N-Substituted l-Iminosugars for the Treatment of Sanfilippo Type B Syndrome

Abstract

Sanfilippo syndrome comprises a group of four genetic diseases due to the lack or decreased activity of enzymes involved in heparan sulfate (HS) catabolism. HS accumulation in lysosomes and other cellular compartments results in tissue and organ dysfunctions, leading to a wide range of clinical symptoms including severe neurodegeneration. To date, no approved treatments for Sanfilippo disease exist. Here, we report the ability of N-substituted l-iminosugars to significantly reduce substrate storage and lysosomal dysfunctions in Sanfilippo fibroblasts and in a neuronal cellular model of Sanfilippo B subtype. Particularly, we found that they increase the levels of defective α-N-acetylglucosaminidase and correct its proper sorting toward the lysosomal compartment. Furthermore, l-iminosugars reduce HS accumulation by downregulating protein levels of exostosin glycosyltransferases. These results highlight an interesting pharmacological potential of these glycomimetics in Sanfilippo syndrome, paving the way for the development of novel therapeutic approaches for the treatment of such incurable disease.

Assessing the Potential of N-Butyl-l-deoxynojirimycin (l-NBDNJ) in Models of Cystic Fibrosis as a Promising Antibacterial Agent

“…With 3 in hand, LiAlH 4 -mediated reduction and subsequent Swern oxidation [(COCl) 2 /DMSO, then Et 3 N], followed by reductive amination [butylamine/AcOH/NaBH 3 CN], allowed us to obtain the protected N -butyl- l -deoxynojirimycin 4 . Notably, differently from our previous reports, herein, the use of butylamine as a source of nitrogen for the reductive amination allows to introduce an already alkylated amino function in the ring. Eventually, treatment of 4 with 1 M BCl 3 in DCM at 0 °C gave access to the desired l -NBDNJ ( ent - 1 ) as a hydrochloride salt in 94% yield.…”

“…As previously described by us, 36 2 was first converted into the corresponding allyl glucoside (AllOH/BF 3 •OEt 2 ), which was then reacted under standard conditions with NaH/BnBr to mice acutely infected by P. aeruginosa. Importantly, the decrease in the recruitment of neutrophils did not increase the bacterial load in the airways; instead, it was accompanied by a dose-dependent decrease of bacteria within the lungs.…”

“…As previously described by us, 2 was first converted into the corresponding allyl glucoside (AllOH/BF 3 ·OEt 2 ), which was then reacted under standard conditions with NaH/BnBr to mask the free hydroxyl groups with a benzyl ether function. The allyl group at the anomeric position was then removed (PdCl 2 ) to afford the 2,3,4,6-tetra- O -benzyl- l -glucopyranose ( 3 ) in 95% yield.…”

“…The purity of l -NBDNJ was assessed by absolute quantitative nuclear magnetic resonance (qNMR) experiments following the “general guidelines for quantitative 1D 1 H NMR (qHNMR) experiments,” provided by the Journal of Medicinal Chemistry and was ≥95% (see the Supporting Information for details). 2,3,4,6-Tetra- O -benzyl- l- glucopyranose ( 3 ) has been synthesized as previously reported …”

“…Eventually, while ent-1 did not work as the inhibitor of the most common glycosidases, thus being more selective compared to its D-enantiomer, its action was efficacious toward enzymes involved in other rare diseases such as Pompe and Sanfilippo type B lysosomal diseases. 36,37 Inspired by these findings, herein, we further investigated the anti-inflammatory properties of L-NBDNJ and its potential anti-infective activity in CF, using a murine model of P. aeruginosa chronic infection that closely resembles the complexity of human CF lung disease. 38,39 Particularly, recruitment of inflammatory cells, bacterial load, and cytokine/chemokine profiles have been explored.…”