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

Clemente F. ; Matassini C. ; Giachetti S. ; Goti A. ; Morrone A. ; Martínez-Bailén M. ; Orta S. ; Merino P. (Universidad de Zaragoza) ; Cardona F.

Resumen: 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.

Idioma: Inglés

DOI: 10.1021/acs.joc.1c01308

Año: 2021

Publicado en: Journal of Organic Chemistry 86, 18 (2021), 12745-12761
ISSN: 0022-3263

Factor impacto JCR: 4.198 (2021)

Categ. JCR: CHEMISTRY, ORGANIC rank: 12 / 56 = 0.214 (2021) - Q1 - T1

Factor impacto SCIMAGO: 0.983 - Organic Chemistry (Q1)

Financiación: info:eu-repo/grantAgreement/ES/DGA/E34-20R
Financiación: info:eu-repo/grantAgreement/ES/MINECO/CTQ2016-77270-R
Financiación: info:eu-repo/grantAgreement/ES/MINECO/PID2019-104090RB-100

Tipo y forma: Article (Published version)

Área (Departamento): Área Química Orgánica (Dpto. Química Orgánica)