Synthesis, in vitro biological stability, and anti-HIV activity of 5-halo-6-alkoxy(or azido)-5,6-dihydro-3'-azido-3'-deoxythymidine diastereomers as potential prodrugs to 3'-azido-3'-deoxythymidine (AZT).
A new class of 5-halo-6-alkoxy(or azido)-5,6-dihydro-3'-azido-3'-deoxythymidines was investigated as potential anti-AIDS drugs. These 5,6-dihydro derivatives, which are also potential prodrugs to 3'-azido-3'-deoxythymidine (AZT), were designed in an effort to enhance the duration of action, lipophilicity, and cephalic delivery to the central nervous system. The 5-halo-6-alkoxy(or azido)-5,6-dihydro-3'-azido-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 = alkoxy, azido) to the 5,6-olefinic bond of AZT. The 5-halo-6-methoxy-5,6-dihydro derivatives of AZT are more lipophilic (P = 3.3-18.8 range) than the parent compound AZT (P = 1.29). These 5-halo-6-methoxy-5,6-dihydro compounds, like AZT, did not undergo glycosidic bond cleavage upon incubation with Escherichia coli thymidine phosphorylase. Regeneration of the 5,6-olefinic bond to give AZT, upon incubation of the 5-halo-6-methoxy-5,6-dihydro compounds with glutathione, mouse blood, or mouse liver homogenate, was dependent upon the nature of the 5-halo substituent (I > Br). No 5,6-olefinic bond regeneration was observed for the 5-chloro analogs. The ability of these 5-halo-6-alkoxy (or azido)-5,6-dihydro-3'-azido-3'-deoxythymidines to protect CEM cells against HIV-induced cytopathogenicity was evaluated. Structure-activity studies showed that the C-5 substituent (I, Br, Cl) was a determinant of anti-HIV-1 activity where the potency order was I > or = Br > Cl. In the 5-bromo series of compounds, the C-6 substituent was also a determinant of activity where 6-OMe and 6-OEt substituents exhibited a greater potency than the corresponding 6-i-PrO, 6-(1-octyloxy), 6-(1-hexadecyloxy), and 6-azido analogs. All of the 5-chloro-6-substituted-5,6-dihydro compounds were inactive, except for the approximately equipotent 6-OMe and 6-azido diastereomeric mixtures which were 2-3 log units less active than the reference drug AZT. The configuration at the C-5 and C-6 positions also influenced potency where the activity of the 5R,6R-diastereomer was generally greater than that of the corresponding 5S,6S-diastereomer.(ABSTRACT TRUNCATED AT 400 WORDS)
Kumar
R
R
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
Wang
L
L
Wiebe
L I
LI
Knaus
E E
EE
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism; D001965:Bromides; D002712:Chlorides; D003545:Cysteine / Q000737:chemistry; D005978:Glutathione / Q000737:chemistry; D015497:HIV-1 / Q000187:drug effects*; D007454:Iodides; D051379:Mice; D015394:Molecular Structure; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D015215:Zidovudine / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*
D000998:Antiviral Agents; D001965:Bromides; D002712:Chlorides; D007454:Iodides; D011355:Prodrugs; D015215:Zidovudine; D005978:Glutathione; D003545:Cysteine