Conjugation with polyamines enhances the antibacterial and anticancer activity of chloramphenicol |
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Authors: | Ourania N Kostopoulou Ekaterini C Kouvela George E Magoulas Thomas Garnelis Ioannis Panagoulias Maria Rodi Georgios Papadopoulos Athanasia Mouzaki George P Dinos Dionissios Papaioannou Dimitrios L Kalpaxis |
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Institution: | 1.Department of Biochemistry, School of Medicine, University of Patras, GR-26504 Patras, Greece;2.Laboratory of Synthetic Organic Chemistry, Department of Chemistry, University of Patras, GR-26504 Patras, Greece;3.Division of Hematology, Department of Internal Medicine, School of Medicine, University of Patras, GR-26504 Patras, Greece;4.Department of Biochemistry and Biotechnology, University of Thessaly, Ploutonos 26, GR-41221 Larissa, Greece |
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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 N8,N8-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. |
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