title: Chemical and enzymatic stability of amino acid derived phosphoramidates of antiviral nucleoside 5'-monophosphates bearing a biodegradable protecting group.
abstract: Ribavirin and 2'-O-methylcytidine 5'-phosphoramidates derived from L-alanine methyl ester bearing either an O-phenyl or a biodegradable O-[3-(acetyloxy)-2,2-bis(ethoxycarbonyl)propyl] or O-[3-(acetyloxymethoxy)-2,2-bis(ethoxycarbonyl)propyl] protecting group were prepared. The kinetics of the deprotection of these pro-drugs by porcine liver esterase and by a whole cell extract of human prostate carcinoma was studied by HPLC-ESI-MS/MS. The 3-(acetyloxymethoxy)-2,2-bis(ethoxycarbonyl)propyl and 3-(acetyloxy)-2,2-bis(ethoxycarbonyl)propyl groups were readily removed releasing the l-alanine methyl ester phosphoramidate nucleotide, the deprotection of the 3-(acetyloxymethoxy) derivative being approximately 20 times faster. The chemical stability of the 2'-O-methylcytidine pro-drugs was additionally determined over a pH range from 7.5 to 10.
authors.affiliation: Department of Chemistry, University of Turku, FIN-20014 Turku, Finland.
authors.forename: Anna
authors.initials: A
authors.lastname: Leisvuori
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Aiba
authors.forename: Tuomas
authors.initials: T
authors.lastname: Lönnberg
authors.forename: Päivi
authors.initials: P
authors.lastname: Poijärvi-Virta
authors.forename: Laurence
authors.initials: L
authors.lastname: Blatt
authors.forename: Leo
authors.initials: L
authors.lastname: Beigelman
authors.forename: Harri
authors.initials: H
authors.lastname: Lönnberg
mesh_terms: D000085:Acetates / Q000737:chemistry*; D000409:Alanine / Q000737:chemistry*; D000577:Amides / Q000737:chemistry*; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry*; D003568:Cytidine Monophosphate / Q000138:chemical synthesis / Q000737:chemistry*; D004795:Enzyme Stability; D004950:Esterases / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D008297:Male; D008314:Malonates / Q000737:chemistry*; D015394:Molecular Structure; D010756:Phosphoric Acids / Q000737:chemistry*; D011471:Prostatic Neoplasms / Q000201:enzymology*; D012254:Ribavirin / Q000737:chemistry*; D013552:Swine; D013997:Time Factors
chemical_list: D000085:Acetates; D000577:Amides; D000998:Antiviral Agents; D008314:Malonates; D010756:Phosphoric Acids; D012254:Ribavirin; C011067:phosphoramidic acid; D004950:Esterases; D003568:Cytidine Monophosphate; D000409:Alanine