Rapid solid-phase syntheses of a peptidic-aminoglycoside library

A library of mono- and di-amino acid peptidic-aminoglycosides (PAs), with kanamycin and neomycin as the model aminoglycosides, was systematically and rapidly synthesized via solid phase peptide synthesis. Aminoglycosides were first converted into N-Boc protected carboxylic acids and fifteen l-amino...

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Bibliographic Details
Published in:Tetrahedron 2018-08, Vol.74 (33), p.4418-4428
Main Authors: Kukielski, Casey, Maiti, Krishnagopal, Bhaduri, Sayantan, Story, Sandra, Arya, Dev P.
Format: Article
Language:English
Subjects:
Aminoglycoside
Deoxystreptamine
Kanamycin
Neomycin
Peptidic library
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Summary:A library of mono- and di-amino acid peptidic-aminoglycosides (PAs), with kanamycin and neomycin as the model aminoglycosides, was systematically and rapidly synthesized via solid phase peptide synthesis. Aminoglycosides were first converted into N-Boc protected carboxylic acids and fifteen l-amino acids were then used in the diversification of the full library. The approach outlined describes a rapid synthetic procedure where >200 PA compounds can be synthesized in a few months with 85–95% purity. UV thermal denaturation assessed the binding stabilization by PAs to model human and bacterial A-site rRNA sequences. Significant differences were found in thermal melting profiles among PAs that were attributed to specific amino acid sequences. Neomycin PAs lead to a much larger variation in the stabilization of A-site rRNA sequences (ΔTm = 2.6–17.1 °C) as compared to kanamycin PAs (ΔTm = 0.4–4.3 °C). Kanamycin PAs had little activity against Gram-negative and Gram-positive bacteria as compared with neomycin PAs that had significant antibacterial activity with MIC ranging from 2 to 16 μM. [Display omitted]
ISSN:0040-4020
1464-5416
DOI:10.1016/j.tet.2018.07.012