Abstract |
The receptor tyrosine kinase c-Met is an attractive target for therapeutic treatment of cancers nowadays. Herein we describe the design and synthesis of a novel series of 1,2,4-triazine derivatives based on our lead NCI 748494/1, possessing different N-linkers to aromatic and heterocyclic rings. In addition, a molecular hybrid series combining the 1,2,4-triazine scaffold to the well-known anticancer drug 6-mercaptopurine (6-MP) was synthesized in order to explore its "double- drug" antitumor effect. The synthesized compounds were evaluated for their in vitro antitumor activity against three c-Met addicted cancer cell lines (A549, HT-29 and MKN-45). Most compounds showed moderate to excellent antitumor activity. Compound 3d showed potent inhibitory activity more than reference Foretinib, BMS-777607 and NCI 748494/1 with IC50 values in the range 0.01-0.31 µM against the cancer cell lines. The calculated IC50 of 3d against c-Met kinase was found to be 2.71 µM, which is more potent than NCI 748494/1 (IC50 = 31.70 µM). Docking studies were performed to identify the binding mode of 3d with c-Met kinase domain in comparison to moderate and weak derivatives. The present study clearly demonstrates that 1,2,4-triazine ring exhibits promising antitumor activity and the double- drug optimization strategy led to identifying 3d as a potent c-Met kinase inhibitor suitable for further development.
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Authors | Marwa H El-Wakil, Hayam M Ashour, Manal N Saudi, Ahmed M Hassan, Ibrahim M Labouta |
Journal | Bioorganic chemistry
(Bioorg Chem)
Vol. 76
Pg. 154-165
(02 2018)
ISSN: 1090-2120 [Electronic] United States |
PMID | 29175587
(Publication Type: Journal Article)
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Copyright | Copyright © 2017 Elsevier Inc. All rights reserved. |
Chemical References |
- Aminopyridines
- Anilides
- Antineoplastic Agents
- GSK 1363089
- N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide
- Protein Kinase Inhibitors
- Pyridones
- Quinolines
- Triazines
- MET protein, human
- Proto-Oncogene Proteins c-met
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Topics |
- Aminopyridines
(pharmacology)
- Anilides
(pharmacology)
- Antineoplastic Agents
(chemical synthesis, chemistry, metabolism, pharmacology)
- Catalytic Domain
- Cell Line, Tumor
- Drug Design
- Drug Screening Assays, Antitumor
- Humans
- Hydrogen Bonding
- Hydrophobic and Hydrophilic Interactions
- Molecular Docking Simulation
- Protein Binding
- Protein Kinase Inhibitors
(chemical synthesis, chemistry, metabolism, pharmacology)
- Proto-Oncogene Proteins c-met
(antagonists & inhibitors, chemistry, metabolism)
- Pyridones
(pharmacology)
- Quinolines
(pharmacology)
- Stereoisomerism
- Structure-Activity Relationship
- Triazines
(chemical synthesis, chemistry, metabolism, pharmacology)
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