Amino acid ester prodrugs of floxuridine: synthesis and effects of structure, stereochemistry, and site of esterification on the rate of hydrolysis.
OBJECTIVE
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.
Vig
Balvinder S
BS
Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, USA.
Lorenzi
Philip J
PJ
Mittal
Sachin
S
Landowski
Christopher P
CP
Shin
Ho-Chul
HC
Mosberg
Henry I
HI
Hilfinger
John M
JM
Amidon
Gordon L
GL
D000596:Amino Acids / Q000737:chemistry* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D002021:Buffers; D018938:Caco-2 Cells; D002851:Chromatography, High Pressure Liquid; D004952:Esters; D005467:Floxuridine / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D015394:Molecular Structure; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000596:Amino Acids; D000970:Antineoplastic Agents; D002021:Buffers; D004952:Esters; D011355:Prodrugs; D005467:Floxuridine