A highly enantioselective intramolecular 1,3-dipolar cycloaddition yields novel pseudo-natural product inhibitors of the Hedgehog signalling pathway
Jie Liu, Ruirui Zhang, Shubhadip Mallick, Sohan Patil, Chantal Wientjens, Jana Flegel, Anna Krupp, Carsten Strohmann, Corentin Grassin, Christian Merten, Axel Pahl, Michael Grigalunas, Herbert Waldmann
Abstract
)-DMBiphep complex. The cycloadditions proceeded in excellent yields (up to 98%) and with very high enantioselectivity (up to 99% ee). Investigation of the resulting PNP collection in cell-based assays monitoring different biological programmes led to the discovery of a structurally novel and potent inhibitor of the Hedgehog signalling pathway that targets the Smoothened protein.
Topics & Concepts
StereocenterEnantioselective synthesisPyrrolidineNatural productIntramolecular forceHedgehog signaling pathwayChemistryCycloadditionSmoothenedStereochemistryHedgehogCombinatorial chemistryOrganic chemistrySignal transductionBiochemistryCatalysisHedgehog Signaling Pathway StudiesGenomics and Chromatin DynamicsEpigenetics and DNA Methylation