{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T18:33:23Z","timestamp":1776710003467,"version":"3.51.2"},"reference-count":36,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2022,6,22]],"date-time":"2022-06-22T00:00:00Z","timestamp":1655856000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Regione Toscana"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>GM1 gangliosidosis is a rare lysosomal disease caused by the deficiency of the enzyme \u03b2-galactosidase (\u03b2-Gal; GLB1; E.C. 3.2.1.23), responsible for the hydrolysis of terminal \u03b2-galactosyl residues from GM1 ganglioside, glycoproteins, and glycosaminoglycans, such as keratan-sulfate. With the aim of identifying new pharmacological chaperones for GM1 gangliosidosis, the synthesis of five new trihydroxypiperidine iminosugars is reported in this work. The target compounds feature a pentyl alkyl chain in different positions of the piperidine ring and different absolute configurations of the alkyl chain at C-2 and the hydroxy group at C-3. The organometallic addition of a Grignard reagent onto a carbohydrate-derived nitrone in the presence or absence of a suitable Lewis Acid was exploited, providing structural diversity at C-2, followed by the ring-closure reductive amination step. An oxidation-reduction process allowed access to a different configuration at C-3. The N-pentyl trihydroxypiperidine iminosugar was also synthesized for the purpose of comparison. The biological evaluation of the newly synthesized compounds was performed on leucocyte extracts from healthy donors and identified two suitable \u03b2-Gal inhibitors, namely compounds 10 and 12. Among these, compound 12 showed chaperoning properties since it enhanced \u03b2-Gal activity by 40% when tested on GM1 patients bearing the p.Ile51Asn\/p.Arg201His mutations.<\/jats:p>","DOI":"10.3390\/molecules27134008","type":"journal-article","created":{"date-parts":[[2022,6,22]],"date-time":"2022-06-22T23:11:19Z","timestamp":1655939479000},"page":"4008","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Synthesis of a New \u03b2-Galactosidase Inhibitor Displaying Pharmacological Chaperone Properties for GM1 Gangliosidosis"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9899-0836","authenticated-orcid":false,"given":"Francesca","family":"Clemente","sequence":"first","affiliation":[{"name":"Dipartimento di Chimica \u201cUgo Schiff\u201d (DICUS), Universit\u00e0 di Firenze, Via Della Lastruccia 3-13, 50019 Sesto Fiorentino, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Macarena","family":"Mart\u00ednez-Bail\u00e9n","sequence":"additional","affiliation":[{"name":"Dipartimento di Chimica \u201cUgo Schiff\u201d (DICUS), Universit\u00e0 di Firenze, Via Della Lastruccia 3-13, 50019 Sesto Fiorentino, Italy"},{"name":"Glycosystems Laboratory, Instituto de Investigaciones Qu\u00edmicas (IIQ), CSIC\u2014Universidad de Sevilla, Av. Am\u00e9rico Vespucio 49, 41092 Sevilla, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8336-383X","authenticated-orcid":false,"given":"Camilla","family":"Matassini","sequence":"additional","affiliation":[{"name":"Dipartimento di Chimica \u201cUgo Schiff\u201d (DICUS), Universit\u00e0 di Firenze, Via Della Lastruccia 3-13, 50019 Sesto Fiorentino, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2890-8179","authenticated-orcid":false,"given":"Amelia","family":"Morrone","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Pharmacology and Child Health (NEUROFARBA), University of Florence, Viale Pieraccini n. 24, 50139 Firenze, Italy"},{"name":"Laboratory of Molecular Biology of Neurometabolic Diseases, Neuroscience Department, Meyer Children\u2019s Hospital, Viale Pieraccini n. 24, 50139 Firenze, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silvia","family":"Falliano","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology of Neurometabolic Diseases, Neuroscience Department, Meyer Children\u2019s Hospital, Viale Pieraccini n. 24, 50139 Firenze, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Caciotti","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology of Neurometabolic Diseases, Neuroscience Department, Meyer Children\u2019s Hospital, Viale Pieraccini n. 24, 50139 Firenze, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6448-7266","authenticated-orcid":false,"given":"Paolo","family":"Paoli","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Biomediche Sperimentali e Cliniche \u201cMario Serio\u201d (DSBSC), University of Florence, Viale Morgagni 50, 50134 Florence, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1081-533X","authenticated-orcid":false,"given":"Andrea","family":"Goti","sequence":"additional","affiliation":[{"name":"Dipartimento di Chimica \u201cUgo Schiff\u201d (DICUS), Universit\u00e0 di Firenze, Via Della Lastruccia 3-13, 50019 Sesto Fiorentino, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6766-4624","authenticated-orcid":false,"given":"Francesca","family":"Cardona","sequence":"additional","affiliation":[{"name":"Dipartimento di Chimica \u201cUgo Schiff\u201d (DICUS), Universit\u00e0 di Firenze, Via Della Lastruccia 3-13, 50019 Sesto Fiorentino, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,22]]},"reference":[{"key":"ref_1","unstructured":"Scriver, C.R., Beaudet, A.L., Sly, W.S., and Valle, D. (2001). \u03b2-Galactosidase deficiency (\u03b2-galactosidosis) GM1 gangliosidosis and Morquio B disease. The Metabolic and Molecular Bases of Inherited Disease, McGraw-Hill."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1016\/j.ymgme.2008.04.012","article-title":"GM1 gangliosidosis: Review of clinical, molecular, and therapeutic aspects","volume":"94","author":"Scaglia","year":"2008","journal-title":"Mol. Genet. Metab."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1016\/j.bbadis.2011.03.018","article-title":"GM1 gangliosidosis and Morquio B disease: An update on genetic alterations and clinical findings","volume":"1812","author":"Caciotti","year":"2011","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1023\/A:1005303332529","article-title":"Infantile generalized GM1 gangliosidosis: High incidence in the Maltese Islands","volume":"20","author":"Lenicker","year":"1997","journal-title":"J. Inherited Metab. Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1740","DOI":"10.1039\/C7SC04712F","article-title":"Tuning protein folding in lysosomal storage diseases: The chemistry behind pharmacological chaperones","volume":"9","author":"Pereira","year":"2018","journal-title":"Chem. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1471","DOI":"10.1021\/acschembio.6b00195","article-title":"Pharmacological Chaperones: Design and Development of New Therapeutic Strategies for the Treatment of Conformational Diseases","volume":"11","author":"Convertino","year":"2016","journal-title":"ACS Chem. Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1138","DOI":"10.1038\/mt.2015.62","article-title":"Pharmacological Chaperone Therapy: Preclinical Development, Clinical Translation, and Prospects for the Treatment of Lysosomal Storage Disorders","volume":"23","author":"Parenti","year":"2015","journal-title":"Mol. Ther."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2705","DOI":"10.1021\/jm301557k","article-title":"Pharmacological Chaperones as Therapeutics for Lysosomal Storage Diseases","volume":"56","author":"Boyd","year":"2013","journal-title":"J. Med. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"6514","DOI":"10.1039\/c2cc32065g","article-title":"Tuning glycosidase inhibition through aglycone interactions: Pharmacological chaperones for Fabry disease and GM1 gangliosidosis","volume":"48","author":"Takai","year":"2012","journal-title":"Chem. Commun."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"5497","DOI":"10.1039\/C6CC01564F","article-title":"Glycomimetic-based pharmacological chaperones for lysosomal storage disorders: Lessons from Gaucher, GM1-gangliosidosis and Fabry diseases","volume":"52","year":"2016","journal-title":"Chem. Commun."},{"key":"ref_11","first-page":"2980","article-title":"Pharmacological Chaperones for \u03b2-Galactosidase Related to GM1 -Gangliosidosis and Morquio B","volume":"21","author":"Thonhofer","year":"2021","journal-title":"Recent Adv. Chem. Rec."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1007\/s40265-019-01090-4","article-title":"Migalastat: A Review in Fabry Disease","volume":"79","author":"McCafferty","year":"2019","journal-title":"Drugs"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1016\/S0387-7604(01)00216-9","article-title":"Galactonojirimycin derivatives restore mutant human \u03b2-galactosidase activities expressed in fibroblasts from enzyme-deficient knockout mouse","volume":"23","author":"Tominaga","year":"2001","journal-title":"Brain Dev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.ymgme.2012.06.007","article-title":"Evaluation of N-nonyl-deoxygalactonojirimycin as a pharmacological chaperone for human GM1 gangliosidosis leads to identification of a feline model suitable for testing enzyme enhancement therapy","volume":"107","author":"Rigat","year":"2012","journal-title":"Mol. Genet. Metab."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"15912","DOI":"10.1073\/pnas.2536657100","article-title":"Chemical chaperone therapy for brain pathology in GM1-gangliosidosis","volume":"100","author":"Matsuda","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1967","DOI":"10.1016\/S0968-0896(02)00005-6","article-title":"Chemical modification of the beta-glucocerebrosidase inhibitor N-octyl-beta-valienamine: Synthesis and biological evaluation of 4-epimeric and 4-O-(beta-d-galactopyranosyl) derivatives","volume":"10","author":"Ogawa","year":"2002","journal-title":"Bioorg. Med. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1038\/mt.2012.263","article-title":"A bicyclic 1-deoxygalactonojirimycin derivative as a novel pharmacological chaperone for GM1 gangliosidosis","volume":"21","author":"Takai","year":"2013","journal-title":"Mol. Ther."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1016\/j.ymgme.2010.03.019","article-title":"DLHex-DGJ, a novel derivative of 1-deoxygalactonojirimycin with pharmacological chaperone activity in human G(M1)-gangliosidosis fibroblasts","volume":"100","author":"Fantur","year":"2010","journal-title":"Gen. Metab."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.ejmech.2016.09.095","article-title":"(5aR)-5a-C-Pentyl-4-epi-isofagomine: A powerful inhibitor of lysosomal \u03b2-galactosidase and a remarkable chaperone for mutations associated with GM1-gangliosidosis and Morquio disease type B","volume":"126","author":"Front","year":"2017","journal-title":"Eur. J. Med. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"5462","DOI":"10.1016\/j.bmc.2018.09.023","article-title":"4-epi-Isofagomine derivatives as pharmacological chaperones for the treatment of lysosomal diseases linked to \u03b2-galactosidase mutations: Improved synthesis and biological investigations","volume":"26","author":"Front","year":"2018","journal-title":"Bioorg. Med. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"4398","DOI":"10.1021\/jo500328u","article-title":"Synthesis of 1,5-Dideoxy-1,5-iminoribitol C-Glycosides through a Nitrone\u2013Olefin Cycloaddition Domino Strategy: Identification of Pharmacological Chaperones of Mutant Human Lysosomal \u03b2-Galactosidase","volume":"79","author":"Siriwardena","year":"2014","journal-title":"J. Org. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1021\/acsmedchemlett.8b00602","article-title":"Stereoselective Synthesis of C-2 Alkylated Trihydroxypiperidines: Novel Pharmacological Chaperones for Gaucher Disease","volume":"10","author":"Clemente","year":"2019","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"103740","DOI":"10.1016\/j.bioorg.2020.103740","article-title":"Glucocerebrosidase (GCase) activity modulation by 2-alkyltrihydroxypiperidines: Inhibition and pharmacological chaperoning","volume":"98","author":"Clemente","year":"2020","journal-title":"Bioorg. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4447","DOI":"10.1002\/ejoc.201901840","article-title":"Reductive Amination Routes in the Synthesis of Piperidine IminoSugars","volume":"2020","author":"Clemente","year":"2020","journal-title":"Eur. J. Org. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"9121","DOI":"10.1039\/C7OB01848G","article-title":"Accessing 2-substituted piperidine iminosugars by organometallic addition\/intramolecular reductive amination: Aldehyde vs. nitrone route","volume":"15","author":"Mirabella","year":"2017","journal-title":"Org. Biomol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3920","DOI":"10.1002\/ejoc.201200587","article-title":"Double Reductive Amination and Selective Strecker Reaction of a d-Lyxaric Aldehyde: Synthesis of Diversely Functionalized 3,4,5-Trihydroxypiperidines","volume":"2012","author":"Matassini","year":"2012","journal-title":"Eur. J. Org. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2890","DOI":"10.1055\/s-0036-1588457","article-title":"On the Oxidation of Hydroxylamines with o-Iodobenzoic acid (IBX)","volume":"49","author":"Parmeggiani","year":"2017","journal-title":"Synthesis"},{"key":"ref_28","first-page":"61","article-title":"Theoretical interpretation of 1\u20132 asymmetric induction: The importance of antiperiplanarity","volume":"1","author":"Anh","year":"1977","journal-title":"Nouv. J. Chim."},{"key":"ref_29","first-page":"320","article-title":"Cheminform abstract: Reaction of organometallics with 2-methoxycyclohexanone and cis- and trans-2-methoxy-4-tert-butylcyclohexanones","volume":"9","author":"Battioni","year":"1978","journal-title":"Chem. Inf."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1171","DOI":"10.1111\/cbdd.13182","article-title":"Biological activities of 3,4,5-trihydroxypiperidines and their N-and O-derivatives","volume":"92","author":"Prichard","year":"2018","journal-title":"Chem. Biol. Drug Des."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"4526","DOI":"10.3390\/molecules25194526","article-title":"Synthesis of \u201cAll-Cis\u201d Trihydroxypiperidines from a Carbohydrate-Derived Ketone: Hints for the Design of New \u03b2-Gal and GCase Inhibitors","volume":"25","author":"Davighi","year":"2020","journal-title":"Molecules"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2054","DOI":"10.1002\/cbic.201500292","article-title":"Human Acid \u03b2-Glucosidase Inhibition by Carbohydrate Derived Iminosugars: Towards New Pharmacological Chaperones for Gaucher Disease","volume":"16","author":"Parmeggiani","year":"2015","journal-title":"ChemBioChem"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"7616","DOI":"10.1002\/ange.200502662","article-title":"Rational Design and Synthesis of Highly Potent \u03b2-Glucocerebrosidase Inhibitors","volume":"117","author":"Zhu","year":"2005","journal-title":"Angew. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1356","DOI":"10.1002\/cbic.200600217","article-title":"Design and synthesis of highly potent and selective pharmacological chaperones for the treatment of Gaucher\u2019s disease","volume":"7","author":"Compain","year":"2006","journal-title":"ChemBioChem"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"7852","DOI":"10.1039\/D0OB01522A","article-title":"Concise asymmetric synthesis of new enantiomeric C-alkyl pyrrolidines acting as pharmacological chaperones against Gaucher disease","volume":"18","author":"Castellan","year":"2020","journal-title":"Org. Biomol. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1080\/07328309408009201","article-title":"Hydroxylated Piperidines: Synthesis of 1,5-Alkylimino-1,5-Dideoxy Derivatives of Xylitol, d- and l-Arabinitol, and Ribitol","volume":"13","author":"McCaig","year":"1994","journal-title":"J. Carbohydr. Chem."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/13\/4008\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:37:43Z","timestamp":1760139463000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/27\/13\/4008"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,22]]},"references-count":36,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2022,7]]}},"alternative-id":["molecules27134008"],"URL":"https:\/\/doi.org\/10.3390\/molecules27134008","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,22]]}}}