Design, synthesis and molecular modeling studies of new series of antitumor 1,2,4-triazines with potential c-Met kinase inhibitory activity.

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.

• 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)
• 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

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)