Design, synthesis and ribosome binding of chloramphenicol nucleotide and intercalator conjugates

• Published in: Bioorganic & medicinal chemistry letters Vol. 15; no. 8; pp. 2079 - 2083
• Main Authors: Johansson, Dorte, Jessen, Carsten H., Pøhlsgaard, Jacob, Jensen, Kenneth B., Vester, Birte, Pedersen, Erik B., Nielsen, Poul
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 15.04.2005; Elsevier
• Subjects: Antibiotics; Antibiotics. Antiinfectious agents. Antiparasitic agents; Binding Sites; Biological and medical sciences; Chloramphenicol - analogs & derivatives; Chloramphenicol - chemistry; Chloramphenicol - metabolism; Conjugates; Drug Design; Footprinting; General aspects; Intercalating Agents - chemistry; Intercalating Agents - metabolism; Medical sciences; Nucleic acids; Nucleotides - chemistry; Nucleotides - metabolism; Organophosphorus Compounds - chemistry; Organophosphorus Compounds - metabolism; Pharmacology. Drug treatments; Ribosomes - metabolism; Conjugates; Footprinting; Nucleic acids; Antibiotics; Spacer arm; Dinucleotide; Pyrene derivatives; Binding site; Modeling; Amine; Ribosomal RNA; Molecular model; Chemical synthesis; Nucleic acid; Enzyme; Transferases; Footprinting technique; Chloramphenicol; Aminoacyltransferases; Antibiotic; Chemical modification; Nucleotide; Peptidyltransferase; Conjugated compound; Crystalline structure
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2005.02.044

[Display omitted] 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.