Synthesis and chelation study of a fluoroionophore and a glycopeptide based on an aza crown iminosugar structure

International audienceCapitalizing on a recently reported iminosugar-based aza-crown (ISAC) accessed by a double Staudinger azaWittig coupling reaction, we have expanded the structural diversity of this new family of sweet cyclam analogs. Replacement of the two secondary amines linking the iminosugar units by two amide bonds obtained a cyclodimerization by with BOP and DIPEA led to a macrocycle that did not demonstrate efficient Zn2+ chelation unlike the parent ISAC. Introduction of two pyrene moieties on the secondary amines of the parent ISAC yielded a new fluoroionophore that selectively binds Hg2+ in methanol

Iminosugar-C-glycosides work as pharmacological chaperones of NAGLU, a glycosidase involved in MPS IIIB rare disease

International audienceMucopolysaccharidosis type IIIB is a devastating neurological disease caused by a lack of the lysosomal enzyme, aN -acetylglucosaminidase (NAGLU), leading to a toxic accumulation of heparan sulfate. Herein we explored a pharmacological chaperone approach to enhance the residual activity of NAGLU in patient fibroblasts. Capitalizing on the three-dimensional structures of two modest homoiminosugar-based NAGLU inhibitors in complex with bacterial homolog of NAGLU, CpGH89, we have synthesized a library of 17 six-membered iminosugar-C-glycosides mimicking N-acetyl-Dglucosamine and bearing various pseudo-anomeric substituents of both a-and b-configuration. Elaboration with the aglycon moiety results in low micromolar selective inhibitors of human recombinant NAGLU, but surprisingly it is the nonfunctionalized and wrongly configured b-homoiminosugar that was proved to act as the most promising pharmacological chaperone, promoting a 2.4 fold activity enhancement of mutant NAGLU at its optimal concentration