Fluoro-labelled sp2-iminoglycolipids with immunomodulatory properties

• Published in: European journal of medicinal chemistry 2023-07, Vol.255, p.115390-115390, Article 115390
• Main Authors: Padilla-Pérez, M. Carmen, Sánchez-Fernández, Elena M., González-Bakker, Aday, Puerta, Adrián, Padrón, José M., Martín-Loro, Francisco, Arroba, Ana I., García Fernández, José Manuel, Mellet, Carmen Ortiz
• Format: Article
• Language: English
• Subjects: Cancer; Fluorinated glycomimetics; Immunomodulation; Inflammation; p38α MAPK; Selectfluor
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2023.115390

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. [Display omitted] •An efficient synthesis of 2-deoxy-2-fluoro-sp2-iminoglycolipids has been implemented.•Fluoro-labelled sp2-iminoglycolipids target cancer and inflammatory disorders.•The non-canonical activation of p38α MAPK signaling pathway is involved.