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

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 intr...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2013-03, Vol.21 (5), p.1199-1208
Main Authors: Krečmerová, Marcela, Jansa, Petr, Dračínský, Martin, Sázelová, Petra, Kašička, Václav, Neyts, Johan, Auwerx, Joeri, Kiss, Eleonóra, Goris, Nesya, Stepan, George, Janeba, Zlatko
Format: Article
Language:English
Subjects:
(Phosphonomethoxy)propyl
Acyclic nucleoside phosphonates
Adenine - analogs & derivatives
Adenine - chemistry
Adenine - pharmacology
antiretroviral agents
Antiviral agents
Antiviral Agents - chemistry
Antiviral Agents - pharmacology
Antivirals
beta-cyclodextrin
byproducts
capillary electrophoresis
carbonates
Cell culture
Data processing
Esters
Feline immunodeficiency virus
HIV
HIV-1 - drug effects
Human immunodeficiency virus
Immunodeficiency Virus, Feline - drug effects
in vitro studies
ingredients
Organophosphorus Compounds - chemistry
Organophosphorus Compounds - pharmacology
PMPDAP
Prodrugs
Prodrugs - chemistry
Prodrugs - pharmacology
Purine
Replication
Stereoisomerism
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Summary: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 TsOCH2P(O)(OiPr)2 or BrCH2P(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.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2012.12.044