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

Dima A Sabbah,Sanaa K Bardaweel,Aya M Al-Zuheiri,Reema Abu Khalaf,Shaima’ E Hasan,Kamal A Sweidan,Khalid M Alqaisi,Rima Hajjo

doi:10.3390/molecules25225348

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.

Highlights

Phosphatidylinositol 3-kinases (PI3Ks) phosphorylate the hydroxyl moiety on position 3(3-OH) of inositol rings, producing phosphatidylinositol 3,4,5 triphosphates (PIP3 )
We identified the key binding residues of MUT H1047R PI3Kα inhibitors through binding free energy calculations recruiting the molecular mechanics/generalized born surface area (MM/GBSA) protocol for PI3Kα molecular dynamic (MD) extracted assemblies [16]
Monitoring the reaction progress was applied by employing thin thin layer chromatography (TLC); disappearance ethylanthranilate anthranilatespot spotindicated indicatedthat that the the layer chromatography (TLC); the the disappearance of of thethe ethyl reaction was completed

Summary

Introduction

(3-OH) of inositol rings, producing phosphatidylinositol 3,4,5 triphosphates (PIP3 ). Class IA PI3Ks compromises PI3Kα, β, and δ isozymes expressed by their discrete genes PIK3CA (PI3Kα), PIK3CB (PI3Kβ), and PIK3CD (PI3Kδ) [4]. The gene PIK3CA is exaggerated, over encrypted, and mutated in many human cancers [5]. Mutations in the helical (E545K and E542K) and kinase (H1047R) domains of PI3Kα are identified in brain, breast, endometrial, and GIT cancers [6,7,8,9]. These oncogenic alterations distort PI3Kα conformation and have lead

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