2026-10-14T15:39:44Z https://api.figshare.com/v2/oai

oai:figshare.com:article/34021673 2026-09-29T07:00:04Z category_1 category_4 category_7 category_12 category_19 category_873 category_46 category_734 category_61 category_64 portal_87 item_type_6 month_year_09_2026

Scorpion-Inspired 1,3,4-Oxadiazole-Based GSK-3β-Targeting Agents: Design, Synthesis, and Biological Evaluation Mustafa Cakir (6330182) Eda Acikgoz (816259) Burak Kuzu (12876169) Biophysics Biochemistry Medicine Cell Biology Pharmacology Chemical Sciences not elsewhere classified Immunology Biological Sciences not elsewhere classified Developmental Biology Cancer GSK-3β oxadiazole phenacylthio derivatives scorpion-inspired design anticancer activity spheroid model <p>Glycogen synthase kinase-3β (GSK-3β) is a promising therapeutic target for anticancer drug development because it is involved in cell proliferation, apoptosis, and tumor progression. However, developing structurally distinct GSK-3β-directed anticancer scaffolds with favorable cancer-cell selectivity remains challenging. In this study, 10 scorpion-inspired 2-(phenacylthio)-1,3,4-oxadiazole derivatives (<b>ODS1-10</b>) were synthesized in 65–97% yields and evaluated for their anticancer potential. Among the synthesized compounds, <b>ODS-7</b> showed the highest activity against MDA-MB-231 cells (IC₅₀ = 32.7 μM), whereas <b>ODS-5</b> was the most active derivative against SH-SY5Y cells (IC₅₀ = 21.2 μM). Structure–activity relationship analysis indicated that the electronic properties and substitution pattern of the aryl moieties substantially influenced antiproliferative activity. <b>ODS-5</b> and <b>ODS-7</b> showed preferential activity toward cancer cells, with <b>ODS-5</b> exhibiting a selectivity index of 2.80 against non-cancerous HaCaT keratinocytes. Both compounds significantly reduced SH-SY5Y clonogenic capacity and disrupted three-dimensional spheroid integrity. Immunofluorescence analysis revealed reduced GSK-3β-associated fluorescence intensity in treated SH-SY5Y cells, while RT-qPCR demonstrated upregulation of BAX and CASP3 and downregulation of BCL2, supporting the involvement of apoptosis in the observed cytotoxic response. Molecular docking also showed favorable predicted binding energies for <b>ODS-5</b> (−8.67 kcal/mol) and <b>ODS-7</b> (−8.44 kcal/mol) within the GSK-3β binding site, comparable to the co-crystallized ligand 3HT (−8.37 kcal/mol). Overall, <b>ODS-5</b> and <b>ODS-7</b> represent promising preliminary lead structures within the 2-(phenacylthio)-1,3,4-oxadiazole series, providing a rational SAR basis for further medicinal chemistry optimization and direct evaluation of GSK-3β target engagement.</p> <p>Multi-panel diagram depicting a scorpion-inspired design, synthesized derivatives, target engagement with GSK-3ß, and mechanistic marker results.</p> 2026-09-29T07:00:04Z Text Journal contribution 10.6084/m9.figshare.34021673.v1 https://figshare.com/articles/journal_contribution/Scorpion-Inspired_1_3_4-Oxadiazole-Based_GSK-3_-Targeting_Agents_Design_Synthesis_and_Biological_Evaluation/34021673 CC BY 4.0