科研之友
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摘要
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 by H-1 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., IC50 at pH 7 = 1.42-230 mu M vs. 2.35 mu M 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 = 0.85-1.32 mu M), 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.
- 出版日期2016-9
