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

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

  • Bioorg Chem. 2020 May;98:103740. doi: 10.1016/j.bioorg.2020.103740.
F Clemente 1,  C Matassini 2,  C Faggi 1,  S Giachetti 1,  C Cresti 1,  A Morrone 3,  P Paoli 4,  A Goti 5,  M Martínez-Bailén 6,  F Cardona 7
Affiliations

Affiliations

  • 1 Department of Chemistry 'Ugo Schiff', University of Firenze, via della Lastruccia 3-13, 50019 Sesto Fiorentino (FI), Italy.
  • 2 Department of Chemistry 'Ugo Schiff', University of Firenze, via della Lastruccia 3-13, 50019 Sesto Fiorentino (FI), Italy. Electronic address: camilla.matassini@unifi.it.
  • 3 Paediatric Neurology Unit and Laboratories, Neuroscience Department, Meyer Children's Hospital, and Department of Neurosciences, Pharmacology and Child Health, University of Florence, Viale Pieraccini n. 24, 50139 Firenze, Italy.
  • 4 Department of Experimental and Clinical Biomedical Sciences, University of Florence, Viale Morgagni 50, 50134 Florence, Italy.
  • 5 Department of Chemistry 'Ugo Schiff', University of Firenze, via della Lastruccia 3-13, 50019 Sesto Fiorentino (FI), Italy; Associated with Consorzio Interuniversitario Nazionale di ricerca in Metodologie e Processi Innovativi di Sintesi (CINMPIS), Italy.
  • 6 Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, c/ Prof. García González 1, E-41012 Sevilla, Spain.
  • 7 Department of Chemistry 'Ugo Schiff', University of Firenze, via della Lastruccia 3-13, 50019 Sesto Fiorentino (FI), Italy; Associated with Consorzio Interuniversitario Nazionale di ricerca in Metodologie e Processi Innovativi di Sintesi (CINMPIS), Italy. Electronic address: francesca.cardona@unifi.it.
PMID: 32200326 DOI: 10.1016/j.bioorg.2020.103740
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.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z