Synthesis,In VitroBiological Stability, and Anti-HIV Activity of 5-Halo (or Methoxy)-6-Alkoxy (Azido or Hydroxy)-5,6-Dihydro-2′,3′-Didehydro-3′-Deoxythymidine Diastereomers as Potential Prodrugs of 2′,3′-Didehydro-3′-deoxythymidine (D4T)

Abstract

Abstract A new class of 5-halo (or methoxy)-6-alkoxy (azido or hydroxy)-5,6-dihydro-2′,3′-didehydro-3′-deoxythymidines (4–17) were investigated as potential anti-AIDS drugs. These 5,6-dihydro derivatives, which are also potential prodmgs of 2′,3′-didehydro-3′-deoxythymidine (D4T) were designed to have properties which would enhance their duration of action, lipophilicity and cephalic delivery to the central nervous system. The 5,6-dihydro derivatives of D4T (4–15), which differ in configuration at the C-5 and C-6 positions, were synthesized by the regiospecific addition of XR (X = Br, Cl, I; R = OMe, OEt, N3, OH) to the 5,6-olefinic bond of D4T. These 5,6-disubstituted-5,6-dihydro analogs of D4T are more lipophilic (P = 0.70 – 4.0 range) than D4T (P = 0.12) and are stable to E. coli thymidine phosphorylase. Regeneration of the 5,6-olefinic bond to give D4T, upon incubation of the 5-bromo- and 5-iodo-6-methoxy-5,6-dihydro derivatives (6, 7, 10, 11) with glutathione or a mouse liver soluble enzyme fraction,...