Stereoselective synthesis of 2-acetamido-1,2-dideoxynojirimycin (DNJNAc) and ureido-DNJNAc derivatives as new hexosaminidase inhibitors

Abstract

2-Acetamido-1,2-dideoxyiminosugars are selective and potent inhibitors of hexosaminidases and therefore show high therapeutic potential for the treatment of various diseases, including several lysosomal storage disorders. A stereoselective synthesis of 2-acetamido-1,2-dideoxynojirimycin (DNJNAc), the iminosugar analog of N-acetylglucosamine, with high overall yield is here described. This novel procedure further allowed accessing ureidoDNJNAc conjugates through derivatization of the endocyclic amine on a key pivotal intermediate. Remarkably, some of the ureido-DNJNAc representatives behaved as potent and selective inhibitors of β-hexosaminidases, including the human enzyme, being the first examples of neutral sp 2 -iminosugar-type inhibitors reported for these enzymes. Moreover, the amphiphilic character of the new ureido-DNJNAc is expected to confer better drug-like properties.

Carbohydrate supramolecular chemistry: beyond the multivalent effect

“…Commun., 2020, 56, 5207--5222 | 5215 the hypothesis that multimerization of a glycomimetic onto a nanometric scaffold elicits binding modes to the glycosidases that can be radically different from the binding mode of the monomer. 164 The authors capitalized on the unique stereoelectronic and chemical properties of the so-called sp 2 -iminosugar glycomimetics, 165 in which the underlining amine group of iminosugars is replaced into a trigonal planar pseudoamidetype nitrogen (N-carbonyl, N-thiocarbonyl, N-imino group), with a substantial sp 2 -hybridization nature (e.g., as in carbamate, 166 thiocarbamate, [167][168][169] urea, [170][171][172] thiourea, [173][174][175][176][177][178][179][180] isourea, [180][181][182][183][184][185][186][187] isothiourea, [187][188][189][190][191][192][193][194][195] guanidine, 196,197 sulfamide 198 or thiohydantoin 199 functionalities), to access stable O-, S-, N-and C-pseudoglycosides. [200][201][202][203][204][205]…”

Stereoselective Synthesis of Nojirimycin α-C-Glycosides from a Bicyclic Acyliminium Intermediate: A Convenient Entry to N,C-Biantennary Glycomimetics

“…Hydrolysis of the cyclic carbamate functionality in 8 was successfully effected by treatment with barium hydroxide in a mixture of methanol and water at 70 °C. − Partition of the reaction mixture between ethyl acetate and water allowed a very convenient separation of the organic product from the inorganic salts, which was instead very problematic when the base-sensitive triacetate 10 was used as the precursor. The allyl tri- O -benzyl-NJ α- C -glycoside 12 was thus obtained in 93% yield.…”

sp2-Iminosugars targeting human lysosomal β-hexosaminidase as pharmacological chaperone candidates for late-onset Tay-Sachs disease

“…Most interestingly, amphiphilic sp 2 -iminosugars exhibited very favourable chaperoning/inhibitory balances in patient-derived neurons 54 and were shown to cross the blood-brain barrier in a murine model 60 , supporting their potential to prevent or slow neurological decline. Devising sp 2 -iminosugars with strong affinity and selectivity towards HexA represents, thus, an appealing tactic towards a PC therapy option for TSD 62 , 63 ( Figure 2 ). To probe this hypothesis, we have now synthesised a series of monocyclic and bicyclic GalNAc mimetics belonging to the sp 2 -iminosugar family bearing varying substituents, determined the inhibitory profile against different glycosidases and evaluated the hexosaminidase-enhancing capabilities in fibroblasts from healthy donors and TSD patients.…”