1. New cyanopyridine-based scaffold as PIM-1 inhibitors and apoptotic inducers: Synthesis and SARs study.
- Author
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Farrag AM, Ibrahim MH, Mehany ABM, and Ismail MMF
- Subjects
- Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Cell Proliferation drug effects, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Humans, Models, Molecular, Molecular Structure, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors chemistry, Proto-Oncogene Proteins c-pim-1 metabolism, Pyridines chemical synthesis, Pyridines chemistry, Structure-Activity Relationship, Tumor Cells, Cultured, Antineoplastic Agents pharmacology, Apoptosis drug effects, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins c-pim-1 antagonists & inhibitors, Pyridines pharmacology
- Abstract
Two novel series of 6-(4-benzamido-/4-phthalimido)-3-cyanopyridine derivatives were designed and synthesized as inhibitors of PIM-1 kinase. Based on cytotoxicity results via MTT assay against prostate carcinoma PC3, human hepatocellular carcinoma HepG2 and breast adenocarcinoma MCF-7 cell lines, the most potent cytotoxic cyanopyridine hits, 6, 7, 8, 12 and 13 were 1.5-3.3 times more inhibitor of cell proliferation than the reference standard, 5-FU. Selectivity profile of the latter compounds on normal human cells (WI-38), was executed, indicating that they are highly selective (IC
50 > 145 μM) in their cytotoxic effect. The promising compounds were further evaluated as PIM-1 kinase inhibitors. These compounds elicited remarkable inhibition of PIM-1 kinase (76.43-53.33%). Extensive studies on apoptosis were conducted for these compounds; they enhanced caspase-3 and boosted the Bax/Bcl-2 ratio 27-folds in comparison to the control. Molecular docking study of the most potent compound, 13 in PIM-1 kinase active site was consistent with the in vitro activity. Finally, prediction of chemo-informatic properties released compound 13 as the most promising ligand., (Copyright © 2020 Elsevier Inc. All rights reserved.)- Published
- 2020
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