PMID: 7932583Oct 14, 1994Paper

Synthesis and antiviral (HIV-1, HBV) activities of 5-halo-6-methoxy(or azido)-5,6-dihydro-3'-fluoro-3'-deoxythymidine diastereomers. Potential prodrugs to 3'-fluoro-3'-deoxythymidine

Journal of Medicinal Chemistry
R KumarE E Knaus

Abstract

A new class of 5-halo-6-methoxy(or azido)-5,6-dihydro-3'-fluoro-3'- deoxythymidines (4-13) were investigated as potential anti-AIDS drugs. These 5,6-dihydro derivatives, which are also potential prodrugs to 3'-fluoro-3'-deoxythymidine (FLT), were designed to have properties which would enhance their duration of action, lipophilicity, and cephalic delivery to the central nervous system. The 5-halo-6-methoxy(or azido)-5,6-dihydro-3'-fluoro-3'-deoxythymidines, 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, N3) to the 5,6-olefinic bond of FLT. These 5-halo-6-methoxy-5,6-dihydro derivatives are more lipophilic (P = 1.5-5.15 range) than the parent compound FLT (P = 0.5). Regeneration of the 5,6-olefinic bond to give FLT, upon incubation of the 5-halo-6-methoxy-5,6-dihydro compounds with glutathione, was dependent on the nature of the 5-halo substituent (I > Br > Cl). The ability of these 5-halo-6-methoxy(or azido)-5,6- dihydro compounds (4-13) to protect CEM cells against HIV-induced cytopathogenicity was evaluated. The C-5 halo substituent was a determinant of anti-HIV-1 activity where the approximately equipotent 5-iodo and 5-bromo were gener...Continue Reading

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