title: Structure-activity relationships of monomeric C2-aryl pyrrolo[2,1-c][1,4]benzodiazepine (PBD) antitumor agents.
abstract: A comprehensive SAR investigation of the C2-position of pyrrolo[2,1-c][1,4]benzodiazepine (PBD) monomer antitumor agents is reported, establishing the molecular requirements for optimal in vitro cytotoxicity and DNA-binding affinity. Both carbocyclic and heterocyclic C2-aryl substituents have been studied ranging from single aryl rings to fused ring systems, and also styryl substituents, establishing across a library of 80 analogues that C2-aryl and styryl substituents significantly enhance both DNA-binding affinity and in vitro cytotoxicity, with a correlation between the two. The optimal C2-grouping for both DNA-binding affinity and cytotoxicity was found to be the C2-quinolinyl moiety which, according to molecular modeling, is due to the overall fit of the molecule in the DNA minor groove, and potential specific contacts with functional groups in the floor and walls of the groove. This analogue (14l) was shown to delay tumor growth in a HCT-116 (bowel) human tumor xenograft model.
authors.affiliation: Cancer Research UK Gene Targeted Drug Design Research Group, The School of Pharmacy, University of London, 29/39 Brunswick Square, London WC1N 1AX, U.K.
authors.forename: Dyeison
authors.initials: D
authors.lastname: Antonow
authors.forename: Maciej
authors.initials: M
authors.lastname: Kaliszczak
authors.forename: Gyoung-Dong
authors.initials: GD
authors.lastname: Kang
authors.forename: Marissa
authors.initials: M
authors.lastname: Coffils
authors.forename: Arnaud C
authors.initials: AC
authors.lastname: Tiberghien
authors.forename: Nectaroula
authors.initials: N
authors.lastname: Cooper
authors.forename: Teresa
authors.initials: T
authors.lastname: Barata
authors.forename: Sibylle
authors.initials: S
authors.lastname: Heidelberger
authors.forename: Colin H
authors.initials: CH
authors.lastname: James
authors.forename: Mire
authors.initials: M
authors.lastname: Zloh
authors.forename: Terence C
authors.initials: TC
authors.lastname: Jenkins
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Reszka
authors.forename: Stephen
authors.initials: S
authors.lastname: Neidle
authors.forename: Sylvie M
authors.initials: SM
authors.lastname: Guichard
authors.forename: Duncan I
authors.initials: DI
authors.lastname: Jodrell
authors.forename: John A
authors.initials: JA
authors.lastname: Hartley
authors.forename: Philip W
authors.initials: PW
authors.lastname: Howard
authors.forename: David E
authors.initials: DE
authors.lastname: Thurston
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D001483:Base Sequence; D001569:Benzodiazepines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D002417:Cattle; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D007097:Imines / Q000737:chemistry; D051379:Mice; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D009691:Nucleic Acid Denaturation / Q000187:drug effects; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D007097:Imines; D011758:Pyrroles; C438462:pyrrolo(2,1-c)(1,4)benzodiazepine; D001569:Benzodiazepines; D004247:DNA