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9-[2-(R)-(Phosphonomethoxy)propyl]-2,6-diaminopurine (R)-PMPDAP and its prodrugs: optimized preparation, including identification of by-products formed, and antiviral evaluation in vitro
M. Krečmerová, P. Jansa, M. Dračínský, P. Sázelová, V. Kašička, J. Neyts, J. Auwerx, E. Kiss, N. Goris, G. Stepan, Z. Janeba,
Language English Country England, Great Britain
Document type Journal Article, Research Support, Non-U.S. Gov't
- MeSH
- Adenine analogs & derivatives chemistry pharmacology MeSH
- Antiviral Agents chemistry pharmacology MeSH
- HIV-1 drug effects MeSH
- Organophosphorus Compounds chemistry pharmacology MeSH
- Prodrugs chemistry pharmacology MeSH
- Stereoisomerism MeSH
- Immunodeficiency Virus, Feline drug effects MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
New large-scale synthetic approach to antiretroviral agent 9-[2-(R)-(phosphonomethoxy)propyl]-2,6-diaminopurine, (R)-PMPDAP, was developed. Reaction of (R)-propanediol carbonate with 2,6-diaminopurine afforded exclusively (R)-9-(2-hydroxypropyl)-2,6-diaminopurine which was subsequently used for introduction of a phosphonomethyl residue using TsOCH(2)P(O)(OiPr)(2) or BrCH(2)P(O)(OiPr)(2) followed by deprotection of ester groups. All minor ingredients and by-products formed during the process were identified and further studied. The final product was obtained in high yield and its high enantiomeric purity (>99%) was confirmed by chiral capillary electrophoretic analysis using β-cyclodextrin as a chiral selector. Antiretroviral activity data of (R)-PMPDAP and its diverse prodrugs against HIV and FIV were investigated. Akin to (R)-PMPDAP, both prodrugs inhibit FIV replication in a selective manner. Compared to the parent molecule, the amidate prodrug was 10-fold less active against FIV in cell culture, whereas the alkoxyalkyl ester prodrug was 200-fold more potent in inhibiting FIV replication in vitro.
References provided by Crossref.org
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