Mannich bases of 1,2,4-triazole-3-thione containing adamantane moiety: Synthesis, preliminary anticancer evaluation, and molecular modeling studies
- 1. Faculty of Medicinal Science, University of Kragujevac, S. Markovića 69, 34000 Kragujevac, Serbia
- 2. Faculty of Science, Department of Chemistry, University of Kragujevac, R. Domanovića 12, 34000 Kragujevac, Serbia
- 3. Faculty of Science, Department of Chemistry, University of Kragujevac, R. Domanovića 12, 34000 Kragujevac, Se
- 4. Insitute of Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia
- 5. Institute for Biological Research "Siniša Stanković", Department of Neurobiology, University of Belgrade, Bulevar Despota Stefana 142, 11060 Belgrade, Serbia
- 6. Faculty of Sciences, University of Novi Sad, Trg D. Obradovića 3, 21000 Novi Sad, Serbia
- 7. Faculty of Chemistry, University of Belgrade, Studentski trg 12–16, 11000 Belgrade, Serbia
Description
A series of 18 novel N-Mannich bases derived from 5-adamantyl-1,2,4-triazole-3-thione was synthesized and characterized using NMR spectroscopy and X-ray diffraction technique. All derivatives were evaluated for their anticancer potential against four human cancer cell lines. Several tested compounds exerted good cytotoxic activities on K562 and HL-60 cell lines, along with pronounced selectivity, showing lower cytotoxicity against normal fibroblasts MRC-5 compared to cancer cells. The effects of compounds 5b, 5e, and 5j on the cell cycle were investigated by flow cytometric analysis. It was found that these compounds cause the accumulation of cells in the subG1 and G1 phases of the cell cycle and induce caspase-dependent apoptosis, while the anti-angiogenic effects of 5b, 5e, and 5j have been confirmed in EA.hy926 cells using a tube formation assay. Further, the interaction of Bax protein with compound 5b was investigated by means of molecular modeling, applying the combined molecular docking/molecular dynamics approach.
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