title: Synthesis of the first example of a C2-C3/C2'-C3'-endo unsaturated pyrrolo[2,1-c][1,4]benzodiazepine dimer.
abstract: We report the first example of a C2-C3/C2'-C3'-endo unsaturated pyrrolo[2,1-c][1,4]benzodiazepine (PBD) dimer 16 synthesised through a new and efficient route, thus establishing that C2-C3-endo unsaturation enhances both cytotoxicity and DNA-binding affinity in A-Ring-linked PBD dimers but to a lesser extent than C2/C2'-exo-unsaturation. This new route has allowed the preparation of multi-gram quantities of the related clinical candidate 1 and should lead to more structurally diverse PBD dimer analogues.
authors.affiliation: CRC Gene Targeted Drug Design Research Group, Cancer Research Laboratories, School of Pharmaceutical Sciences, University of Nottingham, University Park, Nottingham NG7 2RD, UK.
authors.forename: S J
authors.initials: SJ
authors.lastname: Gregson
authors.forename: P W
authors.initials: PW
authors.lastname: Howard
authors.forename: K E
authors.initials: KE
authors.lastname: Corcoran
authors.forename: T C
authors.initials: TC
authors.lastname: Jenkins
authors.forename: L R
authors.initials: LR
authors.lastname: Kelland
authors.forename: D E
authors.initials: DE
authors.lastname: Thurston
mesh_terms: D001381:Azepines / Q000138:chemical synthesis*; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D019281:Dimerization; D006801:Humans; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D001381:Azepines; D011758:Pyrroles; C438462:pyrrolo(2,1-c)(1,4)benzodiazepine; D001569:Benzodiazepines