Molecular Modeling, Synthesis and Biological Evaluation of N -Phenyl-4-Hydroxy-6-Methyl-2-Quinolone-3-CarboxAmides as Anticancer Agents

The emergence of phosphatidylinositol 3-kinase (PI3Kα) in cancer development has accentuated its significance as a potential target for anticancer drug design. Twenty one derivatives of -phenyl-4-hydroxy-6-methyl-2-quinolone-3-carboxamide were synthesized and characterized using NMR ( H and C) and H...

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Bibliographic Details
Published in:Molecules (Basel, Switzerland) Switzerland), 2020-11, Vol.25 (22), p.5348
Main Authors: Sabbah, Dima A, Hasan, Shaima' E, Abu Khalaf, Reema, Bardaweel, Sanaa K, Hajjo, Rima, Alqaisi, Khalid M, Sweidan, Kamal A, Al-Zuheiri, Aya M
Format: Article
Language:English
Subjects:
1-Phosphatidylinositol 3-kinase
Adenocarcinoma
AKT
AKT protein
anticancer
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Binding sites
Caco-2 Cells
Cancer
Colon
Colon cancer
Colorectal cancer
Design
docking
Drug development
Gene Expression Regulation, Neoplastic - drug effects
HCT116 Cells
Humans
Inhibitory Concentration 50
Kinases
Ligands
Models, Molecular
Molecular Docking Simulation
Molecular modelling
Mutation
Phosphatidylinositol 3-Kinases - chemistry
Phosphatidylinositol 3-Kinases - metabolism
PI3Kα
Principal Component Analysis
Protein Kinase Inhibitors - chemistry
Protein Kinase Inhibitors - pharmacology
quinolone-3-carboxamide
Quinolones - chemical synthesis
Quinolones - chemistry
Quinolones - pharmacology
Tumor cell lines
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Summary:The emergence of phosphatidylinositol 3-kinase (PI3Kα) in cancer development has accentuated its significance as a potential target for anticancer drug design. Twenty one derivatives of -phenyl-4-hydroxy-6-methyl-2-quinolone-3-carboxamide were synthesized and characterized using NMR ( H and C) and HRMS. The derivatives displayed inhibitory activity against human epithelial colorectal adenocarcinoma (Caco-2) and human colon cancer (HCT-116) cell lines: compounds (IC Caco-2 = 98 µM, IC HCT-116 = 337 µM) and (IC Caco-2 = 13 µM, IC HCT-116 = 240.2 µM). Results showed that compound significantly affected the gene encoding AKT, BAD, and PI3K. The induced-fit docking (IFD) studies against PI3Kα demonstrated that the scaffold accommodates the kinase domains and forms H-bonds with significant binding residues.
ISSN:1420-3049
1420-3049
DOI:10.3390/molecules25225348