Synthesis of a novel C2/C2'-aryl-substituted pyrrolo[2,1-c][1,4]benzodiazepine dimer prodrug with improved water solubility and reduced DNA reaction rate

Bioorg Med Chem Lett. 2009 Nov 15;19(22):6463-6. doi: 10.1016/j.bmcl.2009.09.012. Epub 2009 Sep 9.

Abstract

A prodrug form (17) of a novel C2/C2'-aryl-substituted pyrrolobenzodiazepine (PBD) dimer (16) has been synthesized by introducing sodium bisulfite groups to the C11/C11'-positions of the parent bis-imine. The prodrug form is highly water soluble, stable in aqueous conditions, and the rate of DNA cross-link formation is much slower compared to the parent bis-imine.

MeSH terms

  • Animals
  • Benzodiazepines / pharmacology
  • Benzodiazepinones / chemical synthesis*
  • Benzodiazepinones / chemistry
  • Benzodiazepinones / pharmacology
  • Cell Line, Tumor
  • Computer Simulation
  • DNA / drug effects*
  • DNA / metabolism
  • Drug Design
  • Drug Resistance, Neoplasm / drug effects*
  • Drug Screening Assays, Antitumor
  • Epoxy Compounds / pharmacology
  • Humans
  • Models, Molecular
  • Prodrugs*
  • Pyrroles / chemical synthesis*
  • Pyrroles / chemistry
  • Pyrroles / pharmacology
  • Solubility / drug effects
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • 1,1'-((propane-1,3-diyl)dioxy)bis(7-methoxy-2-methylidene-1,2,3,10,11,11a-hexahydro-5H-pyrrolo(2,1-c)(1,4)benzodiazepin-5,11-dione)
  • Benzodiazepinones
  • Epoxy Compounds
  • Prodrugs
  • Pyrroles
  • Benzodiazepines
  • DNA