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

TOK F., ERDEM S., Abas B. İ., SAĞLIK ÖZKAN B. N., Karakuş S., ÖZKAY Y., ...Daha Fazla

Journal of Molecular Structure, cilt.1336, 2025 (SCI-Expanded) identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 1336
  • Basım Tarihi: 2025
  • Doi Numarası: 10.1016/j.molstruc.2025.142081
  • Dergi Adı: Journal of Molecular Structure
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, Chemical Abstracts Core, Chimica, Compendex, INSPEC
  • Anahtar Kelimeler: Clopidogrel, DNMT, Molecular docking, PC3, Triazole
  • Bilecik Şeyh Edebali Üniversitesi Adresli: Evet

Özet

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.