N‐Benzyl Substitution of Polyhydroxypyrrolidines: The Way to Selective Inhibitors of Golgi α‐Mannosidase II |
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Authors: | Dr Sergej ?esták Dr Maro? Bella Tomá? Klunda Dr Soňa Gurská Dr Petr D?ubák Florian Wöls Dr Iain B H Wilson Dr Vladimir Sladek Assoc?Prof Marián Hajdúch Dr Monika Poláková Dr Juraj Kóňa |
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Affiliation: | 1. Institute of Chemistry, Center for Glycomics, Slovak Academy of Sciences, Bratislava, Slovakia;2. Laboratory of Experimental Medicine, Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University and University Hospital in Olomouc, Olomouc, Czech Republic;3. Department of Chemistry, University of Natural Resources and Life Sciences, Vienna, Austria |
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Abstract: | 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 (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. |
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Keywords: | cytotoxicity Golgi α -mannosidase II molecular modeling pyrrolidines swainsonine |
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