GM1 gangliosidosis is a rare lysosomal disease caused by the deficiency of the enzyme beta-galactosidase ( beta-Gal; GLB1; E.C. 3.2.1.23), responsible for the hydrolysis of terminal galactosyl residues from GM1 ganglioside, glycoproteins, and glycosaminoglycans, such as keratan-sulfate. With the aim of identifying new pharmacological chaperones for GM1 gangliosidosis, the synthesis of five new trihydroxypiperidine iminosugars is reported in this work. The target compounds feature a pentyl alkyl chain in different positions of the piperidine ring and different absolute configurations of the alkyl chain at C-2 and the hydroxy group at C-3. The organometallic addition of a Grignard reagent onto a carbohydrate-derived nitrone in the presence or absence of a suitable Lewis Acid was exploited, providing structural diversity at C-2, followed by the ring-closure reductive amination step. An oxidation-reduction process allowed access to a different configuration at C-3. The N-pentyl trihydroxypiperidine iminosugar was also synthesized for the purpose of comparison. The biological evaluation of the newly synthesized compounds was performed on leucocyte extracts from healthy donors and identified two suitable beta-Gal inhibitors, namely compounds 10 and 12. Among these, compound 12 showed chaperoning properties since it enhanced beta-Gal activity by 40% when tested on GM1 patients bearing the p.Ile51Asn/p.Arg201His mutations.

Synthesis of a New beta-Galactosidase Inhibitor Displaying Pharmacological Chaperone Properties for GM1 Gangliosidosis / Francesca Clemente, Macarena Martínez-Bailén, Camilla Matassini, Amelia Morrone, Silvia Falliano, Anna Caciotti, Paolo Paoli, Andrea Goti, Francesca Cardona. - In: MOLECULES. - ISSN 1420-3049. - ELETTRONICO. - 27:(2022), pp. 4008-4028. [10.3390/ molecules27134008]

Synthesis of a New beta-Galactosidase Inhibitor Displaying Pharmacological Chaperone Properties for GM1 Gangliosidosis

Francesca Clemente
;
Camilla Matassini
Membro del Collaboration Group
;
Amelia Morrone
Membro del Collaboration Group
;
Anna Caciotti
Membro del Collaboration Group
;
Paolo Paoli
Membro del Collaboration Group
;
Andrea Goti
Membro del Collaboration Group
;
Francesca Cardona
2022

Abstract

GM1 gangliosidosis is a rare lysosomal disease caused by the deficiency of the enzyme beta-galactosidase ( beta-Gal; GLB1; E.C. 3.2.1.23), responsible for the hydrolysis of terminal galactosyl residues from GM1 ganglioside, glycoproteins, and glycosaminoglycans, such as keratan-sulfate. With the aim of identifying new pharmacological chaperones for GM1 gangliosidosis, the synthesis of five new trihydroxypiperidine iminosugars is reported in this work. The target compounds feature a pentyl alkyl chain in different positions of the piperidine ring and different absolute configurations of the alkyl chain at C-2 and the hydroxy group at C-3. The organometallic addition of a Grignard reagent onto a carbohydrate-derived nitrone in the presence or absence of a suitable Lewis Acid was exploited, providing structural diversity at C-2, followed by the ring-closure reductive amination step. An oxidation-reduction process allowed access to a different configuration at C-3. The N-pentyl trihydroxypiperidine iminosugar was also synthesized for the purpose of comparison. The biological evaluation of the newly synthesized compounds was performed on leucocyte extracts from healthy donors and identified two suitable beta-Gal inhibitors, namely compounds 10 and 12. Among these, compound 12 showed chaperoning properties since it enhanced beta-Gal activity by 40% when tested on GM1 patients bearing the p.Ile51Asn/p.Arg201His mutations.
2022
27
4008
4028
Francesca Clemente, Macarena Martínez-Bailén, Camilla Matassini, Amelia Morrone, Silvia Falliano, Anna Caciotti, Paolo Paoli, Andrea Goti, Francesca ...espandi
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1276921
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