Myristoylated Derivatives of 2′,3′-didehydro-2′,3′-dideoxythymidine (stavudine) bi-Functional Prodrugs with Potent Anti-HIV-1 Activity and Low Cytotoxicity

Background: To improve in vitro antiviral activity and selectivity of stavudine (d4T), a range of its bi-functional prodrugs, 5′- O-myristoylated derivatives, have been synthesized. Methods: Stavudine 5′- O-myristoylated esters were synthesized using modified Parang's procedure. The cytotoxicity and anti-HIV activity was evaluated in the established MT-4 cell line. The level of p24 protein in culture medium was assayed, and EC50 and EC90 values were determined. Results: Excellent anti-HIV activity was obtained for stavudine derivatives 2′,3′-didehydro-2′,3′-dideoxy-5′- O-(11-thioethylundecanoyl) thymidine, 2′,3′-didehydro-2′,3′-dideoxy-5′- O-(12-thioethyldodecanoyl) thymidine and 5′- O-(12-azidododecanoyl)-2′,3′-didehydro-2′,3′-dideoxythymidine with C10 and C11 alkyl chains bearing thioethyl- and azido- substituents. These prodrugs were more potent than the parent stavudine, as is clear from their EC50 values: 2′,3′-didehydro-2′,3′-dideoxy-5′- O-(11-thioethylundecanoyl) thymidine (R=CO(CH2)10SC2H5, EC50 0.06 μM), 2′,3′-didehydro-2′,3′-dideoxy-5′- O-(12-thioethyldodecanoyl) thymidine (R=CO(CH2)11SC2H5, EC50 0.09 μM) and 5′- O-(12-azidododecanoyl)-2′,3′-didehydro-2′,3′-dideoxythymidine (R=CO(CH2)11N3, EC50 0.06 μM), while 50% cytotoxic concentration was >16.65 μM, >7.5 μM and >18.53 μM, respectively. Conclusions: Overall data demonstrate that compounds 2′,3′-didehydro-2′,3′-dideoxy-5′- O-(11-thioethylundecanoyl) thymidine, 2′,3′-didehydro-2′,3′-dideoxy-5′- O-(12-thioethyldodecanoyl) thymidine and 5′- O-(12-azidododecanoyl)-2′,3′-didehydro-2′,3′-dideoxythymidine are very potent and selective anti-HIV agents and could be useful in treatment of HIV infections of the central nervous system.