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: Anna Leisvuori, Yuichiro Aiba, Tuomas Lönnberg, Päivi Poijärvi-Virta, Laurence Blatt, Leo Beigelman, Harri Lönnberg
• Journal: Organic & biomolecular chemistry (Org Biomol Chem) Vol. 8 Issue 9 Pg. 2131-41 (May 07 2010) ISSN: 1477-0539 [Electronic] England
• PMID: 20401390 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Acetates
• Amides
• Antiviral Agents
• Malonates
• Phosphoric Acids
• Ribavirin
• phosphoramidic acid
• Esterases
• Cytidine Monophosphate
• Alanine

Topics

• Acetates (chemistry)
• Alanine (chemistry)
• Amides (chemistry)
• Animals
• Antiviral Agents (chemical synthesis, chemistry)
• Cytidine Monophosphate (chemical synthesis, chemistry)
• Enzyme Stability
• Esterases (chemistry, metabolism)
• Humans
• Kinetics
• Liver (enzymology)
• Male
• Malonates (chemistry)
• Molecular Structure
• Phosphoric Acids (chemistry)
• Prostatic Neoplasms (enzymology)
• Ribavirin (chemistry)
• Swine
• Time Factors