Abstract
Sanfilippo syndrome (Mucopolysaccharidosis type III, or MPS III) is an inherited neurodegenerative disorder resulting from mutations in genes encoding lysosomal enzymes that sequentially degrade heparan sulfate. Currently, there are no approved treatments and life expectancy is <20 years. The two most common subtypes are MPS IIIA and IIIB, caused by mutations in N-sulfoglucosamine sulfohydrolase (SGSH) and α-N-acetylglucosaminidase (NAGLU), respectively. Fluorogenic substrates based on a 4-methylumbelliferyl aglycone for both SGSH and NAGLU are critical components of cell-based assays used in drug screening efforts for MPS IIIA and IIIB. However, the reported syntheses suffer from low yields due to poor α-selectivity in the key aromatic glycosylation step. Herein we report new, efficient syntheses of both substrates featuring a completely α-selective glycosylation via the use of a thioglycoside donor pre-activated with diphenyl sulfoxide/triflic anhydride. We also demonstrate the utility of these substrates for quantitating SGSH and NAGLU activity in tissues from MPS IIIA or IIIB mice.
Supplementary materials
Title
NMR data for compounds synthesized.
Description
Copies of 1H, 13C, COSY and HSQC NMR spectra for synthesized compounds.
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