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 =50-76 μm, as determined by enzyme assays) with a significant selectivity index of IC (LManII)/IC (GMIIb) >100. These compounds also showed inhibitory activities in in vitro assays with cancer cell lines (leukemia, IC =92-200 μm) and low cytotoxic activities in normal fibroblast cell lines (IC >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.

N-Alkylated 1,4-dideoxy-1,4-imino-L-lyxitols (N-alkylated polyhydroxypyrrolidines) differing in the alkyl chain length (from C7 to C14) and its capping functional group (methyl, amine, amidine and guanidine) have been synthesized. Based on a...

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Abstractinfections are becoming increasingly prevalent and many clinical isolates are resistant to common azole derivatives treatment. Accordingly, the capacity of a series of 19 alkyl glycosides, mainly mannosides and glucosides but also a cellobioside with aglycone chain-length from C-6 to C-20, to inhibit the growth of laboratory and clinically isolated strains of