Thiol-ene "Click" Synthesis and Pharmacological Evaluation of C -Glycoside sp 2 -Iminosugar Glycolipids

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&#8722;activity relationship studies was therefore highly wanted. Here we show that a reaction sequence consisting in stereoselective <i>C</i>-allylation followed by thiol-ene &#8220;click&#8221; coupling provides a very convenient access to &#945;-<i>C</i>-glycoside sp²-IGLs. Both the glycone moiety and the aglycone tail can be modified by using sp²-iminosugar precursors with different configurational profiles (<span style="font-variant: small-caps;">d</span>-<i>gluco</i> or <span style="font-variant: small-caps;">d</span>-<i>galacto</i> 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 &#945;-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.

Abstract licence: CC BY

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