Potent GH20 N-Acetyl-β-d-hexosaminidase Inhibitors: N-Substituted 3-acetamido-4-amino-5-hydroxymethyl-cyclopentanediols

Abstract

From 1,2;3,4-di-O-isopropylidene-d-galactopyranose, a preliminary series of highly functionalized amino(hydroxymethyl)cyclopentanes was easily available. These amine-containing basic carbasugars featuring the d-galacto configuration are potent inhibitors of the GH20 β-d-hexosaminidases probed and may bear potential as regulators of N-acetyl-d-hexosaminidase activities in vivo.

Mechanistic Insights into the Chaperoning of Human Lysosomal-Galactosidase Activity: Highly Functionalized Aminocyclopentanes and C-5a-Substituted Derivatives of 4-epi-Isofagomine

“…Dansylaminohexyl substituted cyclopentane 17 was synthesized as described [ 55 ]. The corresponding deoxy derivative 31 was prepared from the recently reported [ 57 ] all- cis epimer 23 ( Scheme 2 ). Activation of the free alcohol as a triflate ( 24 ) and treatment of the latter with sodium bromide in DMF gave bromodeoxy derivative 25 with clean inversion of configuration.…”

“…To an ice-cooled solution of alcohol 23 (ref. [ 57 ], 292 mg, 1.00 mmol) in dichloromethane (10 mL), pyridine (0.324 mL, 4.01 mmol) and trifluoromethanesulfonyl anhydride (0.219 mL, 1.30 mmol) were added and the reaction was allowed to reach ambient temp under stirring. After completed conversion of the starting material, the reaction mixture was diluted with dichloromethane and consecutively washed with aqueous HCl (6%) and saturated aqueous sodium bicarbonate.…”

“…A solution of alcohol 23 (ref. [ 57 ], 298 mg, 1.02 mmol) in CH 2 Cl 2 (10 mL) was cooled to 0 °C and treated with pyridine (0.330 mL, 4.09 mmol) and DAST (0.270 mL, 2.05 mmol). When completed conversion of the starting material was observed (2 h), the reaction mixture was quenched with saturated aqueous NaHCO 3 and the organic layer was dried with Na 2 SO 4 , filtered and the solvent was removed under reduced pressure.…”

Diaminocyclopentane-derived O-GlcNAcase inhibitors for combating tau hyperphosphorylation in Alzheimer's disease

“…Its o-N-dansylated amphiphilic C-6 substituent had previously been shown to be largely beneficial for inhibitory activity and detection purposes. 23,24 Its D-gluco-epimer 8 showed a significantly reduced activity with both HexB (IC 50 = 4.48 mM; 500-fold reduction), and with OGA (IC 50 = 0.126 mM; 7-fold reduction) compared with 44. Nevertheless, the selectivity of 8 for OGA over HexB improved 70fold compared with 44 (Fig.…”

Glycomimetics: Design, Synthesis, and Therapeutic Applications

“…Carbasugars are also an important class of pharmacological chaperones. Stütz et al report the synthesis of amine-containing cyclopentanols as hexosamine mimetics featuring the D- galacto configuration [ 21 ]. These compounds were found to be potent inhibitors of GH20 N -Acetyl D-hexosaminidases, and as such are potential pharmacological chaperones for the treatment of Tay Sachs disease.…”