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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
9
|
| pubmed:dateCreated |
1998-5-21
|
| pubmed:abstractText |
The synthesis, hydrolysis, and antiviral evaluation of novel, lipophilic cycloSal-d4TMP derivatives 3a-h of the anti-HIV dideoxynucleoside 2',3'-dideoxy-2',3'-didehydrothymidine (d4T, 1) are reported. This pro-nucleotide concept has been designed to deliver d4TMP (2) by selective chemical hydrolysis. All compounds 3a-h were synthesized using phosphorus(III) chemistry in good yields and in somewhat lower yields using phosphorus(V) chemistry starting from substituted salicyl alcohols 6a-h. The phosphotriesters 3 were obtained without stereochemical preference with respect to the configuration at the phosphorus center as 1:1 diastereomeric mixtures. However, a few of the triesters 3 could be separated into the diastereomers by means of semipreparative HPLC. In a 1-octanol/phosphate buffer mixture, all compounds 3 exhibited 9-100-fold higher lipophilicity as judged from their Pa values as compared to d4T (1). Furthermore, in hydrolysis studies 3 decomposed under mild aqueous basic conditions releasing solely d4TMP (2) and the diols 6 following the designed tandem reaction sequence. A correlation of the electronic properties introduced by the substituents and the half-lives of triesters 3 was observed. Thus, by varying the substituent, the half-lives of 3 could be adjusted over a wide range of compounds still delivering d4TMP (2) selectively. Phosphotriesters 3 exhibited considerable activity against HIV-1 and HIV-2 in wild-type human T-lymphocyte (CEM/O) cells as well as mutant thymidine kinase-deficient (CEM/TK-) cells. Surprisingly, we observed a 3-80-fold difference in antiviral activity between the two diastereomers. Our data clearly prove that the cycloSal-d4TMPs deliver exclusively the nucleotide d4TMP not only under simulated hydrolysis conditions but also under cellular conditions and thus fulfill the thymidine kinase-bypass premise. Therefore, the cycloSal-nucleotide concept is the first reported pro-nucleotide system that delivers the dideoxynucleotide by a pH-driven, chemically activated, tandem reaction without the requirement of an enzymatic contribution.
|
| pubmed:language |
eng
|
| pubmed:journal | |
| pubmed:citationSubset |
IM
|
| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Anti-HIV Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Buffers,
http://linkedlifedata.com/resource/pubmed/chemical/Octanols,
http://linkedlifedata.com/resource/pubmed/chemical/Phosphoric Acid Esters,
http://linkedlifedata.com/resource/pubmed/chemical/Prodrugs,
http://linkedlifedata.com/resource/pubmed/chemical/Stavudine,
http://linkedlifedata.com/resource/pubmed/chemical/Thymidine Kinase,
http://linkedlifedata.com/resource/pubmed/chemical/Thymidine Monophosphate
|
| pubmed:status |
MEDLINE
|
| pubmed:month |
Apr
|
| pubmed:issn |
0022-2623
|
| pubmed:author | |
| pubmed:issnType |
Print
|
| pubmed:day |
23
|
| pubmed:volume |
41
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
1417-27
|
| pubmed:dateRevised |
2006-11-15
|
| pubmed:meshHeading |
pubmed-meshheading:9554875-Animals,
pubmed-meshheading:9554875-Anti-HIV Agents,
pubmed-meshheading:9554875-Buffers,
pubmed-meshheading:9554875-Cattle,
pubmed-meshheading:9554875-Chromatography, High Pressure Liquid,
pubmed-meshheading:9554875-Drug Delivery Systems,
pubmed-meshheading:9554875-HIV-1,
pubmed-meshheading:9554875-HIV-2,
pubmed-meshheading:9554875-Humans,
pubmed-meshheading:9554875-Hydrogen-Ion Concentration,
pubmed-meshheading:9554875-Hydrolysis,
pubmed-meshheading:9554875-Mutation,
pubmed-meshheading:9554875-Octanols,
pubmed-meshheading:9554875-Phosphoric Acid Esters,
pubmed-meshheading:9554875-Prodrugs,
pubmed-meshheading:9554875-Solubility,
pubmed-meshheading:9554875-Stavudine,
pubmed-meshheading:9554875-Stereoisomerism,
pubmed-meshheading:9554875-Structure-Activity Relationship,
pubmed-meshheading:9554875-T-Lymphocytes,
pubmed-meshheading:9554875-Thymidine Kinase,
pubmed-meshheading:9554875-Thymidine Monophosphate,
pubmed-meshheading:9554875-Tumor Cells, Cultured
|
| pubmed:year |
1998
|
| pubmed:articleTitle |
cycloSal-2',3'-dideoxy-2',3'-didehydrothymidine monophosphate (cycloSal-d4TMP): synthesis and antiviral evaluation of a new d4TMP delivery system.
|
| pubmed:affiliation |
Institute of Organic Chemistry, Julius-Maximilians-University of Würzburg, Am Hubland, D-97074 Würzburg, Germany.
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| pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
|