N-Benzyl Substitution of Polyhydroxypyrrolidines: The Way to Selective Inhibitors of Golgi ?-Mannosidase?II.

ABSTRACT: Inhibition of the biosynthesis of complex N-glycans in the Golgi apparatus influences progress of tumor growth and metastasis. Golgi ?-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 ?-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 (Ki =50-76??m, 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??m) and low cytotoxic activities in normal fibroblast cell lines (IC50 >200??m). In addition, they did not show any significant inhibitory activity toward GH47 Aspergillus saitoi?1,2-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.

SUBMITTER: Sestak S 

PROVIDER: S-EPMC6176901 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature