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Facile Preparation of 4-Substituted Quinazoline Derivatives
Published on: February 15, 2016
N-Phenyl-6-Chloro-4-Hydroxy-2-Quinolone-3-CarboxAmides: Molecular Docking, Synthesis, and Biological Investigation as
Dima A Sabbah1, Rawan A Haroon1, Sanaa K Bardaweel2
1Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, Amman 11733, Jordan.
Abstract:
Cancer is a multifactorial disease and the second leading cause of death worldwide. Diverse factors induce carcinogenesis, such as diet, smoking, radiation, and genetic defects. The phosphatidylinositol 3-kinase (PI3Kα) has emerged as an attractive target for anticancer drug design. Eighteen derivatives of N-phenyl-6-chloro-4-hydroxy-2-quinolone-3-carboxamide were synthesized and characterized using FT-IR, NMR (1H and 13C), and high-resolution mass spectra (HRMS). The series exhibited distinct antiproliferative activity (IC50 µM) against human epithelial colorectal adenocarcinoma (Caco-2) and colon carcinoma (HCT-116) cell lines, respectively: compounds 16 (37.4, 8.9 µM), 18 (50.9, 3.3 µM), 19 (17.0, 5.3 µM), and 21 (18.9, 4.9 µM). The induced-fit docking (IFD) studies against PI3Kαs showed that the derivatives occupy the PI3Kα binding site and engage with key binding residues.
Insights
New quinolone-carboxamide derivatives show significant antiproliferative effects against colorectal cancer cells. These compounds target phosphatidylinositol 3-kinase alpha (PI3Kα), offering potential for novel anticancer drug development.
Area of Science:
- Medicinal Chemistry
- Oncology
- Molecular Biology
Background:
- Cancer is a leading global cause of death, driven by diverse factors.
- The phosphatidylinositol 3-kinase alpha (PI3Kα) pathway is a key target in cancer therapy.
- Developing novel anticancer agents with improved efficacy is crucial.
Purpose of the Study:
- To synthesize and characterize novel N-phenyl-6-chloro-4-hydroxy-2-quinolone-3-carboxamide derivatives.
- To evaluate the antiproliferative activity of these compounds against human colorectal cancer cell lines.
- To investigate the binding interactions of these derivatives with PI3Kα using computational methods.
Main Methods:
- Synthesis of eighteen N-phenyl-6-chloro-4-hydroxy-2-quinolone-3-carboxamide derivatives.
- Characterization using FT-IR, NMR (1H and 13C), and high-resolution mass spectrometry (HRMS).
- In vitro antiproliferative assays against Caco-2 and HCT-116 cell lines.
- Induced-fit docking (IFD) studies against PI3Kα.
Main Results:
- Four compounds (16, 18, 19, 21) demonstrated significant antiproliferative activity against Caco-2 and HCT-116 cells, with IC50 values in the low micromolar range.
- Compound 18 showed potent activity against HCT-116 cells (IC50 = 3.3 µM).
- IFD studies confirmed that the derivatives bind to the PI3Kα active site, interacting with key residues.
Conclusions:
- The synthesized quinolone-carboxamide derivatives possess promising anticancer potential.
- These compounds effectively inhibit colorectal cancer cell proliferation.
- The observed activity and binding interactions support PI3Kα as a viable target for these novel agents.
