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Synthesis and Structure‐Activity Relationship of Xenocoumacin 1 and Analogues as Inhibitors of Ribosomal Protein Synthesis
Author(s) -
Zumbrunn Cornelia,
Krüsi Daniela,
Stamm Christina,
Caspers Patrick,
Ritz Daniel,
Rueedi Georg
Publication year - 2021
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202000793
Subject(s) - ribosome , ribosomal rna , protein biosynthesis , ribosomal protein , eukaryotic ribosome , biochemistry , biology , bacteria , natural product , rna , chemistry , gene , genetics
Ribosomal protein synthesis is an important target in antibacterial drug discovery. Numerous natural products have served as starting points for the development of antibiotics. We report here the total synthesis of xenocoumacin 1, a natural product that binds to 16S ribosomal RNA at a highly conserved region, as well as analogues thereof. Preliminary structure–activity relationship studies were aimed at understanding and modulating the selectivity between eukaryotic and prokaryotic ribosomes. Modifications were mainly tolerated in the aromatic region. Whole‐cell activity against Gram‐negative bacteria is limited by efflux and penetration, as demonstrated in genetically modified strains of E. coli . Analogues with high selectivity for eukaryotic ribosomes were identified, but it was not possible to obtain inhibitors selective for bacterial protein synthesis. Achieving high selectivity (albeit not the desired one) was thus possible despite the high homology between eukaryotic and prokaryotic ribosomes in the binding region.