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. 2020 Dec 25;26(1):73.
doi: 10.3390/molecules26010073.

N-Phenyl-6-Chloro-4-Hydroxy-2-Quinolone-3-CarboxAmides: Molecular Docking, Synthesis, and Biological Investigation as Anticancer Agents

Dima A Sabbah  1 , Rawan A Haroon  1 , Sanaa K Bardaweel  2 , Rima Hajjo  1 , Kamal Sweidan  3
Affiliations

N-Phenyl-6-Chloro-4-Hydroxy-2-Quinolone-3-CarboxAmides: Molecular Docking, Synthesis, and Biological Investigation as Anticancer Agents

Dima A Sabbah et al. Molecules. .

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.

Keywords: AKT; PI3Kα; anticancer; colon cancer; docking; quinolone-3-carboxamide.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Chemical structures of 1, 2, and 3.
Figure 2
Figure 2
Phosphatidylinositol 3-kinase (PI3Kα) inhibitor pharmacophore model with compounds 1 (yellow color) and 2 (pink color). Picture captured by MOE [20].
Scheme 1
Scheme 1
Conditions: (a): (i) NaOC2H5, DMSO, 145–150 °C, 72h. (ii) 0.3M HCl (b): (i) THF, DMF, 150 °C, 48–72h.
Figure 3
Figure 3
Relative gene expression of PI3K, AKT, and BAD in HCT116 cells after treatment with Compounds 18 and 19 and the positive control LY-294002. Bars represent mean values ± SEM (lines) of three replicates. Asterisks represent significant change relative to the negative control (* p < 0.05).
Figure 4
Figure 4
Kinase domain of (A) 2RD0 accommodating the IF docked geometries of some of the verified molecules and (B) superposing of the IF docked pose of 10 (pink color) and native pose of (X6K) (gold color). Some of the key binding residues are presented and H atoms are invisible for clarification. Picture made by PYMOL [38].
Figure 5
Figure 5
Binding poses of (A) 9 and (B) 11 in the 2RD0 kinase site. The H-Bond is represented as a blue dotted line. H atoms are hidden for clarification. Picture made by PYMOL [38].
Figure 6
Figure 6
Superposition of the IFdocked X6K pose (blue color) and its native conformation (gold color) in 4L23. Picture made by PYMOL.
Figure 7
Figure 7
PI3Kα inhibitors pharmacophore model with 14 (red color), 15 (green color), 22 (pink color), and 23 (yellow color).
Figure 8
Figure 8
Molecular descriptor analysis. (A) A graphical 2D representation of the principal component analysis of molecular descriptors. PC1 explaining 36.35% of the variation in descriptor values is on the x-axis, and PC2 explaining 22.89% of the variation in descriptor values is on the y-axis. Descriptor used for the analysis belong two major categories of molecular descriptors: (1) drug-like indices; (2) molecular properties and P_VSA-like descriptors. (B) Radar plot of a representative set of 5 molecular drug-like and lead-like molecular descriptors that showed variability for the same compound.
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