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

• Published in: Molecules (Basel, Switzerland) Vol. 25; no. 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: Journal Article
• Language: English
• Published: Switzerland MDPI AG 16-11-2020; MDPI
• 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; quinolone-3-carboxamide; docking; PI3Kα; AKT; colon cancer; anticancer
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules25225348

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.