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

The unique stereoelectronic properties of sp(2)-iminosugars enable their participation in glycosylation reactions, thereby behaving as true carbohydrate chemical mimics. Among sp(2)-iminosugar conjugates, the sp(2)-iminosugar glycolipids (sp(2)-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 sp(2)-IGLs. Both the glycone moiety and the aglycone tail can be modified by using sp(2)-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 sp(2)-IGLs to interfere in the immune system response in a cell line and cell context dependent manner.