Fluoro-labelled sp²-iminoglycolipids with immunomodulatory properties

The unique electronic properties of the fluorine atom make its strategic incorporation into a bioactive compound a very useful tool in the design of drugs with optimized pharmacological properties. In the field of the carbohydrates, its selective installation at C2 position has proven particularly interesting, some 2-deoxy-2-fluorosugar derivatives being currently in the market. We have now transferred this feature into immunoregulatory glycolipid mimetics that contain a sp²-iminosugar moiety, namely sp²-iminoglycolipids (sp²-IGLs). The synthesis of two epimeric series of 2-deoxy-2-fluoro-sp²-IGLs, structurally related to nojirimycin and mannonojirimycin, has been accomplished by sequential Selectfluor-mediated fluorination and thioglycosidation of sp²-iminoglycals. Exclusively the α-anomer is obtained regardless of the configurational profile of the sp²-IGL (d-gluco or d-manno), highlighting the overwhelming anomeric effect in these prototypes. Notably, the combination of a fluorine atom at C2 and an α-oriented sulfonyl dodecyl lipid moiety in compound 11 led to remarkable anti-proliferative properties, featuring similar GI₅₀ values than the chemotherapy drug Cisplatin against several tumor cell lines and better selectivity. The biochemical data further evidence a strong reduction of the number of tumor cell colonies and apoptosis induction. Mechanistic investigations revealed that this fluoro-sp²-IGL induces the non-canonical activation mode of the mitogen-activated protein kinase signaling pathway, causing p38α autoactivation under an inflammatory context.