N‐Benzyl Substitution of Polyhydroxypyrrolidines: The Way to Selective Inhibitors of Golgi α‐Mannosidase II

• DOI: 10.1002/cmdc.201700607
• Publication Date: 2018-01-11T13:53:53Z
• Authors: Sergej Šesták; Maroš Bella; Tomáš Klunda; Soňa Gurská; Petr Džubák; Florian Wöls; Iain B. H. Wilson; Vladimir Sladek; Marián Hajdúch; Monika Poláková; Juraj Kóňa
• Keywords: 0301 basic medicine; Binding Sites; Pyrrolidines; Cell Survival; Nitrogen; Golgi Apparatus; Cell Line; 3. Good health; Fungal Proteins; Molecular Docking Simulation; Inhibitory Concentration 50; Structure-Activity Relationship; 03 medical and health sciences; Aspergillus; Drosophila melanogaster; Catalytic Domain; Mannosidases; Animals; Humans

AbstractInhibition of the biosynthesis of complex N‐glycans in the Golgi apparatus influences progress of tumor growth and metastasis. Golgi α‐mannosidase II (GMII) has become a therapeutic target for drugs with anticancer activities. One critical task for successful application of GMII drugs in medical treatments is to decrease their unwanted co‐inhibition of lysosomal α‐mannosidase (LMan), a weakness of all known potent GMII inhibitors. A series of novel N‐substituted polyhydroxypyrrolidines was synthesized and tested with modeled GH38 α‐mannosidases from Drosophila melanogaster (GMIIb and LManII). The most potent structures inhibited GMIIb (Ki=50–76 μm, as determined by enzyme assays) with a significant selectivity index of IC50(LManII)/IC50(GMIIb) >100. These compounds also showed inhibitory activities in in vitro assays with cancer cell lines (leukemia, IC50=92–200 μm) and low cytotoxic activities in normal fibroblast cell lines (IC50>200 μm). In addition, they did not show any significant inhibitory activity toward GH47 Aspergillus saitoiα1,2‐mannosidase. An appropriate stereo configuration of hydroxymethyl and benzyl functional groups on the pyrrolidine ring of the inhibitor may lead to an inhibitor with the required selectivity for the active site of a target α‐mannosidase.