title: The development of pyrrolobenzodiazepines as antitumour agents.
abstract: BACKGROUND
  DNA interacting agents play a major role in cancer chemotherapy, either as single agents, in combination drug regimens, or as components of novel targeted therapies. The search for more selective and efficacious drugs that can deliver critical DNA damage with minimal side effects continues.
  
  
  METHODS
  The development of the pyrrolobenzodiazepines (PBDs) from their discovery as natural products in the 1960s, through synthetic PBD monomers, PBD hybrids and conjugates, and PBD dimers is described. The latter molecules are capable of forming sequence selective, non-distorting and potently cytotoxic DNA interstrand cross-links in the minor groove of DNA. In particular, the development of PBD dimer SJG-136 (SG2000), currently in Phase II clinical trials, is presented. Potential future cancer therapeutic applications of PBDs, including their use as components of targeting strategies, are also discussed.
  
  
  CONCLUSIONS
  The culmination of over four decades of study on structure-activity relationships of PBDs has led to a detailed understanding of how to introduce structural modification to enhance biological activity and potency. The challenge for the next phase in the development of the PBDs is to harness this activity and potency in a new generation of cancer therapeutics.
authors: UCL Cancer Institute, 72 Huntley St, London, WC1E 6BT, UK. john.hartley@ucl.ac.uk
authors: John A
authors: JA
authors: Hartley
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D001569:Benzodiazepines / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D001570:Benzodiazepinones / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects; D016503:Drug Delivery Systems; D015195:Drug Design; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000503:physiopathology; D011758:Pyrroles / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C423343:1,1'-((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); D000970:Antineoplastic Agents; D001570:Benzodiazepinones; D011758:Pyrroles; C438462:pyrrolo(2,1-c)(1,4)benzodiazepine; D001569:Benzodiazepines