Total synthesis and chemical stability of pseudouridimycin
Christopher F. Cain, Aaron M. Scott, Matthew P. Sarnowski, Juan R. Del Valle
Abstract
We report the chemical synthesis of pseudouridimycin (1), an antimicrobial natural product that potently and selectively inhibits bacterial RNA polymerase. Chemical stability studies revealed intramolecular hydroxamate bond scission to be a major decomposition pathway for 1 in aqueous buffer. Replacement of the hydroxamate bond with a tertiary amide, as in 16, afforded a conformational isostere resistant to degradation. These studies pave the way for the design and synthesis of analogues with improved chemical stability and biological activity.
Topics & Concepts
ChemistryIsostereBond cleavagePeptide bondChemical stabilityIntramolecular forceAmideChemical modificationChemical synthesisChemical decompositionCombinatorial chemistryNatural productPolymeraseChemical structureDecompositionOrganic chemistryStereochemistryBiochemistryEnzymeIn vitroCatalysisCancer therapeutics and mechanismsChemical Synthesis and AnalysisSynthesis and Biological Evaluation