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.
Philip W Howard  1 ,  Zhizhi Chen ,  Stephen J Gregson ,  Luke A Masterson ,  Arnaud C Tiberghien ,  Nectaroula Cooper ,  Min Fang ,  Marissa J Coffils ,  Sarah Klee ,  John A Hartley ,  David E Thurston
Affiliations
  • 1. Spirogen Ltd, The School of Pharmacy, 29-39 Brunswick Square, London WC1N1AX, UK. [email protected]
PMID: 19811912 DOI: 10.1016/j.bmcl.2009.09.012
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.