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′...