, Volume 22, Issue 3, pp 381-389
Date: 21 Mar 2005

A New Class of 5-Fluoro-2′-deoxyuridine Prodrugs Conjugated with a Tumor-Homing Cyclic Peptide CNGRC by Ester Linkers: Synthesis, Reactivity, and Tumor-Cell–Selective Cytotoxicity

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Tumor-targeting prodrugs of 5-fluoro-2′-deoxyuridine (5-FdUrd), which are chemical conjugations of 5-FdUrd with a tumor-homing cyclic peptide CNGRC by succinate and glutarate linkers, were synthesized to investigate the structural effects of linkers on the hydrolytic release of 5-FdUrd and the tumor-cell–selective cytotoxicity.


A solid phase synthesis method was used to produce 5-FdUrd prodrugs. The kinetics and efficiency of hydrolytic 5-FdUrd release from the prodrugs were investigated in phosphate buffer (PB), fetal bovine serum (FBS), HT-1080 cell lysate, MDA-MB-231 cell lysate, and MEM containing 10% FBS. The tumor-cell–selective cytotoxicity of prodrugs was evaluated by an MTT method.


Two tumor-targeting prodrugs CNF1 and CNF2 bearing 5-FdUrd conjugated with a common cyclic peptide CNGRC by succinate and glutarate linkers, respectively, and their control compounds CN1 and CN2 without 5-FdUrd moiety were synthesized and identified. CNF1 underwent hydrolysis to release 5-FdUrd more rapidly and efficiently than CNF2. Both prodrugs were of lower cytotoxicity compared to 5-FdUrd, showing more selective cytotoxicity toward APN/CD13 positive cells (HT-1080) than toward APN/CD13 negative cells (HT-29, MDA-MB-231).


A new class of tumor-targeting 5-FdUrd prodrugs CNF1 and CNF2 were successfully synthesized. These prodrugs targeted a tumor marker APN/CD13 to cause tumor-cell–selective cyctotoxicity due to 5-FdUrd release, the rate of which could be controlled by the structure of ester linker.