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.
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 generally more potent than the 5-chloro derivatives of FLT. Compounds having the (5S,6S)-configuration were more potent than the corresponding (5R,6R)-diastereomer. The most potent anti-HIV-1 agents, which included the (5R,6R)-5-Br,6-OMe (4), (5S,6S)-5-Br,6-OMe (5), and (5S,6S)-5-I,6-OMe (10) derivatives of FLT, exhibited comparable activities to the reference drugs AZT and FLT. Although (5R,6R)-5-bromo-6-methoxy-5,6-dihydro-3'-fluoro-3'-deoxythymidine (4) inhibited hepatitis B virus replication at a 5-6-fold higher concentration (EC50) than the reference drug 2',3'-dideoxycytidine (DDC), it was 3-5-fold less cytotoxic (CC50) than DDC.
Kumar
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Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
Wang
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Wiebe
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Knaus
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D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D003588:Cytopathogenic Effect, Viral; D015224:Dideoxynucleosides / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D015497:HIV-1 / Q000187:drug effects; D006515:Hepatitis B virus / Q000187:drug effects; D015394:Molecular Structure; D011355:Prodrugs / Q000138:chemical synthesis*; D013237:Stereoisomerism; D014779:Virus Replication / Q000187:drug effects; D015215:Zidovudine / Q000494:pharmacology
C090028:5-bromo-6-methoxy-5,6-dihydro-3'-fluoro-3'-deoxythymidine; C090029:5-iodo-6-methoxy-5,6-dihydro-3'-fluoro-3'-deoxythymidine; D000998:Antiviral Agents; D015224:Dideoxynucleosides; D011355:Prodrugs; D015215:Zidovudine; C002854:alovudine