Synthesis, biological evaluation and in silico studies of clopidogrel based new 1,2,4-triazole-3-thione derivatives as DNA methyltransferase inhibitors on prostate cancer cells

IF 4 2区化学 Q2 CHEMISTRY, PHYSICAL

Journal of Molecular Structure Pub Date : 2025-03-19 DOI:10.1016/j.molstruc.2025.142081

Fatih Tok , Sami Erdem , Burçin İrem Abas , Begüm Nurpelin Sağlık Özkan , Sevgi Karakuş , Yusuf Özkay , Zafer Asım Kaplancıklı , Özge Çevik

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引用次数: 0

Abstract

New, selective and effective anticancer agents are urgently needed in drug research and development studies. For this purpose, some new 2,4-dihydro-3H-1,2,4-triazole-3-thione derivatives based on clopidogrel were synthesized and characterized using spectral techniques, including IR, ¹H NMR, ¹³C NMR and MS. The anticancer activities of the synthesized compounds were evaluated in vitro against human prostate cancer cells (PC3) and human umbilical vein endothelial cells (HUVEC). Among these compounds, the ethyl chain-bearing compound 3 and the 4-methoxyphenyl-bearing compound 8 exhibited the most selective anticancer activities against PC3 with IC₅₀ values of 6.81±2.14 µM and 4.68±1.76 µM, respectively. Apoptotic cells were investigated with AO/EB staining. Total DNMT enzyme activity and protein expression levels (DNMT1, DNMT3a, and DNMT3b) were also analyzed in compound 3 and compound 8 treated cells. Compounds 3 and 8 showed DNA methyltransferase inhibitory activity of 63.02±1.40% and 54.08±6.35%, respectively. Molecular docking studies were performed to elucidate the interaction of compounds 3 and 8 with the DNMT1 enzyme. As a result, 3 and 8 were reported to be candidates compounds for the development of DNA methyltransferase inhibitors with potent anticancer activity.

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来源期刊

Journal of Molecular Structure 化学-物理化学

CiteScore

7.10

自引率

15.80%

发文量

2384

审稿时长

45 days

期刊介绍： The Journal of Molecular Structure is dedicated to the publication of full-length articles and review papers, providing important new structural information on all types of chemical species including: • Stable and unstable molecules in all types of environments (vapour, molecular beam, liquid, solution, liquid crystal, solid state, matrix-isolated, surface-absorbed etc.) • Chemical intermediates • Molecules in excited states • Biological molecules • Polymers. The methods used may include any combination of spectroscopic and non-spectroscopic techniques, for example: • Infrared spectroscopy (mid, far, near) • Raman spectroscopy and non-linear Raman methods (CARS, etc.) • Electronic absorption spectroscopy • Optical rotatory dispersion and circular dichroism • Fluorescence and phosphorescence techniques • Electron spectroscopies (PES, XPS), EXAFS, etc. • Microwave spectroscopy • Electron diffraction • NMR and ESR spectroscopies • Mössbauer spectroscopy • X-ray crystallography • Charge Density Analyses • Computational Studies (supplementing experimental methods) We encourage publications combining theoretical and experimental approaches. The structural insights gained by the studies should be correlated with the properties, activity and/ or reactivity of the molecule under investigation and the relevance of this molecule and its implications should be discussed.