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N ‐Benzyl Substitution of Polyhydroxypyrrolidines: The Way to Selective Inhibitors of Golgi α‐Mannosidase II
Author(s) -
Šesták Sergej,
Bella Maroš,
Klunda Tomáš,
Gurská Soňa,
Džubák Petr,
Wöls Florian,
Wilson Iain B. H.,
Sladek Vladimir,
Hajdúch Marián,
Poláková Monika,
Kóňa Juraj
Publication year - 2018
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.201700607
Subject(s) - mannosidase , golgi apparatus , pyrrolidine , chemistry , biochemistry , stereochemistry , enzyme , growth inhibition , in vitro , biology , cell
Inhibition 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 ( K i =50–76 μ m , as determined by enzyme assays) with a significant selectivity index of IC 50 (LManII)/IC 50 (GMIIb) >100. These compounds also showed inhibitory activities in in vitro assays with cancer cell lines (leukemia, IC 50 =92–200 μ m ) and low cytotoxic activities in normal fibroblast cell lines (IC 50 >200 μ m ). In addition, they did not show any significant inhibitory activity toward GH47 Aspergillus saitoi α1,2‐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.