Browsing by Author "Tuzun, Burak"

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A Biochemistry-Oriented Drug Design: Synthesis, Anticancer Activity, Enzymes Inhibition, Molecular Docking Studies of Novel 1,2,4-Triazole Derivatives
(Taylor & Francis Inc, 2024) Yuriy, Karpenko; Kusdemir, Gulnur; Volodymyr, Parchenko; Tuzun, Burak; Taslimi, Parham; Karatas, Omer Faruk; Sayin, Koray
In this study, we researched the reactions of 5-(5-bromofuran-2-yl)-4-methyl-1,2,4-triazole-3-thiol and 5-thiophene-(3-ylmethyl)-4R-1,2,4-triazole-3-thiols with some halogen-containing compounds, a number of new compounds were synthesized (1.1-1.5 and 2.1-2.8). These compounds showed excellent to good inhibitory activities on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. For obtaining the effects of these compounds on AChE and BChE enzymes were determined spectrophotometrically according to Ellman. IC50 values of these enzymes were ranging between 1.63 and 17.68 nM for AChE and 8.71 and 84.02 nM for BChE. After, prostate cancer is the second leading cause of cancer-related mortality for men over the age of 65 in developed countries. Current treatment options remain limited in the treatment of advanced-stage prostate cancer leading to biochemical recurrence in almost 40% of the patients. Therefore, there is an urgent need for development of novel therapeutic tools for treatment of prostate cancer patients. In this study, we aimed at analyzing the potential of all compounds against prostate cancer cells. We found that, of the tested compounds, 2.1, 2.2 and 2.3 showed significant cytotoxic activities against PC3 prostate cancer cells, although their effect on the viability of normal prostate cells was limited. These findings suggest their selective targeting potential for prostate cancer cells and offer them as candidate therapeutic agents against prostate cancer. The inhibitory activities of some chemical compounds, such as (1.1-1.5 and 2.1-2.8) were assessed by performing the molecular docking study in the presence of AChE, BChE and prostate cancer protein. MM/GBSA methods are calculated binding free energy. Finally, ADME/T analysis was performed to examine the drug properties of the 13 studied molecules.Communicated by Ramaswamy H. Sarma
Synthesis and Computational Evaluation of N-Acetyl Schiff Bases Incorporating 1,2,4-Triazoles for Dual Inhibition of Prostate Cancer Cells and Carbonic Anhydrases
(Amer Chemical Soc, 2025) Medetalibeyoglu, Hilal; Aytatli, Abdulmelik; Manap, Sevda; Atalay, Abdurrahman; Ortaakarsu, Ahmet Bugra; Tuzun, Burak; Yuksek, Haydar
In this study, we synthesized a series of novel N-acetyl Schiff bases (6a-e) containing 1,2,4-triazole moiety and evaluated their potential as anticancer agents through both experimental and computational approaches. Cytotoxicity assays on prostate cancer (PC) (DU145) and normal epithelial cells (PNT1a) demonstrated selective inhibition, particularly for compounds 6a, 6d, and 6e, with IC50 values of 73.25, 49.80, and 111.73 mu M, respectively, in DU145 cells. Notably, 6d exhibited a 10-fold selectivity toward cancer cells over normal cells. Enzyme inhibition studies demonstrated that compound 6d exhibited the most potent inhibitory activity against the carbonic anhydrase isoforms hCAI and hCAII, with the lowest recorded IC50 and K i values (7.12 and 9.26 mu M for hCAI, and 10.62 and 11.72 mu M for hCA II, respectively), suggesting strong potential for antiglaucoma therapeutic application. To elucidate molecular interactions, QM/MM molecular docking highlighted the strong affinity of compound 6d for the active sites of CYP17A1, hCAI, and hCAII enzymes. The coordination of functional groups with key residues, particularly the Zn2+ ion and HEM group, was confirmed by detailed binding analyses. Molecular dynamics simulations further validated the stability of these interactions over a 100 ns trajectory, with 6d maintaining robust engagement with the protein targets. This stability was reflected in consistent RMSD and RMSF profiles, with minimal fluctuations, particularly in CYP17A1 complexes, suggesting a stable binding conformation. The Markov State Model (MSM) analysis, integrated with TICA-FES and MM-GBSA calculations, revealed rapid conformational stabilization of 6d, especially in CYP17A1 complexes. The observed deeper energy wells in diffusion maps indicate stronger binding affinities and reduced conformational transitions compared to reference inhibitors, such as abiraterone and acetazolamide. These computational insights align with experimental findings, suggesting that 6d holds significant promise as a potent dual-target inhibitor with applications in prostate cancer therapy and glaucoma treatment.
Synthesis, Molecular Modeling Investigation, Molecular Dynamic and ADME Prediction of Some Novel Mannich Bases Derived from 1,2,4-Triazole, and Assessment of Their Anticancer Activity
(Taylor & Francis Inc, 2024) Manap, Sevda; Medetalibeyoglu, Hilal; Kilic, Ahsen; Karatas, Omer Faruk; Tuzun, Burak; Alkan, Muzaffer; Yuksek, Haydar
A series of biologically active novel Mannich bases containing with a 1H-1,2,4-triazole-5-one ring were developed to evaluate the cytotoxic activity. For this purpose, the synthesized Schiff Bases (S1-5) were reacted with formaldehyde and morpholine, which is a secondary amine to yield novel N-Mannich bases (M1-5) via the Mannich reaction. The structures of the compounds (M1-5) were determined structurally employing 1H/13C-NMR, IR and elemental analysis. In this study, we evaluated the cytotoxic potential of the compounds (M1-5) on the human hypopharyngeal carcinoma FaDu cells. We found that the compound (M3) possesses a significant anticancer feature against FaDu cells that might be evaluated with further in vitro and in vivo studies to understand its anticancer potential better. Lastly, comparisons were made using molecular docking calculations to find the theoretical activities of the compounds (M1-5). The docking score parameter of the compound (M3) against the 2DO4 protein is -5.67, the docking score parameter against the 5JPZ protein is -5.72, and finally, the docking score parameter against the 2H80 protein is -5.50. Molecular dynamic calculations are made for 0-100 ns. The ADME/T calculations were performed to find the drug potential of the compounds (M1-5). The results suggest that our drug candidate compound exhibits strong potential for co-administration with the antigen structures, owing to the low rate of interactions that decreased over time.Communicated by Ramaswamy H. Sarma