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

Abstract

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 N-phenyl-4-hydroxy-6-methyl-2-quinolone-3-carboxamide were synthesized and characterized using NMR (1H and 13C) and HRMS. The derivatives displayed inhibitory activity against human epithelial colorectal adenocarcinoma (Caco-2) and human colon cancer (HCT-116) cell lines: compounds 8 (IC50 Caco-2 = 98 µM, IC50 HCT-116 = 337 µM) and 16 (IC50 Caco-2 = 13 µM, IC50 HCT-116 = 240.2 µM). Results showed that compound 16 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.

N-phenyl-6-chloro-4-hydroxy-2-quinolone-3-carboxamides: Molecular Docking, Synthesis, and Biological Investigation as Anticancer Agents

“…The co-ordinates of WT PI3Kαs (PDB ID: 2RD0) [ 9 ] and (PDB ID: 4L23) [ 39 ] as well as MUT (H1047R) PI3Kα (PDB ID: 3HHM) [ 35 ] were obtained from the RCSB Protein Data Bank [ 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 ]. The template of X6K in 4L23 [ 39 ] was conveyed to 2RD0 and pinpointed as a ligand to extract the grid file.…”

“…Recently, we published a series of N -substituted- 4-hydroxy-2-quinolone-3-carboxamides that demolished human colon carcinoma (HCT116) cell line differentiation and promoted apoptosis by catalyzing caspase-3 activity and damaging cellular DNA represented by 3 [ 23 ]. Also, our continuous attempts released various core nucleus [ 24 , 25 , 26 , 27 , 28 , 29 , 30 ] targeting the kinase domain of PI3Kα.…”

Novel Derivatives of 4,6‐Dihydroxy‐2‐Quinolone‐3‐Carboxamides as Potential PI3Kα Inhibitors

“…To prepare target products 8 (a-l), excess primary amine (ArNH 2 ) in DMF under reflux was reacted with 7, as shown in Table 1 and Scheme 1, the lack on the TLC plate of starting material 7 spot was used as an indication of the completion of the reaction. The chemical structures identification were verified employing IR, NMR ( 1 H-NMR, 13 C-NMR, DEPT-135, HMQC, COSY, and HMBC), MS and elemental analysis. The particularised experimental data and spectroscopic assignments endorse the identity of the target analogues.…”

“…[9] As a lead PI3Kα inhibitor, we disclosed N-benzyl-4-hydroxy-2-quinolone-3-carboxamide (1) against both H1047R (Mutant) and wild type PI3Kα, respectively, (Figure 2). [10] Successive lead optimization strategies released series of Nphenyl-4-hydroxy-2-quinolone-3-carboxamides, [11] N-substituted-4-hydroxy-2-quinolone-3-carboxamide, [12] N-phenyl-4-hydroxy-6-methyl-2-quinolone-3-carboxamide, [13] N-phenyl-6chloro-4-hydroxy-2-quinolone-3-carboxamide, and N-phenyl-6-Fluoro-4-Hydroxy-2-Quinolone-3-Carboxamides. [14] Continuous efforts reported diverse scaffolds targeting PI3Kα kinase cleft.…”

“…Successive lead optimization strategies released series of N ‐phenyl‐4‐hydroxy‐2‐quinolone‐3‐carboxamides, [11] N ‐substituted‐4‐hydroxy‐2‐quinolone‐3‐carboxamide, [12] N ‐phenyl‐4‐hydroxy‐6‐methyl‐2‐quinolone‐3‐carboxamide, [13] N ‐phenyl‐6‐chloro‐4‐hydroxy‐2‐quinolone‐3‐carboxamide, and N‐ phenyl‐6‐ Fluoro‐4‐Hydroxy‐2‐Quinolone‐3‐Carboxamides [14] . Continuous efforts reported diverse scaffolds targeting PI3Kα kinase cleft [15] .…”