title: Conjugation with polyamines enhances the antibacterial and anticancer activity of chloramphenicol.
abstract: Chloramphenicol (CAM) is a broad-spectrum antibiotic, limited to occasional only use in developed countries because of its potential toxicity. To explore the influence of polyamines on the uptake and activity of CAM into cells, a series of polyamine-CAM conjugates were synthesized. Both polyamine architecture and the position of CAM-scaffold substitution were crucial in augmenting the antibacterial and anticancer potency of the synthesized conjugates. Compounds 4 and 5, prepared by replacement of dichloro-acetyl group of CAM with succinic acid attached to N4 and N1 positions of N(8),N(8)-dibenzylspermidine, respectively, exhibited higher activity than CAM in inhibiting the puromycin reaction in a bacterial cell-free system. Kinetic and footprinting analysis revealed that whereas the CAM-scaffold preserved its role in competing with the binding of aminoacyl-tRNA 3'-terminus to ribosomal A-site, the polyamine-tail could interfere with the rotatory motion of aminoacyl-tRNA 3'-terminus toward the P-site. Compared to CAM, compounds 4 and 5 exhibited comparable or improved antibacterial activity, particularly against CAM-resistant strains. Compound 4 also possessed enhanced toxicity against human cancer cells, and lower toxicity against healthy human cells. Thus, the designed conjugates proved to be suitable tools in investigating the ribosomal catalytic center plasticity and some of them exhibited greater efficacy than CAM itself.
authors.affiliation: Department of Biochemistry, School of Medicine, University of Patras, GR-26504 Patras, Greece.
authors.forename: Ourania N
authors.initials: ON
authors.lastname: Kostopoulou
authors.affiliation: Department of Biochemistry, School of Medicine, University of Patras, GR-26504 Patras, Greece.
authors.forename: Ekaterini C
authors.initials: EC
authors.lastname: Kouvela
authors.affiliation: Division of Hematology, Department of Internal Medicine, School of Medicine, University of Patras, GR-26504 Patras, Greece.
authors.forename: George E
authors.initials: GE
authors.lastname: Magoulas
authors.affiliation: Division of Hematology, Department of Internal Medicine, School of Medicine, University of Patras, GR-26504 Patras, Greece.
authors.forename: Thomas
authors.initials: T
authors.lastname: Garnelis
authors.affiliation: Laboratory of Synthetic Organic Chemistry, Department of Chemistry, University of Patras, GR-26504 Patras, Greece.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Panagoulias
authors.affiliation: Laboratory of Synthetic Organic Chemistry, Department of Chemistry, University of Patras, GR-26504 Patras, Greece.
authors.forename: Maria
authors.initials: M
authors.lastname: Rodi
authors.affiliation: Department of Biochemistry and Biotechnology, University of Thessaly, Ploutonos 26, GR-41221 Larissa, Greece.
authors.forename: Georgios
authors.initials: G
authors.lastname: Papadopoulos
authors.affiliation: Laboratory of Synthetic Organic Chemistry, Department of Chemistry, University of Patras, GR-26504 Patras, Greece.
authors.forename: Athanasia
authors.initials: A
authors.lastname: Mouzaki
authors.affiliation: Department of Biochemistry, School of Medicine, University of Patras, GR-26504 Patras, Greece.
authors.forename: George P
authors.initials: GP
authors.lastname: Dinos
authors.affiliation: Division of Hematology, Department of Internal Medicine, School of Medicine, University of Patras, GR-26504 Patras, Greece.
authors.forename: Dionissios
authors.initials: D
authors.lastname: Papaioannou
authors.affiliation: Department of Biochemistry, School of Medicine, University of Patras, GR-26504 Patras, Greece dimkal@med.upatras.gr.
authors.forename: Dimitrios L
authors.initials: DL
authors.lastname: Kalpaxis
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D001665:Binding Sites; D045744:Cell Line, Tumor; D002701:Chloramphenicol / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D004926:Escherichia coli / Q000187:drug effects; D006801:Humans; D011073:Polyamines / Q000737:chemistry*; D011500:Protein Synthesis Inhibitors / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D012270:Ribosomes / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D011073:Polyamines; D011500:Protein Synthesis Inhibitors; D002701:Chloramphenicol