title: Design, synthesis and ribosome binding of chloramphenicol nucleotide and intercalator conjugates.
abstract: Molecular modelling based on X-ray structures of the antibiotic drug chloramphenicol bound in a bacterial ribosome has been used for design of chloramphenicol derivatives. Conjugates of the chloramphenicol amine through appropriate linkers to either a pyrene moiety or to a mono- or dinucleotide moiety were designed to improve binding to ribosomes by providing specific interactions in the peptidyl transferase site or to the P-loop in the ribosome. Specific binding of the conjugates were investigated by footprinting analysis using chemical modifications of accessible nucleotides in ribosomal RNA. The pyrene chloramphenicol conjugate shows enhanced binding to the chloramphenicol binding site compared to the native chloramphenicol, whereas the four nucleotide conjugates could not be shown to bind to the chloramphenicol binding site or to the P-loop.
authors.affiliation: Nucleic Acid Center, Department of Chemistry, University of Southern Denmark, 5230 Odense M, Denmark.
authors.forename: Dorte
authors.initials: D
authors.lastname: Johansson
authors.forename: Carsten H
authors.initials: CH
authors.lastname: Jessen
authors.forename: Jacob
authors.initials: J
authors.lastname: Pøhlsgaard
authors.forename: Kenneth B
authors.initials: KB
authors.lastname: Jensen
authors.forename: Birte
authors.initials: B
authors.lastname: Vester
authors.forename: Erik B
authors.initials: EB
authors.lastname: Pedersen
authors.forename: Poul
authors.initials: P
authors.lastname: Nielsen
mesh_terms: D001665:Binding Sites; D002701:Chloramphenicol / Q000031:analogs & derivatives / Q000737:chemistry* / Q000378:metabolism; D015195:Drug Design; D007364:Intercalating Agents / Q000737:chemistry* / Q000378:metabolism; D009711:Nucleotides / Q000737:chemistry* / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000737:chemistry / Q000378:metabolism; D012270:Ribosomes / Q000378:metabolism*
chemical_list: D007364:Intercalating Agents; D009711:Nucleotides; D009943:Organophosphorus Compounds; C434331:phosphoramidite; D002701:Chloramphenicol