Design and green synthesis of novel quinolinone derivatives of potential anti-breast cancer activity against MCF-7 cell line targeting multi-receptor tyrosine kinases

Mohamed Mokhtar; Khadijah S Alghamdi; Nesreen S Ahmed; Dina Bakhotmah; Tamer S Saleh

doi:10.1080/14756366.2021.1944126

Design and green synthesis of novel quinolinone derivatives of potential anti-breast cancer activity against MCF-7 cell line targeting multi-receptor tyrosine kinases

J Enzyme Inhib Med Chem. 2021 Dec;36(1):1454-1471. doi: 10.1080/14756366.2021.1944126.

Authors

Mohamed Mokhtar¹, Khadijah S Alghamdi², Nesreen S Ahmed³, Dina Bakhotmah¹, Tamer S Saleh^{4

5}

Affiliations

¹ Chemistry Department, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia.
² Chemistry Department, Faculty of Science, Albaha University, Albaha, Saudi Arabia.
³ Department of Therapeutic Chemistry, National Research Centre, Cairo,Egypt.
⁴ Department of Chemistry, University of Jeddah, College of Science, Jeddah, Saudi Arabia.
⁵ Green Chemistry Department, National Research Centre, Giza, Egypt.

Abstract

A new set of 4,6,7,8-tetrahydroquinolin-5(1H)-ones were designed as cytotoxic agents against breast cancer cell line (MCF-7) and synthesised under ultrasonic irradiation using chitosan decorated copper nanoparticles (CS/CuNPs) catalyst. The new compounds 4b, 4j, 4k, and 4e exhibited the most potent cytotoxic activity of IC₅₀ values (0.002 - 0.004 µM) comparing to Staurosporine of IC₅₀; 0.005 μM. The latter derivatives exhibited a promising safety profile against the normal human WI38 cells of IC₅₀ range 0.0149 - 0.048 µM. Furthermore, the most promising cytotoxic compounds 4b, 4j were evaluated as multi-targeting agents against the RTK protein kinases; EGFR, HER-2, PDGFR-β, and VEGFR-2. Compound 4j showed promising inhibitory activity against HER-2 and PDGFR-β of IC₅₀ values 0.17 × 10^-3, 0.07 × 10^-3 µM in comparison with the reference drug sorafenib of IC₅₀; 0.28 × 10^-3, 0.13 × 10^-3 µM, respectively. In addition, 4j induced apoptotic effect and cell cycle arrest at G2/M phase preventing the mitotic cycle in MCF-7 cells.

Keywords: 4,6,7,8-Tetrahydroquinolin-5(1H)-one; HER-2 inhibitors; apoptosis; breast cancer; molecular docking study.

MeSH terms

Antineoplastic Agents / pharmacology
Breast Neoplasms / enzymology
Breast Neoplasms / pathology
Breast Neoplasms / prevention & control*
Cell Line
Drug Design
Drug Screening Assays, Antitumor
Female
Green Chemistry Technology*
Humans
MCF-7 Cells
Molecular Docking Simulation
Protein Kinase Inhibitors / pharmacology
Quinolones / chemical synthesis
Quinolones / chemistry*
Quinolones / pharmacology*
Receptor Protein-Tyrosine Kinases / drug effects*
Spectrum Analysis / methods

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Quinolones
Receptor Protein-Tyrosine Kinases

Grants and funding

This work was supported by the Deanship of Scientific Research (DSR) at King Abdulaziz University, Jeddah, Saudi Arabia, under grant no. DF-838–130-1441.