Thiol-ene "Click" Synthesis and Pharmacological Evaluation of C-Glycoside sp2-Iminosugar Glycolipids

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.

Anti-Inflammatory (M2) Response Is Induced by a sp2-Iminosugar Glycolipid Sulfoxide in Diabetic Retinopathy

“…Biochemical and computational data support a mechanism involving noncanonical auto-phosphorylation of p38a mitogen-activated protein kinase (MAPK), a key player in the inflammatory cascade, via binding of the sp 2 -IGL to the lipid binding site of the protein (6,9). Contrary to other immuno-regulatory glycolipids, the sp 2 -IGLs are metabolically stable and can be prepared in the laboratory in pure anomeric form with total stereo-selectivity, thereby providing a suitable platform for glyco-drug design (10)(11)(12)(13)(14)(15)(16).…”

Stereoselective Synthesis of Nojirimycin α-C-Glycosides from a Bicyclic Acyliminium Intermediate: A Convenient Entry to N,C-Biantennary Glycomimetics

“…Lineweaver–Burk plots and a double-reciprocal analysis provided accurate K i values and confirmed the inhibition mode. 76 , 77 …”

Synthesis of sp2-Iminosugar Selenoglycolipids as Multitarget Drug Candidates with Antiproliferative, Leishmanicidal and Anti-Inflammatory Properties

“…The ensemble of data collected on the immunomodulatory behavior of sp 2 -IGLs [45][46][47][48][49][50][51][52][53][54][55] instils that linear aliphatic tails with a length equal or higher than C 8 are required to elicit significant anticancer, antiparasitic and/or anti-inflammatory responses. Accordingly, we focused on n-octyl and n-docecyl aglycone lipid tails in this study.…”

“…Conjugates conjoining a sp 2 -minosugar glycone and an α-oriented lipid aglycone, generically termed sp 2 -iminosugar glycolipids (sp 2 -IGLs), have also shown promising abilities as innate immune system regulators with anti-inflammatory [45][46][47], anticancer [48,49] and antiparasitic [50,51] behaviors. A variety of sp 2 -IGLs with C-, N-, Oand S-pseudoglycosidic bonds are already on record [52][53][54]. Structure-activity relationship studies have shown that (i) the lipid aglycone plays an essential role in the therapeutic effect of the sp 2 -IGLs; and (ii) the nature of the glycosidic functionality bridging the aglycone and lipid moieties is also critical for activity.…”