A1 Refereed original research article in a scientific journal
Chemical and enzymatic stability of amino acid derived phosphoramidates of antiviral nucleoside 5 '-monophosphates bearing a biodegradable protecting group
Authors: Leisvuori A, Aiba Y, Lönnberg T, Poijärvi-Virta P, Blatt L, Beigelman L, Lönnberg H
Publisher: ROYAL SOC CHEMISTRY
Publication year: 2010
Journal: Organic and Biomolecular Chemistry
Journal name in source: ORGANIC & BIOMOLECULAR CHEMISTRY
Journal acronym: ORG BIOMOL CHEM
Volume: 8
Issue: 9
First page : 2131
Last page: 2141
Number of pages: 11
ISSN: 1477-0520
DOI: https://doi.org/10.1039/b924321f
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.
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.
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