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

Year: 2019

Authors: Clemente F., Matassini C., Goti, A., Morrone A., Paoli P., Cardona F.

Autors Affiliation: Univ Firenze, Dept Chem Ugo Schiff, Via Lastruccia 3-13, I-50019 Sesto Fiorentino, FI, Italy; CNR, INO, Via N Carrara 1, I-50019 Sesto Fiorentino, FI, Italy; LENS, Via N Carrara 1, I-50019 Sesto Fiorentino, FI, Italy; Consorzio Interuniv Nazl Ric Metodol & Proc Innov, I-70125 Bari, Italy; Univ Florence, Meyer Childrens Hosp, Neurosci Dept, Paediat Neurol Unit & Labs, Viale Pieraccini 24, I-50139 Florence, Italy; Univ Florence, Dept Neurosci Pharmacol & Child Hlth, Viale Pieraccini 24, I-50139 Florence, Italy; Univ Florence, Dept Expt & Clin Biomed Sci, Viale Morgagni 50, I-50134 Florence, Italy.

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.

Journal/Review: ACS MEDICINAL CHEMISTRY LETTERS

Volume: 10 (4)      Pages from: 621  to: 626

More Information: This work was supported by Fondazione Cassa di Risparmio di Pistoia e Pescia (Bando Giovani@Ricerca scientifica 2017, Iminosugar-based Pharmacological Chaperones for the treatment of Gaucher-related Parkinson Disease) and partially from AMMeC (Associazione Malattie Metaboliche Congenite) fundings for NGS and Biochemical Studies on Inborn Errors of Metabolism. P.P. research was supported by University of Firenze, Fondi Ateneo (ex 60%). P.P. and F. Cardona thank MIUR for the Finanziamento annuale individuale delle attivita base di ricerca.
KeyWords: Lysosomal storage disorders; Gaucher disease; pharmacological chaperones; iminosugars; trihydroxypiperidines
DOI: 10.1021/acsmedchemlett.8b00602

Citations: 23
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