SYNTHESIS, IN-VITRO BIOLOGICAL STABILITY, AND ANTI-HIV ACTIVITY OF 6-HALO-6-ALKOXY(OR AZIDO)-5,6-DIHYDRO-3'-AZIDO-3'-DEOXYTHYMIDINE DIASTEREOMERS AS POTENTIAL PRODRUGS TO 3'-AZIDO-3'-DEOXYTHYMIDINE (AZT)

Citation
R. Kumar et al., SYNTHESIS, IN-VITRO BIOLOGICAL STABILITY, AND ANTI-HIV ACTIVITY OF 6-HALO-6-ALKOXY(OR AZIDO)-5,6-DIHYDRO-3'-AZIDO-3'-DEOXYTHYMIDINE DIASTEREOMERS AS POTENTIAL PRODRUGS TO 3'-AZIDO-3'-DEOXYTHYMIDINE (AZT), Journal of medicinal chemistry, 37(25), 1994, pp. 4297-4306
Citations number
46
Categorie Soggetti
Chemistry Medicinal
ISSN journal
00222623
Volume
37
Issue
25
Year of publication
1994
Pages
4297 - 4306
Database
ISI
SICI code
0022-2623(1994)37:25<4297:SIBSAA>2.0.ZU;2-K
Abstract
A new class of 5-halo-6-alkoxy(or azido)-5,6-dihydro-3'-azido-3'-deoxy thymides was investigated as potential anti-AIDS drugs. These 5,6-dihy dro derivatives, which are also potential prodrugs to 3'-azido-3'-deox ythymidine (AZT), were designed in an effort to enhance the duration o f action, lipophilicity, and cephalic delivery to the central nervous system. The 5-halo-6-alkoxy(or azido)-5,6-dihydro-3'-azido-3'-deoxythy midines, which differ in configuration at the C-5 and C-6 positions, w ere 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 rang e) 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. Regene ration of the 5,6-olefinic bond to give AZT, up on incubation of the 5 -halo-6-methoxy-5,6-dihydro compounds with glutathione, mouse blood, o r mouse liver homogenate, was dependent upon the nature of the 5-halo substituent I > Br). No 5,6-olefinic bond regeneration was observed fo r 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 studi es showed that the C-5 substituent (I, Br, Cl) was a determinant of an ti-HIV-1 activity where the potency order was I greater than or equal to Br > Cl. In the 5-bromo-series of compounds, the C-6 substituent wa s also a determinant of activity where 6-OMe and 6-OEt substituents ex hibited a greater potency than the corresponding 6-i-PrO, 6-(1-octylox y), 6-(1-hexadecyloxy), and 6-azido analogs. All of the 5-chloro-6-sub stituted-5,6-dihydro compounds were inactive, except for the approxima tely equipotent 6-OMe and 6-azido diastereomeric mixtures which were 2 -3 log units less active than the reference drug AZT. The configuratio n at the C-5 and C-6 positions also influenced potency where the activ ity of the 5R,6R-diastereomer was generally greater than that of the c orresponding 5S,6S-diastereomer. The most potent anti-HIV-1 agents, wh ich included the (5R,6R)-5-bromo-6-methoxy, (5R,6R)-5-iodo-6-methoxy, (5S,6S)-5-iodo-6-methoxy, and (5R,6R)-5-bromo-6-ethoxy analogs of AZT, were equipotent to the reference drug AZT. These 5-iodo(bromo)-6-meth oxy-5,6-dihydro derivatives of AZT are potential prodrugs to AZT that provide a rapid release of AZT in vivo.