Amino Acid-Based Synthesis and Glycosidase Inhibition of Cyclopropane-Containing Iminosugars

Abstract

Synthesis of four iminosugars fused to a cyclopropane ring is described using L-serine as the chiral pool. The key steps are large-scale preparation of an α,β-unsaturated piperidinone followed by completely stereoselective sulfur ylide cyclopropanation. Stereochemistry of compounds has been studied by nuclear Overhauser effect spectroscopy (NOESY) experiments and 1 H homonuclear decoupling to measure constant couplings. The activity of these compounds against different glycosidases has been evaluated. Although inhibition activity was low (compound 8a presents a (K i ) of 1.18 mM against βgalactosidase from Escherichia coli), interestingly, we found that compounds 8a and 8b increase the activity of neuraminidase from Vibrio cholerae up to 100%.

Recent Efforts in Identification of Privileged Scaffolds as Antiviral Agents

“…Although the amount of inhibition was minimal (compound 76 has a (Ki) of 1.18 mM against Escherichia coli's galactosidase), it is interesting to note that compounds 76 and 77 (Figure 31) significantly boost the activity of Vibrio cholerae's neuraminidase, increasing it by up to 100 %. [52] Kwak et al created a nanopore-based method for analyzing the enzymatic activity of NA, allowing for a quick and highly accurate diagnosis of IAV. Galactose cleaved from sialylgalactose 78 (Figure 32) by NA of the influenza virus can be identified in real-time and at the single-molecule level, according to the recent blocking analysis of the D-glucose/Dgalactose-binding protein (GBP) trapped inside a type I ClyA-AS (ClyA mutant) nanopore.…”

“…These substances have been tested for their ability to inhibit various glycosidases. Although the amount of inhibition was minimal (compound 76 has a (Ki) of 1.18 mM against Escherichia coli‘s galactosidase), it is interesting to note that compounds 76 and 77 (Figure 31) significantly boost the activity of Vibrio cholerae‘s neuraminidase, increasing it by up to 100 % [52] …”

Synthesis of thiodisaccharides related to 4-thiolactose. Specific structural modifications increase the inhibitory activity against E. coli β-galactosidase

“…[4][5][6][7] Glycomimetics have been used for different purposes and an area of growth is their use as inhibitors of enzymes that are involved in key biological processes. [8][9][10][11][12][13][14] They are commonly recognized by enzymes, but often show resistance to hydrolysis and metabolic degradation and in many cases act as enzyme inhibitors. In recent years, special attention has been paid to β-galactosidase from E. coli, [15][16][17][18] a paradigmatic enzyme in glycobiology and widely used as a biocatalyst for the synthesis of oligosaccharides and glycosides.…”

“…4–7 Glycomimetics have been used for different purposes and an area of growth is their use as inhibitors of enzymes that are involved in key biological processes. 8–14…”