title: 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.
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.
authors.affiliation: Spirogen Ltd, The School of Pharmacy, 29-39 Brunswick Square, London WC1N1AX, UK. philip.howard@spirogen.com
authors.forename: Philip W
authors.initials: PW
authors.lastname: Howard
authors.forename: Zhizhi
authors.initials: Z
authors.lastname: Chen
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Gregson
authors.forename: Luke A
authors.initials: LA
authors.lastname: Masterson
authors.forename: Arnaud C
authors.initials: AC
authors.lastname: Tiberghien
authors.forename: Nectaroula
authors.initials: N
authors.lastname: Cooper
authors.forename: Min
authors.initials: M
authors.lastname: Fang
authors.forename: Marissa J
authors.initials: MJ
authors.lastname: Coffils
authors.forename: Sarah
authors.initials: S
authors.lastname: Klee
authors.forename: John A
authors.initials: JA
authors.lastname: Hartley
authors.forename: David E
authors.initials: DE
authors.lastname: Thurston
mesh_terms: D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology; D001570:Benzodiazepinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D003198:Computer Simulation; D004247:DNA / Q000187:drug effects* / Q000378:metabolism; D015195:Drug Design; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D004852:Epoxy Compounds / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D011355:Prodrugs; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012995:Solubility / Q000187:drug effects; D013237:Stereoisomerism; 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); D001570:Benzodiazepinones; D004852:Epoxy Compounds; D011355:Prodrugs; D011758:Pyrroles; D001569:Benzodiazepines; D004247:DNA