PubMed İndeksli Yayınlar Koleksiyonu
Permanent URI for this collectionhttps://hdl.handle.net/20.500.12573/397
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Article Citation - WoS: 1Citation - Scopus: 1Targeting Cholinergic Dysfunction and Neuroinflammation through Rationally Designed Thieno[3,2-d]Pyrimidine Hybrids(Academic Press Inc Elsevier Science, 2026-07) Acar, Ozden Ozgun; Acar, Busra; Senol, Halil; Tokali, Feyzi Sinan; Sen, Alaattin; Demir, Yeliz; Cakir, FurkanNeurodegenerative diseases involve the convergence of cholinergic dysfunction, neuronal loss, and sustained neuroinflammatory responses, necessitating the development of multifunctional therapeutic agents. In this study, a series of novel thieno[3,2-d]pyrimidine-phenolic Mannich base hybrids were rationally designed, synthesized, and evaluated as dual cholinesterase inhibitors with neuroprotective and anti-neuroinflammatory potential. The synthesized compounds exhibited potent inhibition against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), with inhibition constants in the low nanomolar range. Among them, compounds 5 and 9 emerged as the most active derivatives, displaying Ki values of 8.79 and 14.11 nM for AChE and 7.04 and 11.75 nM for BChE, surpassing the reference inhibitors tacrine and donepezil. Molecular docking and molecular dynamics simulations supported the experimental findings, and Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) binding free energy calculations further confirmed their superior binding affinities compared with donepezil. Cytotoxicity profiling in SH-SY5Y neuronal cells and RAW 264.7 and THP-1 immune cells identified a narrow sub-cytotoxic concentration window (EC05-EC10 = 1.2-2.1 mu M), ensuring biological effects independent of nonspecific cell damage. Within this range, both compounds exerted pronounced antineuroinflammatory activity. Notably, compound 9 significantly downregulated pro-inflammatory mediators, reducing IL-1 beta, IL-6, and NF-kappa B1 gene expression by up to 2.78-, 3.37-, and 4.84-fold, respectively. Consistently, it suppressed nitric oxide production in LPS-stimulated macrophages to levels comparable with ascorbic acid and markedly decreased Iba1 expression in activated THP-1 cells. This integrated enzymatic, computational, and cellular investigation identifies compounds 5 and 9 as promising multifunctional lead combining dual cholinesterase inhibition with robust anti-neuroinflammatory activity. The results provide a strong foundation for future in vivo studies and further optimization toward disease-modifying agents for neurodegenerative disorders.Article A Small Indole Derivative Isolated From Caper (Capparis Ovata) as an Inducer of P53-Mediated Apoptosis in Prostate Cancer: Comprehensive In Vitro and In Silico Studies(Wiley, 2025-12-31) Acar, Ozden Ozgun; Gazioglu, Isil; Oruc, Hatice; Kale, Elif; Senol, Halil; Topcu, Gulacti; Sen, AlaattinNatural products with stunning chemical diversity have been extensively researched for their anticancer potential for more than fifty years. This study aimed to determine the effect of indole derivative 1H-indole-2-hydroxy-3-carboxylic acid (IHCA), isolated as a novel alkaloid from Capparis ovata, on selected tumor suppressor, apoptotic, and cell cycle regulatory genes, which are known to be important in cancer pathophysiology, on Caco-2 and LNCaP cells in comparison with Taxol. The molecular mechanism of IHCA's anticancer activity is essentially undefined. Different concentrations of IHCA increased the expression levels of apoptosis-related genes, including BCL-2 and TNF-alpha. In addition, the tumor suppressor genes PTEN, P53, and RB were increased in LNCaP and Caco-2 cells. KRAS, an oncogenic gene, was significantly downregulated by IHCA in LNCaP cells. Western blot results showed that the protein expression levels of P53 and PTEN in LNCaP cells were increased when treated with IHCA, whereas CDK4 and TNF-alpha were decreased. Finally, IHCA and doxorubicin significantly increased P53-driven luciferase activity compared to the control. The results strongly suggest that the novel natural compound IHCA has an anticancer effect involving the regulation of the P53 gene and its networks in vitro. The molecular docking and MD simulation analyses reveal that IHCA exhibits superior binding potential to the MDM2 protein compared to Nutlin-3a. MD simulations further confirm that IHCA maintains a more stable and consistent interaction with MDM2, as indicated by lower RMSD values and reduced ligand fluctuation. These results highlight IHCA's potential as a more effective MDM2 inhibitor, suggesting its promise as a lead compound for anticancer drug development.Clinical Trial Registration: Not applicable.