title: Neomycin B-cyclen conjugates and their Zn(II) complexes as RNA-binding agents.
abstract: Three new conjugates featuring the aminoglycoside antibiotic neomycin B linked to the 1,4,7,10-tetraazacyclododecane (cyclen) macrocycle via alkyl chains of varying lengths were synthesized from suitably protected derivatives of these precursors via conventional peptide coupling protocols. The final products were characterized by1H NMR spectroscopy, mass spectrometry, and elemental analysis. FRET-based measurements examining the ability of the compounds to displace coumarin-labelled kanamycin A or neomycin B from Dy547-labelled prokaryotic ribosomal A-site RNA revealed that they bind to the A-site with slightly higher affinities than the parent aminoglycoside (e.g., IC50at pH7=1.42-2.30μM vs. 2.35μM for neomycin B). This is attributed to the higher overall positive charge of the conjugates, resulting from protonation of the macrocylic amines. Consistent with a predominantly electrostatic mode of interaction, the binding affinities of the conjugates were found to increase with decreasing pH, reflecting a greater degree of protonation at lower pH. The zinc(II) complexes of the neomycin B-cyclen conjugates were found to bind to A-site RNA with even higher affinities (IC50=0.85-1.32μM), due to the Zn(II)-cyclen motif forming coordinative (and/or electrostatic) interactions with the uracil bases and/or phosphate groups within the A-site. These results highlight the potential for the nucleic acid-binding properties of aminoglycosides to be tuned via the covalent attachment of metal complexes, which could ultimately prove useful to the development of new anti-bacterial and anti-viral agents.
authors.affiliation: School of Chemistry, Monash University, Victoria 3800, Australia.
authors.forename: Bopha
authors.initials: B
authors.lastname: Kong
authors.affiliation: School of Chemistry, Monash University, Victoria 3800, Australia. Electronic address: tanmaya.joshi@monash.edu.
authors.forename: Tanmaya
authors.initials: T
authors.lastname: Joshi
authors.affiliation: Department of Microbiology, Monash University, Victoria 3800, Australia.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Belousoff
authors.affiliation: Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0358, United States.
authors.forename: Yitzhak
authors.initials: Y
authors.lastname: Tor
authors.affiliation: Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia. Electronic address: bim.graham@monash.edu.
authors.forename: Bim
authors.initials: B
authors.lastname: Graham
authors.affiliation: School of Chemistry, Monash University, Victoria 3800, Australia. Electronic address: leone.spiccia@monash.edu.
authors.forename: Leone
authors.initials: L
authors.lastname: Spiccia
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry*; D001665:Binding Sites; D002413:Cations, Divalent; D003374:Coumarins / Q000737:chemistry; D000080027:Cyclams; D005601:Framycetin / Q000737:chemistry*; D006001:Glycoconjugates / Q000737:chemistry*; D006571:Heterocyclic Compounds / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D007612:Kanamycin / Q000737:chemistry; D008958:Models, Molecular; D011522:Protons; D012336:RNA, Ribosomal, 16S / Q000737:chemistry*; D013194:Staining and Labeling; D055672:Static Electricity; D015032:Zinc / Q000737:chemistry*
chemical_list: D000900:Anti-Bacterial Agents; D002413:Cations, Divalent; D003374:Coumarins; D000080027:Cyclams; D006001:Glycoconjugates; D006571:Heterocyclic Compounds; D011522:Protons; D012336:RNA, Ribosomal, 16S; D005601:Framycetin; D007612:Kanamycin; C038072:cyclen; D015032:Zinc
keywords: 1,4,7,10-Tetraazacyclododecane; Aminoglycoside derivatives; Antibiotics; RNA; Zinc(II) complexes