Synthesis of N-benzyl substituted 1,4-imino-l-lyxitols with a basic functional group as selective inhibitors of Golgi α-mannosidase IIb.

Inhibition of the biosynthesis of complex N-glycans in the Golgi apparatus is one of alternative ways to suppress growth of tumor tissue. Eight N-benzyl substituted 1,4-imino-l-lyxitols with basic functional groups (amine, amidine, guanidine), hydroxyl and fluoro groups were prepared, optimized their syntheses and tested for their ability to inhibit several α-mannosides from the GH family 38 (GMIIb, LManII and JBMan) as models for human Golgi and lysosomal α-mannoside II. All compounds were found to be selective inhibitors of GMIIb. The most potent structure bearing guanidine group, inhibited GMIIb at the micromolar level (Ki  = 19 ± 2 µM) while no significant inhibition (>2 mM) of LManII and JBMan was observed. Based on molecular docking and pKa calculations this structure may form two salt bridges with aspartate dyad of the target enzyme improving its inhibitory potency compared with other N-benzyl substituted derivatives published in this and previous studies.