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    Alzheimer tedavisi için yeni kumarin türevlerinin moleküler modelleme tabanlı tasarımı, sentezi, in vitro enzim-aktivite çalışmaları ve antiproliferatif etkilerinin belirlenmesi
    (Çanakkale Onsekiz Mart Üniversitesi, 2025) Ural, Kadircan; Önder, Ferah Cömert
    Bu tez çalışmasında moleküler modelleme yöntemleri ile kumarin esaslı yeni ve etkili inhibitör adayları tasarlanmıştır. Sentezlenen kumarin karboksamit türevlerinin asetilkolinesteraz (AChE) ve bütirilkolinesteraz (BChE) enzimleri üzerindeki inhibitör etkileri in vitro yöntemler ile araştırılmıştır. Sentezi tamamlanan bileşiklerin kimyasal yapıları FTIR, ¹H NMR, ¹³C NMR ve MS teknikleri ile karakterize edilmiştir. Moleküler modelleme çalışmaları sonucunda bileşiklerin AChE ve BChE enzimlerinin bağlanma cebinde yüksek ilgi ile bağlandıkları belirlenmiştir. Sentezlenen bileşikler arasında, AChE-CM4 ve BChE-CM5 kompleksleri daha güçlü bağlanma profilleri sergilemiştir. İn siliko ADME (Absorpsiyon, Dağılım, Metabolizma, Atılım) analizleri bileşiklerin farmakokinetik özelliklerinin genel olarak iyi olduğunu ortaya koymuştur. Moleküler modelleme çalışmaları ile sentezlenen bileşiklerin hedef enzimlerin bağlanma cebinde anahtar amino asitler AChE için Trp84 ve Phe330, Tyr334 ve BChE için Trp82 ve Phe329 ile H-bağı, pi-pi etkileşimleri belirlenmiştir. İn vitro enzim aktivite sonuçlarına göre AChE hedefine yönelik CM4 ve CM8 bileşiklerinin donepezil'den, CM1-CM3, CM5-CM7 ve CM9 bileşiklerinin Takrin'den (1,2,3,4-tetrahidroakridin-9-amin), BChE hedefine yönelik ise CM1-CM9 bileşiklerinin takrin'den daha güçlü inhibisyon etkisi göstermiştir. Ayrıca, CM1 ve CM9 bileşiklerinin meme ve kolon kanseri hücre hatlarında antiproliferatif etkinlik sergilediği bulunmuştur. Bu tez çalışmasından elde edilen veriler ile kumarin karboksamit türevlerinin nörodejeneratif hastalıklar ve kanserin tedavisinde kullanılabilecek yeni inhibitör adaylarının geliştirilmesi açısından umut verici bir potansiyele sahip olduğu belirlenmiştir.
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    Öğe
    Boron Containing Curcumin-Like Compound as an Acetylcholinesterase Inhibitor and Anticancer Agent: Synthesis, Biological Evaluation, and Computational Insights
    (Humana Press Inc, 2025) Comert Onder, Ferah; Ural, Kadircan; Onder, Alper; Ozpolat, Bulent; Ay, Mehmet
    Alzheimer's disease (AD) and cancer are significant global health challenges that highlight the need for the development of new therapeutics. Targeting biological mechanisms involved in both AD and cancer could be an effective treatment strategy for developing novel inhibitors. In this study, we investigated the effect of a newly synthesized boron containing curcumin-like compound as a potential acetylcholinesterase (AChE) inhibitor along with its cytotoxic effects on breast and colorectal cancer cell lines. Compound A exhibited a potent AChE inhibitory activity (IC50 = 22.89 +/- 2.32 nM), demonstrating that it was more effective than the known inhibitors donepezil (IC50 = 28.32 +/- 3.27 nM) and tacrine. Compound A showed a moderate cytotoxic activity on MCF-7 and BT20 cells with the IC50 values 40.70 +/- 2.31 mu M and 41.71 +/- 4.51 mu M, respectively. Throughout molecular dynamics (MD) simulations, the RMSD value of the protein was calculated as 1.56 +/- 0.20 & Aring; and 1.65 +/- 0.19 & Aring; for the complexes of compound A and curcumin, respectively. The interactions with specific amino acid residues such as Tyr124, Tyr337, and Trp86 for AChE, and Trp82, His438, and Tyr332 for BChE were obtained. Additionally, MM/GBSA calculations demonstrated that Compound A had the highest binding free energies (-88.89 +/- 8.34 kcal/mol for AChE and -73.25 +/- 8.83 kcal/mol for BChE) compared to curcumin (-67.87 +/- 5.48 kcal/mol for AChE and -51.68 +/- 5.28 kcal/mol for BChE) and tacrine (-56.67 +/- 2.22 kcal/mol for BChE) were calculated. Overall, these findings suggest that Compound A is a promising agent with its potent AChE inhibitory activity and anticancer potential, making it a valuable candidate for further research in neurodegenerative diseases and cancer therapy.
  • [ X ]
    Öğe
    New and potential boron-containing compounds for treatment of Alzheimer's disease and cancers
    (Taylor & Francis Ltd, 2025) Comert Onder, Ferah; Ural, Kadircan; Onder, Alper; Ozpolat, Bulent; Ay, Mehmet
    AimIn this study, new boron-containing carbamate compounds were synthesized and evaluated as potential acetylcholinesterase (AChE) inhibitors by in vitro and in silico analyses.Materials & methodsThe structures were characterized by spectroscopic analysis including 1H NMR, 13C NMR, 11B NMR, and MS. The purities of the compounds were determined by HPLC analysis. In vitro and in silico analyses were performed.ResultsBased on our findings, compounds (1-4) demonstrated more potent AChE inhibitory activity compared to tacrine, which is an FDA-approved AChE inhibitor. Compound 4 had the highest inhibitory activity with an IC50 of 37.87 +/- 0.96 nM and was more effective than tacrine (74.23 +/- 0.83 nM). Compounds 1, 2, and 3, respectively, showed 1.78-, 1.73-, and 1.58-fold more potent enzyme inhibition activity compared to tacrine. The strong interactions with critical residues in the binding pocket of AChE were identified between protein and the compounds. Furthermore, compound 4 exerted an antiproliferative activity against various human cancer cell lines (32.91 +/- 4.92 mu M in HT29 and 42.38 +/- 2.73 mu M in MCF-7).ConclusionOur study indicates the discovery of new boron-containing AChE inhibitors as potential candidates for the treatment of Alzheimer's disease and cancer.