Structure-Guided Semisynthesis of Blasticidin S-Amicetin Chimeras as Selective Ribosome Inhibitors.

ABSTRACT: Peptidyl nucleosides are broad-acting inhibitors, but their dense functionality and complex reactivity have historically limited the modification of these scaffolds. Guided by structural overlays and molecular modeling, we designed blasticidin S-amicetin chimeras to exploit a bacterial-specific pocket of the ribosomal PTC while reducing eukaryotic ribosome engagement. To test this hypothesis, we developed a semisynthetic route enabling sequential C6' derivatization and C4 amine coupling on the blasticidin S scaffold, facilitated by counterion exchange to prevent side reactions. This approach furnished four C6' classes (acid, methyl ester, primary amide, phenethyl amide), each diversified at C4 with para-aminobenzoate motifs, delivering densely functionalized chimeras in as few as fo

SUBMITTER: Gannett C 

PROVIDER: S-EPMC12856912 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature