Abstract
We report a straightforward synthetic strategy for the preparation of trihydroxypiperidine azasugars decorated with lipophilic chains at both the nitrogen and the adjacent carbon as potential inhibitors of the lysosomal enzyme glucocerebrosidase (GCase), which is involved in Gaucher disease. The procedure relies on the preparation of C-erythrosyl N-alkylated nitrones 10 through reaction of aldehyde 8 and primary amines 13 followed by oxidation of the imines formed in situ with the methyltrioxorhenium catalyst and urea hydrogen peroxide. The addition of octylMgBr to nitrone 10e provided access to both epimeric hydroxylamines 21 and 22 with opposite configuration at the newly created stereocenter in a stereodivergent and completely stereoselective way, depending on the absence or presence of BF3·Et2O. Final reductive amination and acetonide deprotection provided compounds 14 and 15 from low-cost d-mannose in remarkable 43 and 32% overall yields, respectively, over eight steps. The C-2 R-configured bis-alkylated trihydroxypiperidine 15 was the best ligand for GCase (IC50 = 15 μM), in agreement with MD simulations that allowed us to identify the chair conformation corresponding to the best binding affinity.
Highlights
IntroductionImino- and azasugar-based glycomimetics became attractive as potential therapeutic agents toward lysosomal storage disorders (LSDs), following the observation of their counter-intuitive effect in enhancing the enzyme activity, acting as chaperones
Iminosugars [e.g., deoxynojirimycin, DNJ (1), Figure 1] are among the most fascinating monosaccharide analogues in investigated in the last thirty years as glycosidase[2] and glycosyltransferase inhibitors.[3]More recently, imino- and azasugar-based glycomimetics became attractive as potential therapeutic agents toward lysosomal storage disorders (LSDs), following the observation of their counter-intuitive effect in enhancing the enzyme activity, acting as chaperones
The observed orientation for the piperidine ring is different with respect to that observed in a known chaperone [5hydroxymethyl-3,4-dihydroxypiperidine, IFG (2), Figure 1], loosing interactions of hydroxyl groups with Asp[127], Trp[179], and Asn[396] that form new interactions with Ser[237], Asp[283], and Gln[284]
Summary
Imino- and azasugar-based glycomimetics became attractive as potential therapeutic agents toward lysosomal storage disorders (LSDs), following the observation of their counter-intuitive effect in enhancing the enzyme activity, acting as chaperones. In the pharmacological chaperone therapy (PTC) of LSDs, these glycomimetics are employed at sub-inhibitory concentration to favor the mutated enzyme correct folding in the endoplasmic reticulum (ER), facilitate its translocation to the lysosomes, and recover some hydrolytic activity, compromised as a consequence of diverse genetic mutations.[4]. The which a nitrogen atom replaces the endocyclic oxygen.[1] Together with azasugars, [e.g. isofagomine, IFG (2), or 1,5dideoxy-1,5-iminoxylitol, DIX (3), Figure 1], which are characterized by a nitrogen atom replacing the anomeric carbon of monosaccharides, iminosugars have been extensively
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