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 |
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Authors: | Marcela Krečmerová Petr Jansa Martin Dračínský Petra Sázelová Václav Kašička Johan Neyts Joeri Auwerx Eleonóra Kiss Nesya Goris George Stepan Zlatko Janeba |
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Affiliation: | 1. Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i. Flemingovo nám. 2, 16610 Prague 6, Czech Republic;2. Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium;3. Okapi Sciences NV, Ambachtenlaan 1, B-3001 Heverlee, Belgium;4. Gilead Sciences, Inc., Foster City, CA 94404, USA |
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Abstract: | 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. |
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