title: 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.
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 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.
authors: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i. Flemingovo nám. 2, 16610 Prague 6, Czech Republic. marcela@uochb.cas.cz
authors: Marcela
authors: M
authors: Krečmerová
authors: Petr
authors: P
authors: Jansa
authors: Martin
authors: M
authors: Dračínský
authors: Petra
authors: P
authors: Sázelová
authors: Václav
authors: V
authors: Kašička
authors: Johan
authors: J
authors: Neyts
authors: Joeri
authors: J
authors: Auwerx
authors: Eleonóra
authors: E
authors: Kiss
authors: Nesya
authors: N
authors: Goris
authors: George
authors: G
authors: Stepan
authors: Zlatko
authors: Z
authors: Janeba
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects; D016089:Immunodeficiency Virus, Feline / Q000187:drug effects; D009943:Organophosphorus Compounds / Q000737:chemistry* / Q000494:pharmacology; D011355:Prodrugs / Q000737:chemistry* / Q000494:pharmacology; D013237:Stereoisomerism
chemical_list: C090125:9-(2-phosphonylmethoxypropyl)-2,6-diaminopurine; D000998:Antiviral Agents; D009943:Organophosphorus Compounds; D011355:Prodrugs; D000225:Adenine
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