N‐Benzyl Substitution of Polyhydroxypyrrolidines: the Way to Selective Inhibitors of Golgi Α‐mannosidase II

Inhibition of the biosynthesis of complex N-glycans in the Golgi apparatus influences progress of tumor growth and metastasis. Golgi -mannosidaseII (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 -mannosidase (LMan), a weakness of all known potent GMII inhibitors. A series of novel N-substituted polyhydroxypyrrolidines was synthesized and tested with modeled GH38 -mannosidases from Drosophila melanogaster (GMIIb and LManII). The most potent structures inhibited GMIIb (K-i=50-76m, as determined by enzyme assays) with a significant selectivity index of IC50(LManII)/IC50(GMIIb) >100. These compounds also showed inhibitory activities in invitro assays with cancer cell lines (leukemia, IC50=92-200m) and low cytotoxic activities in normal fibroblast cell lines (IC50>200m). In addition, they did not show any significant inhibitory activity toward GH47 Aspergillus saitoi1,2-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 -mannosidase.