Towards catalytic aminoglycoside: Probing the modification of kanamycin B at the 3'- and 4'-positions

The chemistry of selective modification of kanamycin B at the 3'- and 4'-positions of ring I and the evaluation of the resulting derivatives in cell-free translation inhibition and MIC assays are presented. The first synthesis of 3'-epi-kanamycin B (4) and its 3'-amine analogue, 3'-amino-3'- deoxy-epi-kanamycin B (5) was accomplished from commercial kanamycin B. 4'-O-alkylation retained the antibacterial activity of the parent compound and afforded protection against certain kanamycin-resistant strains. The new derivative, compound 5, showed only a moderate reduction in activity and comparative molecular dynamics simulations within the bacterial rRNA decoding site suggested that such a modification can provide excellent positioning of the desired general acid arm in the targeted catalytic antibiotic.