Discovery of the Biginelli hybrids as novel caspase-9 activators in apoptotic machines: Lipophilicity, molecular docking study, influence on angiogenesis gene and miR-21 expression levels
- 1. Department of Chemistry, Faculty of Science, University of Kragujevac, Radoja Domanovića 12, 34000 Kragujevac, Serbia
- 2. Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Novi Sad, Hajduk Veljkova 3, 21000 Novi Sad, Serbia
- 3. Department of Chemistry, Biochemistry and Environmental Protection, University of Novi Sad, Trg Dositeja Obradovića 3, 21000 Novi Sad, Serbia
- 4. Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia
- 5. Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000 Belgrade, Serbia; Vinča Institute of Nuclear Science, University of Belgrade, P.O. Box 522, 11001 Belgrade, Serbia
- 6. Vinča Institute of Nuclear Science, University of Belgrade, P.O. Box 522, 11001 Belgrade, Serbia
Description
In order to investigate potential therapeutically agents, novel products of Biginelli reaction (4a-l) were synthesized and exposed to cytotoxic and caspase activities, angiogenesis, cell cycle distribution, gene and microRNA expression levels, lipophilicity assessment and docking study. Among the twelve novel compounds (4a-l) evaluated for the cytotoxic activity, five of them (4c, 4d, 4f, 4k and 4l) that showed excellent activity on the tested cell lines (HeLa, LS174 and A549) were selected for further evaluation. Interestingly, compound 4f has up to three times higher selectivity index (SI) towards cancer cells than cisplatin (on HeLa, LS174 and A549 SI = 18.2, 13.5 and 11.2, respectively). The obtained results from cell cycle distribution and caspase activity indicate that tested compounds (4c, 4d, 4f, 4k and 4l) promoted caspase-9 activation, implicated in the intrinsic pathway of apoptosis. Lipophilicity of 4a-l was determinate by using reversed-phase high-performance liquid chromatography.
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- Ministry of Education, Science and Technological Development
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