title: Design, synthesis, and biophysical and biological evaluation of a series of pyrrolobenzodiazepine-poly(N-methylpyrrole) conjugates.
abstract: A novel series of methyl ester-terminated C8-linked pyrrolobenzodiazepine (PBD)-poly(N-methylpyrrole) conjugates (50a-f) has been synthesized and their DNA interaction evaluated by thermal denaturation, DNA footprinting, and in vitro transcription stop assays. The synergistic effect of attaching a PBD unit to a polypyrrole fragment is illustrated by the large increase in DNA binding affinity (up to 50-fold) compared to the individual PBD and pyrrole components. 50a-f were found to bind mainly to identical DNA sequences but with apparent binding site widths increasing with molecular length and the majority of sites conforming to the consensus motif 5'-XGXWz (z = 3 +/- 1; W = A or T; X = any base but preferably a purine). They also provided robust sequence-selective blockade of transcription at sites corresponding approximately to their DNA footprints. 50a-f were shown to have good cellular/nuclear penetration properties, and a degree of correlation between cytotoxicity and DNA-binding affinity was observed.
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, UK.
authors.forename: Geoff
authors.initials: G
authors.lastname: Wells
authors.forename: Christopher R H
authors.initials: CR
authors.lastname: Martin
authors.forename: Philip W
authors.initials: PW
authors.lastname: Howard
authors.forename: Zara A
authors.initials: ZA
authors.lastname: Sands
authors.forename: Charles A
authors.initials: CA
authors.lastname: Laughton
authors.forename: Arnaud
authors.initials: A
authors.lastname: Tiberghien
authors.forename: Chi Kit
authors.initials: CK
authors.lastname: Woo
authors.forename: Luke A
authors.initials: LA
authors.lastname: Masterson
authors.forename: Marissa J
authors.initials: MJ
authors.lastname: Stephenson
authors.forename: John A
authors.initials: JA
authors.lastname: Hartley
authors.forename: Terence C
authors.initials: TC
authors.lastname: Jenkins
authors.forename: Steven D
authors.initials: SD
authors.lastname: Shnyder
authors.forename: Paul M
authors.initials: PM
authors.lastname: Loadman
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Waring
authors.forename: David E
authors.initials: DE
authors.lastname: Thurston
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D002467:Cell Nucleus / Q000378:metabolism; D004247:DNA / Q000737:chemistry; D018983:DNA Footprinting; D004354:Drug Screening Assays, Antitumor; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D009691:Nucleic Acid Denaturation; D010539:Permeability; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic
chemical_list: D000970:Antineoplastic Agents; D006575:Heterocyclic Compounds, 3-Ring; D011758:Pyrroles; D001569:Benzodiazepines; D004247:DNA