title: 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.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Energy and Hydrocarbon Chemistry, Graduate School of Engineering, Kyoto University, Katsura Campus, Nishikyo-ku, Kyoto 615-8510, Japan.
authors.forename: Zhouen
authors.initials: Z
authors.lastname: Zhang
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hatta
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Tanabe
authors.forename: Sei-ichi
authors.initials: S
authors.lastname: Nishimoto
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000633:toxicity; D045744:Cell Line, Tumor; D004952:Esters; D005467:Floxuridine / Q000138:chemical synthesis* / Q000633:toxicity; D006801:Humans; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000633:toxicity; D011355:Prodrugs / Q000138:chemical synthesis* / Q000633:toxicity
chemical_list: D000970:Antineoplastic Agents; D004952:Esters; D010456:Peptides, Cyclic; D011355:Prodrugs; D005467:Floxuridine