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.

• MeSH
• Aspergillus enzymologie   MeSH
• buněčné linie MeSH
• Drosophila melanogaster enzymologie   MeSH
• dusík chemie   MeSH
• fungální proteiny antagonisté a inhibitory   metabolismus   MeSH
• Golgiho aparát enzymologie   MeSH
• inhibiční koncentrace 50 MeSH
• katalytická doména MeSH
• lidé MeSH
• mannosidasy antagonisté a inhibitory   metabolismus   MeSH
• pyrrolidiny chemie   metabolismus   farmakologie   MeSH
• simulace molekulového dockingu MeSH
• vazebná místa MeSH
• viabilita buněk účinky léků   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• Publikační typ
• abstrakty MeSH