Amino acid ester prodrugs of floxuridine: Synthesis and effects of structure, stereochemistry, and site of esterification on the rate of hydrolysis

Balvinder S. Vig, Philip J. Lorenzi, Sachin Mittal, Christopher P. Landowski, Ho Chul Shin, Henry I. Mosberg, John M. Hilfinger, Gordon L. Amidon

Research output: Contribution to journalArticleScientificpeer-review

56 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1381-1388
Number of pages8
JournalPharmaceutical Research
Volume20
Issue number9
DOIs
Publication statusPublished - 1 Sep 2003
MoE publication typeA1 Journal article-refereed

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Floxuridine
Stereochemistry
Esterification
Prodrugs
Hydrolysis
Esters
Amino Acids
Caco-2 Cells
Valine
Phenylalanine
Proline

Keywords

  • Amino acid
  • Caco-2
  • Floxuridine
  • Hydrolysis
  • Prodrug
  • Stability

Cite this

Vig, Balvinder S. ; Lorenzi, Philip J. ; Mittal, Sachin ; Landowski, Christopher P. ; Shin, Ho Chul ; Mosberg, Henry I. ; Hilfinger, John M. ; Amidon, Gordon L. / Amino acid ester prodrugs of floxuridine : Synthesis and effects of structure, stereochemistry, and site of esterification on the rate of hydrolysis. In: Pharmaceutical Research. 2003 ; Vol. 20, No. 9. pp. 1381-1388.
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title = "Amino acid ester prodrugs of floxuridine: Synthesis and effects of structure, stereochemistry, and site of esterification on the rate of hydrolysis",
abstract = "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.",
keywords = "Amino acid, Caco-2, Floxuridine, Hydrolysis, Prodrug, Stability",
author = "Vig, {Balvinder S.} and Lorenzi, {Philip J.} and Sachin Mittal and Landowski, {Christopher P.} and Shin, {Ho Chul} and Mosberg, {Henry I.} and Hilfinger, {John M.} and Amidon, {Gordon L.}",
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Amino acid ester prodrugs of floxuridine : Synthesis and effects of structure, stereochemistry, and site of esterification on the rate of hydrolysis. / Vig, Balvinder S.; Lorenzi, Philip J.; Mittal, Sachin; Landowski, Christopher P.; Shin, Ho Chul; Mosberg, Henry I.; Hilfinger, John M.; Amidon, Gordon L.

In: Pharmaceutical Research, Vol. 20, No. 9, 01.09.2003, p. 1381-1388.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Amino acid ester prodrugs of floxuridine

T2 - Synthesis and effects of structure, stereochemistry, and site of esterification on the rate of hydrolysis

AU - Vig, Balvinder S.

AU - Lorenzi, Philip J.

AU - Mittal, Sachin

AU - Landowski, Christopher P.

AU - Shin, Ho Chul

AU - Mosberg, Henry I.

AU - Hilfinger, John M.

AU - Amidon, Gordon L.

PY - 2003/9/1

Y1 - 2003/9/1

N2 - 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.

AB - 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.

KW - Amino acid

KW - Caco-2

KW - Floxuridine

KW - Hydrolysis

KW - Prodrug

KW - Stability

UR - http://www.scopus.com/inward/record.url?scp=0141567450&partnerID=8YFLogxK

U2 - 10.1023/A:1025745824632

DO - 10.1023/A:1025745824632

M3 - Article

C2 - 14567631

AN - SCOPUS:0141567450

VL - 20

SP - 1381

EP - 1388

JO - Pharmaceutical Research

JF - Pharmaceutical Research

SN - 0724-8741

IS - 9

ER -