Source:http://linkedlifedata.com/resource/pubmed/id/12852759
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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
15
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pubmed:dateCreated |
2003-7-10
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pubmed:abstractText |
The synthesis and biological evaluation of a bicyclo[3.1.0]hexene nucleoside designed as a conformational mimic of the anti-HIV agent stavudine (1, D4T) is described. The unsaturated methanocarbocyclic pseudosugar of N-MCD4T (2) was constructed from an iodo-substituted precursor by a DBU-catalyzed olefination reaction. Mitsunobu coupling with N(3)-benzoylthymine afforded the desired target after deprotection. Both D4T and N-MCD4T are in the North (N) hemisphere of the pseudorotational cycle but 70 degrees away from a perfect N (P = 0 degrees ) conformation toward the East and West hemispheres, respectively. Despite this large difference, the double bond reduces the puckering amplitude (nu(max)) of N-MCD4T to 6.81 degrees, and the superposition of both structures showed a RMS deviation of only 0.039 A. The combined structural analysis of P and nu(max) shows that while the value of P may differ substantially, the low nu(max) resolves the differences and becomes the dominant pseudorotational parameter. N-MCD4T is active against HIV-1 and HIV-2 in CEM, MT-2, and MT-4 cells, and while it is somewhat less potent than D4T, it also appears to be less toxic. The triphosphate (N-MCD4TTP) inhibits HIV reverse transcriptase with a 10-fold higher IC(50) than D4TTP. By virtue of its carbocyclic nature, N-MCD4T (2) is a more robust molecule stable to conditions that would cleave D4T.
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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/Anti-HIV Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Bicyclo Compounds,
http://linkedlifedata.com/resource/pubmed/chemical/HIV Reverse Transcriptase,
http://linkedlifedata.com/resource/pubmed/chemical/Reverse Transcriptase Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Stavudine,
http://linkedlifedata.com/resource/pubmed/chemical/Thymidine
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pubmed:status |
MEDLINE
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pubmed:month |
Jul
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pubmed:issn |
0022-2623
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pubmed:author |
pubmed-author:BalzariniJanJ,
pubmed-author:BarchiJoseph JJJJr,
pubmed-author:BoyerPaul LPL,
pubmed-author:ChoiYongseokY,
pubmed-author:CominMaria JMJ,
pubmed-author:GeorgeCliffordC,
pubmed-author:HughesStephen HSH,
pubmed-author:JacobsonKenneth AKA,
pubmed-author:KimHak SungHS,
pubmed-author:MarquezVictor EVE,
pubmed-author:MitsuyaHiroakiH
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pubmed:issnType |
Print
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pubmed:day |
17
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pubmed:volume |
46
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
3292-9
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pubmed:dateRevised |
2007-11-15
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pubmed:meshHeading |
pubmed-meshheading:12852759-Animals,
pubmed-meshheading:12852759-Anti-HIV Agents,
pubmed-meshheading:12852759-Bicyclo Compounds,
pubmed-meshheading:12852759-Cell Line,
pubmed-meshheading:12852759-Crystallography, X-Ray,
pubmed-meshheading:12852759-HIV Reverse Transcriptase,
pubmed-meshheading:12852759-HIV-1,
pubmed-meshheading:12852759-HIV-2,
pubmed-meshheading:12852759-Humans,
pubmed-meshheading:12852759-Lymphocytes,
pubmed-meshheading:12852759-Molecular Conformation,
pubmed-meshheading:12852759-Molecular Mimicry,
pubmed-meshheading:12852759-Reverse Transcriptase Inhibitors,
pubmed-meshheading:12852759-Stavudine,
pubmed-meshheading:12852759-Stereoisomerism,
pubmed-meshheading:12852759-Structure-Activity Relationship,
pubmed-meshheading:12852759-Thymidine
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pubmed:year |
2003
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pubmed:articleTitle |
A conformationally locked analogue of the anti-HIV agent stavudine. An important correlation between pseudorotation and maximum amplitude.
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pubmed:affiliation |
Laboratory of Medicinal Chemistry, Center for Cancer Research, National Cancer Institute-Frederick, National Institutes of Health, Frederick, Maryland 21702, USA.
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pubmed:publicationType |
Journal Article
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