Artículo
Fluoro-labelled sp2-iminoglycolipids with immunomodulatory properties
Autor/es | Padilla Pérez, María del Carmen
Sánchez Fernández, Elena Matilde González-Bakker, Aday Puerta, Adrián Padrón, José M. Martín-Loro, Francisco García Fernández, José Manuel Ortiz Mellet, Carmen |
Departamento | Universidad de Sevilla. Departamento de Química orgánica |
Fecha de publicación | 2023 |
Fecha de depósito | 2023-05-10 |
Publicado en |
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Resumen | 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 ... 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 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. |
Agencias financiadoras | Ministerio de Ciencia e Innovación (MICIN). España Agencia Estatal de Investigación. España European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER) Universidad de Sevilla Instituto de Salud Carlos III Junta de Andalucía Gobierno de Canarias. España |
Identificador del proyecto | PID2019-105858RB-I00
RTI2018-097609-B-C21 PID2021-124247OB-C21 PID2021-123059OB-I00 P20_00166 PI22/01718 PI20-01331 ACIISI/TESIS2020010055 PI20-0036 |
Cita | Padilla 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. |
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