Padilla Pérez, María del CarmenSánchez Fernández, Elena MatildeGonzález-Bakker, AdayPuerta, AdriánPadrón, José M.Martín-Loro, FranciscoGarcía Fernández, José ManuelOrtiz Mellet, Carmen2023-05-102023-05-102023Padilla Pérez, M.d.C., Sánchez Fernández, E.M., González-Bakker, A., Puerta, A., Padrón, J.M., Martín-Loro, F.,...,Ortiz Mellet, C. (2023). Fluoro-labelled sp2-iminoglycolipids with immunomodulatory properties. European Journal of Medicinal Chemistry, 255, 115390. https://doi.org/10.1016/j.ejmech.2023.115390.0223-5234https://hdl.handle.net/11441/145750The 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 carbo- hydrates, 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 glyco- lipid 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 autoacti- vation under an inflammatory context.application/pdf19 p.engAtribución 4.0 Internacionalhttp://creativecommons.org/licenses/by/4.0/Fluorinated glycomimeticsSelectfluorImmunomodulationCancerInflammationp38α MAPKinfo:eu-repo/semantics/articleinfo:eu-repo/semantics/openAccesshttps://doi.org/10.1016/j.ejmech.2023.115390