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 |
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| Affiliation: | 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. Vinča Institute of Nuclear Science, University of Belgrade, P.O. Box 522, 11001 Belgrade, Serbia;1. Universidade Estadual de Goiás, Anápolis, GO, Brazil;2. Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil;3. Universidade Federal de Juiz de Fora, MG, Brazil;4. Centro Universitário de Anápolis, GO, Brazil;1. University of Kragujevac, Faculty of Science, Department of Chemistry, Radoja Domanovića 12, 34000, Kragujevac, Serbia;2. University of Kragujevac, Institute for Information Technologies Kragujevac, Department of Science, Jovana Cvijića bb, Kragujevac, 34000, Serbia;3. "VINČA" Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, P.O. Box 522, 11001, Belgrade, Serbia;1. Baku State University, ICRL, Z. Khalilov 23, Baku, AZ, 1148, Azerbaijan;2. Université de Lorraine, CNRS, CRM2, F-54000, Nancy, France;3. Institute of Radiation Problems of ANAS, B. Vahabzada 9, Baku, AZ, 1143, Azerbaijan;4. Laboratoire de Chimie des Matériaux, Université de Carthage, Faculté des Sciences de Bizerte, 7021, Zarzouna, Tunisia;5. Universita di Pavia, V.le Taramelli 10, 27100, Pavia, Italy;1. H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan;2. Department of Biochemistry, Abdul Wali Khan University, Mardan, KP, Pakistan;3. Department of Clinical Pharmacy, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, P.O. Box 31441, Dammam, Saudi Arabia;4. Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan;5. PCSIR Laboratories Complex, Karachi, Shahrah-e-Dr. Salimuzzaman Siddiqui, Karachi 75280, Pakistan;1. PSG Institute of Advanced Studies, Coimbatore, Tamil Nadu 641 004, India;2. PSG Center for Molecular Medicine and Therapeutics, PSG Institute of Medical Sciences & Research (Affiliated to the Tamil Nadu Dr MGR Medical University), Coimbatore, Tamil Nadu India;3. Amity Institute of Nanotechnology (AINTK), Amity University Kolkata, West Bengal 700135, India |
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| Abstract: | 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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| Keywords: | Biginelli scaffold Selectivity index Apoptosis Caspase-9 Lipophilicity |
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