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.

Piperidine Azasugars Bearing Lipophilic Chains: Stereoselective Synthesis and Biological Activity as Inhibitors of Glucocerebrosidase (GCase) / Francesca Clemente, Camilla Matassini, Sara Giachetti, Andrea Goti, Amelia Morrone, Macarena Martínez-Bailén, Sara Orta, Pedro Merino, Francesca Cardona. - In: JOURNAL OF ORGANIC CHEMISTRY. - ISSN 0022-3263. - STAMPA. - 86:(2021), pp. 12745-12761. [10.1021/acs.joc.1c01308]

Piperidine Azasugars Bearing Lipophilic Chains: Stereoselective Synthesis and Biological Activity as Inhibitors of Glucocerebrosidase (GCase)

Francesca Clemente
Membro del Collaboration Group
;
Camilla Matassini
Membro del Collaboration Group
;
Sara Giachetti
Membro del Collaboration Group
;
Andrea Goti
Membro del Collaboration Group
;
Amelia Morrone
Membro del Collaboration Group
;
Macarena Martínez-Bailén
Membro del Collaboration Group
;
Francesca Cardona
Conceptualization
2021

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.
2021
86
12745
12761
Francesca Clemente, Camilla Matassini, Sara Giachetti, Andrea Goti, Amelia Morrone, Macarena Martínez-Bailén, Sara Orta, Pedro Merino, Francesca Cardona
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1245093
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