期刊论文详细信息
卷:255
Fluoro-labelled sp(2)-iminoglycolipids with immunomodulatory properties
Article
关键词: GLYCOMIMETICS;    ANALOGS;    PROTEIN;    KINASE;   
DOI  :  10.1016/j.ejmech.2023.115390
来源: SCIE
【 摘 要 】

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 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 sp(2)-iminosugar moiety, namely sp(2)-iminoglycolipids (sp(2)-IGLs). The synthesis of two epimeric series of 2-deoxy-2-fluoro-sp(2)-IGLs, structurally related to nojirimycin and mannonojirimycin, has been accomplished by sequential Selectfluor-mediated fluorination and thioglycosidation of sp(2)-iminoglycals. Exclusively the a-anomer is obtained regardless of the configurational profile of the sp(2)-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 a-oriented sulfonyl dodecyl lipid moiety in compound 11 led to remarkable anti-proliferative properties, featuring similar GI(50) 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-sp(2)-IGL induces the non-canonical activation mode of the mitogen-activated protein kinase signaling pathway, causing p38a autoacti-vation under an inflammatory context.

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