyano-3 -deoxythymidine

Another contrast with the 2, 3 -dideoxynucleoside family of HIV inhibitors is elucidated by the data in Table 3. Potent activity among the 4 -derivatives is maintained even when a nonpolar substituent (e.g., methyl) is present. While in the case of 2, 3 -dideoxynucleosides, in order to maintain activity, the 3 a position must be hydrogen or certain electronegative groups like azido, fiuoro, or thiol. For example, 3 -deoxy-3 -methylthymidine and 3 -(propyl-2-ene)-2, 3 -dideoxyuridine are known to be inactive against HIV. Furthermore, while 3 -cyano-3 -deoxythymidine is inactive, 4 -cyano-thymidine is among the most potent nucleoside inhibitors known. Thus, the activity elicited by a substituent at the 3 -position of thymidine is not at all predictive of the activity to be expected when the same substituent resides at the 4 -position. 

AIDS Acquired immune deficiency syndrome CNT 3 -C-cyano-3 -deoxythymidine HIV Human immunodeficiency virus... 

Fig. 8. Synthesis of 3 -C-Cyano-3 -deoxythymidine derivatives by glycosylation reactions...

A number of 4 -substituted thymidine nucleosides recently have been synthesized and show unexpected potency. The 4 -azido and 4 -azidomethyl analogs were both potent and selective, however insufficient data was provided in the preliminary publications to fully assess the selectivity of the other analogs. The azido function was not an essentid requirement for activity by this series of compounds since 4 -methyl and 4 -hydroxymethyl analogs also showed activity. It is interesting to note that 4 -cyanothymidine was quite active whereas 4 -cyano-3 -deoxythymidine was not. 

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