Journal
PHARMACEUTICAL RESEARCH
Volume 20, Issue 9, Pages 1381-1388Publisher
SPRINGER/PLENUM PUBLISHERS
DOI: 10.1023/A:1025745824632
Keywords
floxuridine; prodrug; hydrolysis; stability; amino acid; Caco-2
Funding
- NIGMS NIH HHS [1R01GM 37188] Funding Source: Medline
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Purpose. To synthesize amino acid ester prodrugs of floxuridine ( FUdR) and to investigate the effects of structure, stereochemistry, and site of esterification of promoiety on the rates of hydrolysis of these prodrugs in Caco-2 cell homogenates. Methods. Amino acid ester prodrugs of FUdR were synthesized using established procedures. The kinetics of hydrolysis of prodrugs was evaluated in human adenocarcinoma cell line (Caco-2) homogenates and pH 7.4 phosphate buffer. Results. 3'-Monoester, 5'-monoester, and 3',5'-diester prodrugs of FUdR utilizing proline, L-valine, D-valine, L-phenylalanine, and D-phenylalanine as promoieties were synthesized and characterized. In Caco-2 cell homogenates, the L-amino acid ester prodrugs hydrolyzed 10 to 75 times faster than the corresponding D-amino acid ester prodrugs. Pro and Phe ester prodrugs hydrolyzed much faster (3- to 30-fold) than the corresponding Val ester prodrugs. Further, the 5'-monoester prodrugs hydrolyzed significantly faster ( 3- fold) than the 3',5'-diester prodrugs. Conclusions. Novel amino acid ester prodrugs of FUdR were successfully synthesized. The results presented here clearly demonstrate that the rate of FUdR prodrug activation in Caco-2 cell homogenates is affected by the structure, stereochemistry, and site of esterification of the promoiety. Finally, the 5'-Val and 5'-Phe monoesters exhibited desirable characteristics such as good solution stability and relatively fast enzymatic conversion rates.
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