1. Discovery of new pyridine-quinoline hybrids as competitive and non-competitive PIM-1 kinase inhibitors with apoptosis induction and caspase 3/7 activation capabilities.
- Author
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El-Miligy MMM, Abdelaziz ME, Fahmy SM, Ibrahim TM, Abu-Serie MM, Mahran MA, and Hazzaa AA
- Subjects
- Male, Humans, Proto-Oncogene Proteins c-pim-1 metabolism, Proto-Oncogene Proteins c-pim-1 pharmacology, Caspase 3 metabolism, Molecular Docking Simulation, Cell Line, Tumor, Kinetics, Caco-2 Cells, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors metabolism, Pyridines pharmacology, Apoptosis, Cell Proliferation, Drug Screening Assays, Antitumor, Antineoplastic Agents pharmacology, Quinolines pharmacology
- Abstract
New quinoline-pyridine hybrids were designed and synthesised as PIM-1/2 kinase inhibitors. Compounds 5b , 5c , 6e, 13a , 13c, and 14a showed in-vitro low cytotoxicity against normal human lung fibroblast Wi-38 cell line and potent in-vitro anticancer activity against myeloid leukaemia (NFS-60), liver (HepG-2), prostate (PC-3), and colon (Caco-2) cancer cell lines. In addition, 6e, 13a, and 13c significantly induced apoptosis with percentage more than 66%. Moreover, 6e, 13a, and 13c significantly induced caspase 3/7 activation in HepG-2 cell line. Furthermore, 5c, 6e, and 14a showed potent in-vitro PIM-1 kinase inhibitory activity. While, 5b showed potent in-vitro PIM-2 kinase inhibitory activity. Kinetic studies using Lineweaver-Burk double-reciprocal plot indicated that 5b , 5c , 6e, and 14a behaved as competitive inhibitors while 13a behaved as both competitive and non-competitive inhibitor of PIM-1 kinase enzyme. Molecular docking studies indicated that, in-silico affinity came in coherence with the observed in-vitro inhibitory activities against PIM-1/2 kinases.
- Published
- 2023
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