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

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Structural Biology

Background:

• Peptidyl nucleosides are potent inhibitors but difficult to modify due to their complex structure and reactivity.
• Previous attempts at modification were limited, hindering the development of selective inhibitors.

Purpose of the Study:

• To design and synthesize blasticidin S-amicetin chimeras targeting bacterial ribosomes while minimizing interaction with eukaryotic ribosomes.
• To develop a versatile semisynthetic route for creating diverse, densely functionalized peptidyl nucleoside analogs.

Main Methods:

• Utilized structural overlays and molecular modeling to guide chimera design.
• Developed a semisynthetic strategy involving sequential C6' derivatization and C4 amine coupling on the blasticidin S scaffold.
• Synthesized four C6' derivatives and diversified them with para-aminobenzoate motifs at C4.

Main Results:

• Successfully synthesized densely functionalized chimeras in as few as four steps with yields up to 38%.
• Achieved retained antibacterial potency alongside a sharp decrease in mammalian cytotoxicity (selectivity indices >50).
• Structural analysis and modeling explained selectivity gains through preferential binding to a bacterial ribosomal pocket.

Conclusions:

• Demonstrated structure-guided semisynthesis as an effective method for modifying complex natural products like blasticidin S.
• Established a practical framework for diversifying chemically challenging scaffolds into selective translation inhibitors.
• Developed promising antibacterial agents with high selectivity against mammalian cells.