Synthesis of neamine-derived pseudodisaccharides by stereo- and regio-selective functional group transformations

Abstract

Neamine is normally found as a core structure of aminoglycoside antibiotics. In order to understand the relationship between the antibiotic activity and the configurations of the functional groups of neamine, a series of novel neamine analogues with functional group manipulations on the 2-deoxystreptamine (2-DOS) ring or the sugar ring were designed and synthesized. The synthetic approach involved the construction of 2-DOS derivatives by catalytic Ferrier II rearrangement, stereo- and regio-selective functional group transformations, glycosyl coupling reaction, and global deprotection. Of the synthetic neamine analogues, four compounds showed comparable 16S rRNA binding affinities with neamine, whereas they displayed lower binding affinities towards 18S rRNA than neamine, implying a lower toxicity to mammals. This strategy might have applications in the chemical synthesis of other neamine derivatives and new aminoglycoside antibiotics with improved biological activities.