Pharmacological chaperones (PCs) are small molecules that bind and stabilize enzymes. They can rescue the enzymatic activity of misfolded or deficient enzymes when they are used at subinhibitory concentration, thus with minimal side effects. Pharmacological Chaperone Therapy (PCT) is an emerging treatment for many lysosomal storage disorders (LSDs) including Gaucher disease, the most common, which is characterized by a deficiency in the GCase enzyme. We report herein a straightforward synthetic strategy to afford C-2 substituted trihydroxypiperidines with different alkyl chains starting from low cost D-mannose. Stereoselective Grignard reagent addition onto a key nitrone intermediate in the presence or absence of a suitable Lewis acid afforded both epimers of the target compounds, after a final reductive amination-ring closure step. We show that the shift of the alkyl chain from the endocyclic nitrogen to the C-2 position leads to a considerable increase in chaperoning efficacy, affording a new compound (4a) able to induce a remarkable 1.9-fold maximal increase in GCase activity.

Stereoselective Synthesis of C‑2 Alkylated Trihydroxypiperidines: Novel Pharmacological Chaperones for Gaucher Disease / Francesca Clemente, Camilla Matassini, Andrea Goti, Amelia Morrone, Paolo Paoli, Francesca Cardona. - In: ACS MEDICINAL CHEMISTRY LETTERS. - ISSN 1948-5875. - STAMPA. - 10:(2019), pp. 621-626. [10.1021/acsmedchemlett.8b00602]

Stereoselective Synthesis of C‑2 Alkylated Trihydroxypiperidines: Novel Pharmacological Chaperones for Gaucher Disease

CLEMENTE, FRANCESCA
Membro del Collaboration Group
;
Camilla Matassini
Membro del Collaboration Group
;
Andrea Goti
Membro del Collaboration Group
;
Amelia Morrone
Membro del Collaboration Group
;
Paolo Paoli
Membro del Collaboration Group
;
Francesca Cardona
Membro del Collaboration Group
2019

Abstract

Pharmacological chaperones (PCs) are small molecules that bind and stabilize enzymes. They can rescue the enzymatic activity of misfolded or deficient enzymes when they are used at subinhibitory concentration, thus with minimal side effects. Pharmacological Chaperone Therapy (PCT) is an emerging treatment for many lysosomal storage disorders (LSDs) including Gaucher disease, the most common, which is characterized by a deficiency in the GCase enzyme. We report herein a straightforward synthetic strategy to afford C-2 substituted trihydroxypiperidines with different alkyl chains starting from low cost D-mannose. Stereoselective Grignard reagent addition onto a key nitrone intermediate in the presence or absence of a suitable Lewis acid afforded both epimers of the target compounds, after a final reductive amination-ring closure step. We show that the shift of the alkyl chain from the endocyclic nitrogen to the C-2 position leads to a considerable increase in chaperoning efficacy, affording a new compound (4a) able to induce a remarkable 1.9-fold maximal increase in GCase activity.
2019
10
621
626
Francesca Clemente, Camilla Matassini, Andrea Goti, Amelia Morrone, Paolo Paoli, Francesca Cardona
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1149934
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