Abstract
The unique stereoelectronic properties of sp2-iminosugars enable their participation in glycosylation reactions, thereby behaving as true carbohydrate chemical mimics. Among sp2-iminosugar conjugates, the sp2-iminosugar glycolipids (sp2-IGLs) have shown a variety of interesting pharmacological properties ranging from glycosidase inhibition to antiproliferative, antiparasitic, and anti-inflammatory activities. Developing strategies compatible with molecular diversity-oriented strategies for structure–activity relationship studies was therefore highly wanted. Here we show that a reaction sequence consisting in stereoselective C-allylation followed by thiol-ene “click” coupling provides a very convenient access to α-C-glycoside sp2-IGLs. Both the glycone moiety and the aglycone tail can be modified by using sp2-iminosugar precursors with different configurational profiles (d-gluco or d-galacto in this work) and varied thiols, as well as by oxidation of the sulfide adducts (to the corresponding sulfones in this work). A series of derivatives was prepared in this manner and their glycosidase inhibitory, antiproliferative and antileishmanial activities were evaluated in different settings. The results confirm that the inhibition of glycosidases, particularly α-glucosidase, and the antitumor/leishmanicidal activities are unrelated. The data are also consistent with the two later activities arising from the ability of the sp2-IGLs to interfere in the immune system response in a cell line and cell context dependent manner.
Highlights
Since their conception in the mid-1990s, sp2 -iminosugars have consolidated as a unique class of glycomimetics in terms of chemical and structural versatility
This strategy has been exploited for the development of glycosidase activity enhancers as pharmacological chaperone candidates against several lysosomal storage disorders [18,19,20], including Gaucher [21,22,23,24,25,26], Fabry [27,28], GM1 -gangliosidosis [29,30], Tay–Sachs [31], and α-mannosidosis [32] diseases
The pseudoamide functional group influences the stereoelectronic properties at the pseudoanomeric region, which translates into an exacerbated anomeric effect that imparts a high chemical stability to axially-oriented heteroatom substituents
Summary
Since their conception in the mid-1990s, sp2 -iminosugars have consolidated as a unique class of glycomimetics in terms of chemical and structural versatility. Oxidation to the corresponding sulfone derivative (DSO2 -ONJ) considerably improved the potency as leishmanicidal (up to 5-fold) without reducing the antiproliferative efficiency against different human tumor cell lines (GI50 < 20 μM) Initially these behaviors were ascribed to the ability of inhibiting α-glucosidase, further evidence suggested that this might not be the case, as illustrated by the fact that the 5N,6O-oxomethylidenenojirimycin (OGJ) epimers (DS-OGJ and DSO2 -OGJ, respectively, displayed similar antiproliferative and antiparasitic trends (Figure 1).
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