A new acivicin prodrug designed for tumor-targeted delivery

Bioorg Med Chem. 2001 Nov;9(11):2843-8. doi: 10.1016/s0968-0896(01)00145-6.

Abstract

Acivicin is an antitumor agent known to inhibit cell growth. A new prodrug 9b of acivicin 10 was synthesized, based on a p-hydroxybenzylcarbamate self-immolative spacer capable to release acivicin under esterase activity. The prodrug includes a maleimide-containing arm for linkage with thiol-containing macromolecules such as antibodies. This molecule is intended for the conception of bioconjugates to target an inactive acivicin precursor to tumor cells, when linked to a monoclonal antibody (mAb) which recognizes a tumor-specific antigen. Prodrug cleavage by plasmatic esterases will then restore the acivicin's activity toward tumor cells. We report here the synthesis and the in vitro characteristics of the prodrug. As expected, its inhibitory activity against the gamma-glutamyl transpeptidase (gamma-GT) enzyme and its cytotoxicity towards HL-60 cells were highly reduced compared to the parent drug. The chemical and plasmatic hydrolysis kinetics of the compound was studied by HPLC. The prodrug is stable, being slowly hydrolyzed in pH 7.6 buffer at 37 degrees C with a half-life of 37 h. It is converted into an active acivicin under the effect of pig liver esterase, and its half-life in human plasma is 3 h. These results indicate this compound may be further used as a prodrug-antibody conjugate, to target acivicin to malignant cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacokinetics*
  • Cell Division / drug effects
  • Cell Survival / drug effects
  • Chromatography, High Pressure Liquid
  • Drug Delivery Systems
  • Drug Design
  • Drug Stability
  • Esterases / metabolism
  • HL-60 Cells / drug effects
  • Half-Life
  • Humans
  • Inhibitory Concentration 50
  • Isoxazoles / chemical synthesis
  • Isoxazoles / chemistry
  • Isoxazoles / pharmacokinetics*
  • Liver / enzymology
  • Prodrugs / chemical synthesis*
  • Prodrugs / chemistry
  • Prodrugs / pharmacokinetics
  • Swine
  • gamma-Glutamyltransferase / antagonists & inhibitors

Substances

  • Antineoplastic Agents
  • Isoxazoles
  • Prodrugs
  • gamma-Glutamyltransferase
  • Esterases
  • acivicin