Nitrogen-functionalized 2-deoxy sp²-iminoglycolipids: Stereoselective synthesis and biological evaluation

(1R)-1-Dodecylsulfonyl-5N,6O-oxomethylidenenojirimycin is considered a prominent representative member of the sp²-iminoglycolipid (sp²-IGL) family. Numerous structure-activity relationship studies performed over the years have provided valuable information that allow the validation of the hydrophobic tail of twelve carbon atoms connected to the sulfonyl group as responsible for the immunomodulatory potential. Additionally, recent studies underpin the relevant role played by the glycone space in combination with the validated aglycone fragment to enhance the activity as anti-inflammatory, antiproliferative and leishmanicidal agents. Specifically, replacement of the hydroxyl group placed at C2 of 5N,6O-oxomethylidenenojirimycin by fluorine or hydrogen atoms, as well as the installation of monocyclic aromatic hydrocarbons at O3 position, have considerably improved the biological utility of these glycolipid mimetics. Building on these findings, novel structural modifications based on nitrogen-functionalities at C2 (azido, amino, acetamido and acetylhydrazino) have been implemented in this work. Biological information collected from in vitro models reveal that the epimeric compounds 8-NJ and 14-MJ, which feature the azido group, are the most potent antiproliferative sp²-IGLs against a representative panel of human tumor cell lines. These data are consistent with the remarkable leishmanicidal potential against two species of protozoan parasites of the genus Leishmania (Leishmania donovani and Leishmania major). Both sp²-IGLs induce mitochondrial oxidative stress in L. donovani. Likewise, research conducted with the 2-azido-2-deoxy derivative 8-NJ in in vitro (retinal immune cells) and ex vivo (retinal explants) diabetic retinopathy-related inflammatory models, confirm its anti-inflammatory potential by downregulating key pro-inflammatory cytokines, attenuating inflammasome activation, activating the heme oxygenase-1 and reducing reactive gliosis.