Design, Synthesis and Anticancer Evaluation of Substituted Cinnamic Acid Bearing 2-Quinolone Hybrid Derivatives.

Ali H Abu Almaaty,Ola A Abu Ali,Mohammed El Behery,Nermeen A Elgrahy,Lamiaa A A Barakat,Eman Fayad,Ahmed R E Mahdy

doi:10.3390/molecules26164724

Ali H Abu Almaaty, Ola A Abu Ali + Show 5 more

Open Access

https://doi.org/10.3390/molecules26164724

Copy DOI

Abstract

A new series of hybrid molecules containing cinnamic acid and 2-quinolinone derivatives were designed and synthesized. Their structures were confirmed by 1H-NMR, 13C-NMR and mass analyses. All the synthesized hybrid molecules were assessed for their in vitro antiproliferative activity against more than one cancer cell lines. Compound 3-(3,5-dibromo-7,8-dihydroxy-4-methyl-2-oxoquinolin-1(2H)-ylamino)-3-phenylacrylic acid (5a) with IC50 = 1.89 μM against HCT-116 was proved to the most potent compound in this study, as compared to standard drug staurosporin. DNA flow cytometry assay of compound 5a revealed G2/M phase arrest and pre-G1 apoptosis. Annexin V-FITC showed that the percentage of early and late apoptosis was increased. The results of topoisomerase enzyme inhibition activity showed that the hybrid molecule 5a displays potent inhibitory activity compared with control.

Highlights

Molecular hybridization is a commonly molecular modification approach to obtain multiple compounds with therapeutic advantages over the two different drugs [1,2,3,4,5,6,7,8]
Subsequent, introduction of hydrophilic side chain to 2-quinolone scaffold led to the discovery of topotecan and irinotecan which currently used as anticancer drugs [17]
Hybrid molecules containing cinnamic acid and 2-quinolinone derivatives (4a–c) were synthesized via the reaction of cinnamic acid derivatives with 1-amino7,8-dihydroxy-4-methylquinolin-2(1H)-one (3), which was obtainable in the reaction of 7,8-hydroxy-4-methylcoumarin (2) with hydrazine hydrate in pyridine

Summary

Introduction

Molecular hybridization is a commonly molecular modification approach to obtain multiple compounds with therapeutic advantages over the two different drugs [1,2,3,4,5,6,7,8]. The hydroxy cinnamic acids are natural products arisen from the deamination of the phenyl alanine. The 13C-NMR spectrum of compound 3 showed four carbon Molecules 2021, 26, x FOR PEER REVIEsiWgnals at δ 160.73, 154.44, 150.01 and 143.75 ppm assigned to carbonyl function (C=O4),otfw1o5 carbons (C-O) and one carbon (C-N) groups. 13C-NMR spectrum of compound 4a showed three signals at δ 168.31, 160.74 and 18.73 ppm assigned to the carbons of two carbonyl and methyl groups, respectively. The 13C-NMR spectrum of compound 4a displayed an additional carbon signals in the region of δ 134.77–110.62 ppm attributed to the carbons of quinoline, aromatic and olefinic carbons. In the 1H-NMR spectrum of compound 5a Protons of the aromatic and H-6 of quinolinone ring were observed as multiplet signals within the expected chemical shift region at δ 7.35–7.69 ppm. Carbons of the aromatic and quinolinone rings were observed a characteristic carbon signals in the region δ 138.68–107.12 ppm

In Vitro Cytotoxic Activity against Three Cancer Cell Line

Cell Cycle Analysis

Topoisomerase II Inhibitory Activity

Molecular Docking Study

In Vitro Topoismerase Inhibitory Assay

Conclusions