Biosynthesis, synthesis, and biological activities of pyrrolobenzodiazepines

Med Res Rev. 2012 Mar;32(2):254-93. doi: 10.1002/med.20212. Epub 2010 Jun 13.

Abstract

Pyrrolobenzodiazepines (PBDs) are sequence selective DNA alkylating agents with remarkable antineoplastic activity. They are either naturally produced by actinomycetes or synthetically produced. The remarkable broad spectrum of activities of the naturally produced PBDs encouraged the synthesis of several PBDs, including dimeric and hybrid PBDs yielding to an improvement in the DNA-binding sequence specificity and in the potency of this class of compounds. However, limitation in the chemical synthesis prevented the testing of one of the most potent PBDs, sibiromycin, a naturally produced glycosylated PBDs. Only recently, the biosynthetic gene clusters for PBDs have been identified opening the doors to the production of glycosylated PBDs by mutasynthesis and biosynthetic engineering. This review describes the recent studies on the biosynthesis of naturally produced pyrrolobenzodiazepines. In addition, it provides an overview on the isolation and characterization of naturally produced PBDs, chemical synthesis of PBDs, mechanism of DNA alkylation, and DNA-binding affinity and cytotoxic properties of both naturally produced and synthetic pyrrolobenzodiazepines.

Publication types

  • Review

MeSH terms

  • Actinobacteria / genetics
  • Actinobacteria / metabolism*
  • Aminoglycosides / biosynthesis
  • Anthramycin / biosynthesis
  • Antineoplastic Agents, Alkylating / chemical synthesis
  • Antineoplastic Agents, Alkylating / metabolism*
  • Antineoplastic Agents, Alkylating / pharmacology
  • Benzodiazepines / chemical synthesis*
  • Benzodiazepines / metabolism
  • Benzodiazepines / pharmacology*
  • DNA / metabolism*
  • Models, Molecular
  • Multigene Family
  • Pyrroles / chemical synthesis*
  • Pyrroles / metabolism
  • Pyrroles / pharmacology*
  • Structure-Activity Relationship

Substances

  • Aminoglycosides
  • Antineoplastic Agents, Alkylating
  • Pyrroles
  • pyrrolo(2,1-c)(1,4)benzodiazepine
  • Anthramycin
  • sibiromycin
  • Benzodiazepines
  • DNA