Abstract
A synthetic approach to 1,4-imino-L-lyxitols with various modifications at the C-5 position is reported. These imino-L-lyxitol cores were used for the preparation of a series of N-(4-halobenzyl)polyhydroxypyrrolidines. An impact of the C-5 modification on the inhibition and selectivity against GH38 α-mannosidases from Drosophila melanogaster, the Golgi (GMIIb) and lysosomal (LManII) mannosidases and commercial jack bean α-mannosidase from Canavalia ensiformis was evaluated. The modification at C-5 affected their inhibitory activity against the target GMIIb enzyme. In contrast, no inhibition effect of the pyrrolidines against LManII was observed. The modification of the imino-L-lyxitol core is therefore a suitable motif for the design of inhibitors with desired selectivity against the target GMIIb enzyme.
Highlights
Carbohydrates as chiral templates for a construction of bioactive compounds are of steady interest in medicinal chemistry [1,2,3]
In a series of our previous papers, it has been found that a combination of a saccharide core (D-mannose, D-mannose with modification at C-6) and hydrophobic linker has an impact on the inhibition efficiency of the tested synthetic compound against the target GMIIb enzyme
We explored structure–activity relationships (SAR) of pyrrolidine derivatives 1 with different modifications at position 5
Summary
Carbohydrates as chiral templates for a construction of bioactive compounds are of steady interest in medicinal chemistry [1,2,3]. In a series of our previous papers, it has been found that a combination of a saccharide core (D-mannose, D-mannose with modification at C-6) and hydrophobic linker (benzyl, phenethyl) has an impact on the inhibition efficiency of the tested synthetic compound against the target GMIIb enzyme. Evaluation of these derivatives revealed that benzyl is a suitable hydrophobic linker. The synthesis of modified pyrrolidine derivatives 2–5 (Figure 1) and GH38 α-mannosidases inhibition studies are reported
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