Synthesis and biological evaluation of prodrugs based on the natural antibiotic duocarmycin for use in ADEPT and PMT

Chemistry. 2011 Feb 7;17(6):1922-9. doi: 10.1002/chem.201002798. Epub 2011 Jan 7.

Abstract

Chemotherapy of malign tumors is usually associated with serious side effects as common anticancer drugs lack selectivity. An approach to deal with this problem is the antibody-directed enzyme prodrug therapy (ADEPT) and the prodrug monotherapy (PMT). Herein, the synthesis and biological evaluation of new glycosidic prodrugs suitable for both concepts are described. All prodrugs but one are stable in human serum and show QIC(50) values (IC(50) of prodrug/IC(50) of prodrug in the presence of the appropriate glycohydrolase) of up to 6500. This is the best value found so far for compounds interacting with DNA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies / therapeutic use
  • DNA / metabolism*
  • Drug Design*
  • Drug Screening Assays, Antitumor
  • Duocarmycins
  • Glucuronidase / metabolism
  • Humans
  • Indoles* / chemical synthesis
  • Indoles* / chemistry
  • Indoles* / therapeutic use
  • Inhibitory Concentration 50
  • Molecular Structure
  • Prodrugs* / chemical synthesis
  • Prodrugs* / chemistry
  • Prodrugs* / therapeutic use
  • Pyrroles / chemical synthesis
  • Pyrroles / chemistry
  • Pyrroles / therapeutic use

Substances

  • Antibodies
  • Duocarmycins
  • Indoles
  • Prodrugs
  • Pyrroles
  • duocarmycin SA
  • DNA
  • Glucuronidase