The enzyme glucocerebrosidase (GCase) has become an important therapeutic target due to its involvement in pathological disorders consequent to enzyme deficiency, such as the lysosomal storage Gaucher disease (GD) and the neurological Parkinson disease (PD). Pharmacological chaperones (PCs) are small compounds able to stabilize enzymes when used at sub-inhibitory concentrations, thus rescuing enzyme activity. We report the stereodivergent synthesis of trihydroxypiperidines alkylated at C-2 with both configurations, by means of the stereoselective addition of Grignard reagents to a carbohydrate-derived nitrone in the presence or absence of Lewis acids. All the target compounds behave as good GCase inhibitors, with IC50 in the micromolar range. Moreover, compound 11a behaves as a PC in fibroblasts derived from Gaucher patients bearing the N370/RecNcil mutation and the homozygous L444P mutation, rescuing the activity of the deficient enzyme by up to 1.9-and 1.8-fold, respectively. Rescues of 1.2–1.4-fold were also observed in wild-type fibroblasts, which is important for targeting sporadic forms of PD.

Glucocerebrosidase (GCase) activity modulation by 2-alkyl trihydroxypiperidines: Inhibition and pharmacological chaperoning / Francesca Clemente, Camilla Matassini, Cristina Faggi, Sara Giachetti, Cosimo Cresti, Amelia Morrone, Paolo Paoli, Andrea Goti, Macarena Martínez-Bailén, Francesca Cardona. - In: BIOORGANIC CHEMISTRY. - ISSN 0045-2068. - STAMPA. - 98:(2020), pp. 103740-103762. [10.1016/j.bioorg.2020.103740]

Glucocerebrosidase (GCase) activity modulation by 2-alkyl trihydroxypiperidines: Inhibition and pharmacological chaperoning

Francesca Clemente
Conceptualization
;
Camilla Matassini
Conceptualization
;
Cristina Faggi
Membro del Collaboration Group
;
Sara Giachetti
Membro del Collaboration Group
;
Amelia Morrone
Membro del Collaboration Group
;
Paolo Paoli
Membro del Collaboration Group
;
Andrea Goti
Membro del Collaboration Group
;
Francesca Cardona
Conceptualization
2020

Abstract

The enzyme glucocerebrosidase (GCase) has become an important therapeutic target due to its involvement in pathological disorders consequent to enzyme deficiency, such as the lysosomal storage Gaucher disease (GD) and the neurological Parkinson disease (PD). Pharmacological chaperones (PCs) are small compounds able to stabilize enzymes when used at sub-inhibitory concentrations, thus rescuing enzyme activity. We report the stereodivergent synthesis of trihydroxypiperidines alkylated at C-2 with both configurations, by means of the stereoselective addition of Grignard reagents to a carbohydrate-derived nitrone in the presence or absence of Lewis acids. All the target compounds behave as good GCase inhibitors, with IC50 in the micromolar range. Moreover, compound 11a behaves as a PC in fibroblasts derived from Gaucher patients bearing the N370/RecNcil mutation and the homozygous L444P mutation, rescuing the activity of the deficient enzyme by up to 1.9-and 1.8-fold, respectively. Rescues of 1.2–1.4-fold were also observed in wild-type fibroblasts, which is important for targeting sporadic forms of PD.
98
103740
103762
Francesca Clemente, Camilla Matassini, Cristina Faggi, Sara Giachetti, Cosimo Cresti, Amelia Morrone, Paolo Paoli, Andrea Goti, Macarena Martínez-Bailén, Francesca Cardona
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2158/1191699
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