Academic Journal
Design, synthesis, and biological evaluation of secondary amine-containing flavonoids with anti-osteosarcoma activity associated with modulation of AKT signaling and EMT-related gene expression.
| Τίτλος: | Design, synthesis, and biological evaluation of secondary amine-containing flavonoids with anti-osteosarcoma activity associated with modulation of AKT signaling and EMT-related gene expression. |
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| Συγγραφείς: | Santos I; LAQV, REQUIMTE, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal., Albuquerque HMT; LAQV, REQUIMTE, Department of Chemistry, Campus Universitário de Santiago, University of Aveiro, 3810-193 Aveiro, Portugal., Ferreira de Oliveira JMP; LAQV, REQUIMTE, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal. Electronic address: jmoliveira@ff.up.pt., Fernandes E; LAQV, REQUIMTE, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal. Electronic address: egracas@ff.up.pt. |
| Πηγή: | Bioorganic chemistry [Bioorg Chem] 2026 Oct 05; Vol. 181, pp. 110433. Date of Electronic Publication: 2026 Aug 25. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Elsevier Country of Publication: United States NLM ID: 1303703 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1090-2120 (Electronic) Linking ISSN: 00452068 NLM ISO Abbreviation: Bioorg Chem Subsets: MEDLINE |
| Imprint Name(s): | Publication: Amsterdam : Elsevier Original Publication: New York, London, Academic Press. |
| Ιατρικοί όροι (MeSH): | Flavonoids*/pharmacology , Flavonoids*/chemistry , Flavonoids*/chemical synthesis , Proto-Oncogene Proteins c-akt*/metabolism , Proto-Oncogene Proteins c-akt*/antagonists & inhibitors , Osteosarcoma*/drug therapy , Osteosarcoma*/pathology , Osteosarcoma*/metabolism , Antineoplastic Agents*/pharmacology , Antineoplastic Agents*/chemical synthesis , Antineoplastic Agents*/chemistry , Amines*/chemistry , Amines*/pharmacology , Epithelial-Mesenchymal Transition*/drug effects , Epithelial-Mesenchymal Transition*/genetics , Drug Design*, Signal Transduction/drug effects ; Cell Proliferation/drug effects ; Humans ; Structure-Activity Relationship ; Drug Screening Assays, Antitumor ; Molecular Structure ; Dose-Response Relationship, Drug ; Cell Line, Tumor |
| Περίληψη: | The development of more effective therapeutics for osteosarcoma is frequently hindered by chemoresistance, metastatic progression, and chemotherapy-associated toxicity. Targeting key oncogenic signaling pathways, such as the PI3K/AKT axis - a key driver of osteosarcoma progression, migration, EMT-like processes, and chemoresistance - represents a rational therapeutic strategy for improving treatment outcomes. In this study, five flavonoid-based derivatives bearing a trimethoxy moiety on the B-ring and distinct secondary amines at C-7 of the A-ring were designed, synthesized, and screened against the 143B osteosarcoma cell line with high propensity to metastasize. Derivatives 6a and 6b demonstrated potent anticancer activity, exhibiting high selectivity toward the osteosarcoma cell line and low toxicity toward non-malignant MRC-5 lung fibroblasts. Interestingly, both compounds synergistically interacted with doxorubicin, substantially reducing the required dose of the chemotherapeutic agent. Mechanistically, both compounds, as single agents and in combination with doxorubicin, were associated with reduced AKT phosphorylation and downregulation of downstream mediators associated with tumor progression and epithelial-mesenchymal transition (EMT), including ZEB1, MMP2, and MMP9. Collectively, these findings show that 6a and 6b exert anti-osteosarcoma effects that are consistent with modulation of the AKT signaling pathway and EMT-related gene expression. Here, we demonstrate that secondary amine functionalities in the flavonoid backbone provide a rational framework for the development of targeted therapeutic strategies for osteosarcoma. (Copyright © 2026 The Authors. Published by Elsevier Inc. All rights reserved.) |
| Competing Interests: | Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. |
| Contributed Indexing: | Keywords: AKT signaling; Chemical synthesis; Drug synergism; Flavonoid-based compounds; Osteosarcoma |
| Substance Nomenclature: | 0 (Flavonoids) EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) 0 (Antineoplastic Agents) 0 (Amines) |
| Entry Date(s): | Date Created: 20260828 Date Completed: 20260909 Latest Revision: 20260909 |
| Update Code: | 20260909 |
| DOI: | 10.1016/j.bioorg.2026.110433 |
| PMID: | 42664600 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 1090-2120 |
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| DOI: | 10.1016/j.bioorg.2026.110433 |