Abstract
A novel methodology is described for the efficient and divergent synthesis of pseudodisaccharides, molecules comprising of amino carbasugar analogues linked to natural sugars. The methodology is general and enables the introduction of diversity both at the carbasugar and the natural sugar components of the pseudodisaccharides. Using this approach, a series of pseudodisaccharides are synthesised that mimic the repeating backbone unit of heparan sulfate, and are tested for inhibition of heparanase, a disease-relevant enzyme that hydrolyses heparan sulfate. A new homology model of human heparanase is described based on a family 79 β-glucuronidase. This model is used to postulate a computational rationale for the observed activity of the different pseudodisaccharides and provide valuable information that informs the design of potential inhibitors of this enzyme.
Highlights
Glycosyl hydrolases control many significant biological transformations, and are implicated in numerous pathophysiological events[1,2,3]
Starting from glucose, we first prepared vinylsugar 12a-12c via transetherification with butyl vinyl ether, in the presence of Pd(II) as a catalyst (Figure 5)[26,27]. These vinyl sugars were transformed to the corresponding pseudosaccharides through a multistep chemical synthesis outlined below (Figure 6)
Analysis of the modes of binding of these molecules within the catalytic site of heparanase, reveals that even though the molecules do not have the same configuration at the carbasugar unit, the molecules are able to adopt a conformation that allows an interaction between their respective amino group and the Glu225 residue of the catalytic domain (Figure 15)
Summary
Glycosyl hydrolases control many significant biological transformations, and are implicated in numerous pathophysiological events[1,2,3]. This is postulated to be due to the enhanced binding affinity of pseudodisaccharides as the result of the increase in enzyme-substrate interactions, which leads to a better competitiveness with the enzyme’s natural substrate within the active site.
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