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Predicate | Object |
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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
25
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pubmed:dateCreated |
1995-1-13
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pubmed:abstractText |
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)
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pubmed:language |
eng
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pubmed:journal | |
pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Antiviral Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Bromides,
http://linkedlifedata.com/resource/pubmed/chemical/Chlorides,
http://linkedlifedata.com/resource/pubmed/chemical/Cysteine,
http://linkedlifedata.com/resource/pubmed/chemical/Glutathione,
http://linkedlifedata.com/resource/pubmed/chemical/Iodides,
http://linkedlifedata.com/resource/pubmed/chemical/Prodrugs,
http://linkedlifedata.com/resource/pubmed/chemical/Zidovudine
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pubmed:status |
MEDLINE
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pubmed:month |
Dec
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pubmed:issn |
0022-2623
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pubmed:author | |
pubmed:issnType |
Print
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pubmed:day |
9
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pubmed:volume |
37
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
4297-306
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pubmed:dateRevised |
2006-11-15
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pubmed:meshHeading |
pubmed-meshheading:7996541-Animals,
pubmed-meshheading:7996541-Antiviral Agents,
pubmed-meshheading:7996541-Blood-Brain Barrier,
pubmed-meshheading:7996541-Brain,
pubmed-meshheading:7996541-Bromides,
pubmed-meshheading:7996541-Chlorides,
pubmed-meshheading:7996541-Cysteine,
pubmed-meshheading:7996541-Glutathione,
pubmed-meshheading:7996541-HIV-1,
pubmed-meshheading:7996541-Iodides,
pubmed-meshheading:7996541-Mice,
pubmed-meshheading:7996541-Molecular Structure,
pubmed-meshheading:7996541-Prodrugs,
pubmed-meshheading:7996541-Rats,
pubmed-meshheading:7996541-Stereoisomerism,
pubmed-meshheading:7996541-Structure-Activity Relationship,
pubmed-meshheading:7996541-Zidovudine
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pubmed:year |
1994
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pubmed:articleTitle |
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).
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pubmed:affiliation |
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
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pubmed:publicationType |
Journal Article,
Comparative Study,
Research Support, Non-U.S. Gov't
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