{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T13:36:17Z","timestamp":1785418577378,"version":"3.56.0"},"reference-count":29,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T00:00:00Z","timestamp":1779840000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000780","name":"European Union","doi-asserted-by":"crossref","award":["FP7-PEOPLE-2013-IAPP"],"award-info":[{"award-number":["FP7-PEOPLE-2013-IAPP"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000780","name":"European Union","doi-asserted-by":"crossref","award":["GA 612347"],"award-info":[{"award-number":["GA 612347"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"crossref"}]},{"award":["FP7-PEOPLE-2013-IAPP"],"award-info":[{"award-number":["FP7-PEOPLE-2013-IAPP"]}],"id":[{"id":"https:\/\/ror.org\/019w4f821","id-type":"ROR","asserted-by":"publisher"}]},{"award":["GA 612347"],"award-info":[{"award-number":["GA 612347"]}],"id":[{"id":"https:\/\/ror.org\/019w4f821","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia"},{"id":[{"id":"https:\/\/ror.org\/00snfqn58","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: Protein\u2013carbohydrate interactions are implicated in amyloid aggregation pathways associated with Alzheimer\u2019s disease (AD). Designing glycomimetics that modulate amyloid assembly represents a promising strategy. In addition, the interaction of A\u03b21\u201342 oligomers (A\u03b2o) with prion protein (PrPC) activates Fyn kinase and leads to Tau hyperphosphorylation, another process characterizing AD. Thus, we generated a library of phenyl 2-acetamidoselenogalactoside mimetics to evaluate their interactions with A\u03b2o and disruption of A\u03b2o\u2013PrPC binding, and consequently their potential to inhibit Fyn kinase activation. Methods: The synthetic approach comprised azidophenylselenylation, a modified one-pot Staudinger reduction\u2013acylation, a selective \u03b1-glycosylation, and deacetylation. Structural diversity was achieved mainly via acylation or ureation. The compounds were screened for binding to A\u03b2o using STD-NMR, 19F-NMR, and rapid equilibrium dialysis (RED). ADME properties were assessed through microsomal metabolism and solubility assays, while cytotoxicity was evaluated by MTT assays in human embryonic kidney (HEK) cells. Results: Several compounds bound A\u03b2o in STD-NMR experiments, mainly through aromatic and anomeric protons, and phenyl 2-deoxy-2-phenylureido-1-seleno-\u03b1-d-galactopyranoside (34) showed the most consistent response, with &gt;50% increase in relative binding signal in competition assays, demonstrating also some inhibition of A\u03b2o\u2013PrPC interactions (12%). Selenium at the anomeric position enhanced binding compared to sulphur and oxygen analogs. RED experiments confirmed weak binding interactions, consistent with STD-NMR results. ADME revealed that acetylated compounds undergo microsomal metabolism, whereas deacetylated derivatives displayed high aqueous solubility (&gt;100 \u03bcM) and showed no cytotoxicity. Conclusions: Phenyl 2-acetamidoselenogalactosides are a novel class of amyloid-binding glycomimetics. Among them, 34 emerges as the most promising compound, combining favorable solubility, metabolic stability, low toxicity, and measurable interference with A\u03b2o and A\u03b2o\u2013PrPC interactions, thus supporting further developments toward therapeutic applications in AD.<\/jats:p>","DOI":"10.3390\/ph19060836","type":"journal-article","created":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T14:36:56Z","timestamp":1779892616000},"page":"836","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Synthesis of Phenyl 2-Acetamidoselenogalactoside Mimetics and Interaction with Amyloid \u03b21\u201342"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4741-115X","authenticated-orcid":false,"given":"Jo\u00e3o","family":"Barros","sequence":"first","affiliation":[{"name":"Centro de Qu\u00edmica Estrutural, Institute of Molecular Sciences, Faculdade de Ci\u00eancias, Universidade de Lisboa, Ed C8, Piso 5, 1749-016 Lisboa, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"Dreyfus","sequence":"additional","affiliation":[{"name":"Independent Researcher, Chemin de Joulens, 1, 1110 Morges, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary","family":"Sharman","sequence":"additional","affiliation":[{"name":"Independent Researcher, Basingstoke RG25, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Evans","sequence":"additional","affiliation":[{"name":"Independent Researcher, Ascot SL5, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beining","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Sheffield, Brookhill, Shefield S3 7HF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cleide S.","family":"Souza","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Sheffield, Brookhill, Shefield S3 7HF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4828-4738","authenticated-orcid":false,"given":"Gon\u00e7alo C.","family":"Justino","sequence":"additional","affiliation":[{"name":"Mass Spectrometry Facility, Centro de Qu\u00edmica Estruttural, Instituto Superior T\u00e9cnico, Av. Rovisco Pais, 1049-001 Lisboa, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3068-4920","authenticated-orcid":false,"given":"Maria C.","family":"Oliveira","sequence":"additional","affiliation":[{"name":"Mass Spectrometry Facility, Centro de Qu\u00edmica Estruttural, Instituto Superior T\u00e9cnico, Av. Rovisco Pais, 1049-001 Lisboa, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3790-7952","authenticated-orcid":false,"given":"Am\u00e9lia P.","family":"Rauter","sequence":"additional","affiliation":[{"name":"Centro de Qu\u00edmica Estrutural, Institute of Molecular Sciences, Faculdade de Ci\u00eancias, Universidade de Lisboa, Ed C8, Piso 5, 1749-016 Lisboa, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1002\/med.21440","article-title":"Bridging type 2 diabetes and Alzheimer\u2019s disease: Assembling the puzzle pieces in the quest for the molecules with therapeutic and preventive potential","volume":"38","author":"Matos","year":"2018","journal-title":"Med. Res. 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