Rapid Solid-phase Syntheses of 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 fourteen 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 (ΔT_m = 2.6-17.1 °C) as compared to kanamycin PAs (ΔT_m = 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 - 16 μM.