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sp2-Iminosugar glycolipid mimetics as immunoregulatory agents

AuthorsSánchez-Fernández, E. M.; García-Moreno, M. I.; Arroba, A. I.; Aguilar-Diosdado, M.; Padrón, J. M.; García-Hernández, R.; Gamarro, Francisco; García Fernández, J. M.; Sánchez-Aparicio, J.-E; Masgrau, L.; Ortiz Mellet, C.
Issue Date19-Feb-2020
AbstractMonosaccharide analogs of the sp2-minosugar family offer unprecedented opportunities to access enzymatically and chemically stable glycoconjugate mimetics amenable to drug discovery programs. In this context, the 1-dodecylsulfonyl-5N,6O-oxomethylidenenojirimycin (DSO2-ONJ) (Figure 1), a sp2-iminoglycolipid (IGL) representative, has shown outstandinganti-inflammatory activity in microglia, reducing gliosis in diabetic db/db mice.1DSO2-ONJ further inhibited the activation of human monocyte-derived dendritic cells (DCs) by lipopolysaccharide (LPS) in vitro and in vivo in amouse model of acute inflammation.2Biochemical studies and computational docking experiments endorsed a mechanism of action that implies attachment to the allosteric lipid binding pocket of p38-mitogen-activated protein kinase (MAPK), a key protein in the regulation of the innate immuneresponse. This binding mode has also been demonstrated with sp2-IGLs incorporating at the pseudoanomeric position different polyfluoroalkyl segments of varied lengths that facilitate passage through cell membranes. This modification resulted in a 10-fold higher effectiveness at eliciting p38 (Figure 1).3 In this communication we will present the synthesis of differentfluorinated sp2-IGLs and their biological evaluation in the context of three pathologiesthat share common signaling pathways: cancer, Leishmania infection and inflammation.
Appears in Collections:(IPBLN) Comunicaciones congresos
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