Fluoro-labelled sp2-iminoglycolipids with immunomodulatory properties

  • Eur J Med Chem. 2023 Jul 5;255:115390. doi: 10.1016/j.ejmech.2023.115390.
M Carmen Padilla-Pérez  1 ,  Elena M Sánchez-Fernández  2 ,  Aday González-Bakker  3 ,  Adrián Puerta  3 ,  José M Padrón  4 ,  Francisco Martín-Loro  5 ,  Ana I Arroba  6 ,  José Manuel García Fernández  7 ,  Carmen Ortiz Mellet  1
Affiliations
  • 1. Department of Organic Chemistry, Faculty of Chemistry, University of Sevilla, C/ Profesor García González 1, 41012, Sevilla, Spain.
  • 2. Department of Organic Chemistry, Faculty of Chemistry, University of Sevilla, C/ Profesor García González 1, 41012, Sevilla, Spain. Electronic address: [email protected].
  • 3. BioLab, Instituto Universitario de Bio-Orgánica "Antonio González", Universidad de la Laguna, C/ Astrofísico Francisco Sánchez 2, 38206, La Laguna, Spain.
  • 4. BioLab, Instituto Universitario de Bio-Orgánica "Antonio González", Universidad de la Laguna, C/ Astrofísico Francisco Sánchez 2, 38206, La Laguna, Spain. Electronic address: [email protected].
  • 5. Biomedical Research and Innovation Institute of Cádiz (INiBICA) Research Unit, Puerta del Mar University Hospital, Av/ Ana de Viya 21, 11009, Cádiz, Spain.
  • 6. Biomedical Research and Innovation Institute of Cádiz (INiBICA) Research Unit, Puerta del Mar University Hospital, Av/ Ana de Viya 21, 11009, Cádiz, Spain; Department of Biomedicine, Biotechnology and Public Health Immunology Area, University of Cádiz Pl. Falla, 9, 11003, Cádiz, Spain.
  • 7. Instituto de Investigaciones Químicas (IIQ), CSIC - Universidad de Sevilla, C/ Américo Vespucio 49, Isla de la Cartuja, 41092, Sevilla, Spain.
PMID: 37137247 DOI: 10.1016/j.ejmech.2023.115390
Abstract

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.

Keywords
Cancer; Fluorinated glycomimetics; Immunomodulation; Inflammation; Selectfluor; p38α MAPK.
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