Risultati scientifici

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

Anno: 2019

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

Affiliazione autori: 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.

Giornale/Rivista: ACS MEDICINAL CHEMISTRY LETTERS

Volume: 10 (4)      Da Pagina: 621  A: 626

Parole chiavi: Lysosomal storage disorders; Gaucher disease; pharmacological chaperones; iminosugars; trihydroxypiperidines
DOI: 10.1021/acsmedchemlett.8b00602

Citazioni: 10
dati da “WEB OF SCIENCE” (of Thomson Reuters) aggiornati al: 2022-01-23
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