Synthesis of some quinazolinones inspired from the natural alkaloid L - norephedrine as EGFR inhibitors and radiosensitizers

Mostafa M Ghorab; Maged S Abdel-Kader; Ali S Alqahtani; Aiten M Soliman

doi:10.1080/14756366.2020.1854243

Synthesis of some quinazolinones inspired from the natural alkaloid L - norephedrine as EGFR inhibitors and radiosensitizers

J Enzyme Inhib Med Chem. 2021 Dec;36(1):218-237. doi: 10.1080/14756366.2020.1854243.

Authors

Mostafa M Ghorab¹, Maged S Abdel-Kader^{2

3}, Ali S Alqahtani^{4

5}, Aiten M Soliman¹

Affiliations

¹ Department of Drug Radiation Research, National Center for Radiation Research and Technology (NCRRT), Egyptian Atomic Energy Authority (EAEA), Cairo, Egypt.
² Department of Pharmacognosy, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj, Saudi Arabia.
³ Department of Pharmacognosy, College of Pharmacy, Alexandria University, Alexandria, Egypt.
⁴ Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
⁵ Medicinal, Aromatic and Poisonous Plants Research Center (MAPPRC), College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.

Abstract

A set of quinazolinones synthesized by the aid of L-norephedrine was assembled to generate novel analogues as potential anticancer and radiosensitizing agents. The new compounds were evaluated for their cytotoxic activity against MDA-MB-231, MCF-7, HepG-2, HCT-116 cancer cell lines and EGFR inhibitory activity. The most active compounds 5 and 6 were screened against MCF-10A normal cell line and displayed lower toxic effects. They proved their relative safety with high selectivity towards MDA-MB-231 breast cancer cell line. Measurement of the radiosensitizing activity for 5 and 6 revealed that they could sensitize the tumour cells after being exposed to a single dose of 8 Gy gamma radiation. Compound 5 was able to induce apoptosis and arrest the cell cycle at the G2-M phase. Molecular docking of 5 and 6 in the active site of EGFR was performed to gain insight into the binding interactions with the key amino acids.

Keywords: EGFR; Quinazolinone; anticancer; cytotoxicity; docking.

MeSH terms

Apoptosis / drug effects
Apoptosis / radiation effects
Binding Sites
Cell Line
Cell Proliferation / drug effects
Cell Proliferation / radiation effects
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / metabolism
Enzyme Inhibitors / pharmacology
Epithelial Cells / cytology
Epithelial Cells / drug effects
Epithelial Cells / radiation effects
ErbB Receptors / antagonists & inhibitors
ErbB Receptors / chemistry
ErbB Receptors / metabolism
Gamma Rays
HCT116 Cells
Hep G2 Cells
Humans
Inhibitory Concentration 50
MCF-7 Cells
Molecular Docking Simulation
Phenylpropanolamine / chemistry*
Phenylpropanolamine / metabolism
Phenylpropanolamine / pharmacology
Protein Binding
Protein Conformation, alpha-Helical
Protein Conformation, beta-Strand
Protein Interaction Domains and Motifs
Quinazolinones / chemical synthesis*
Quinazolinones / metabolism
Quinazolinones / pharmacology
Radiation-Sensitizing Agents / chemical synthesis*
Radiation-Sensitizing Agents / metabolism
Radiation-Sensitizing Agents / pharmacology
Stereoisomerism
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Quinazolinones
Radiation-Sensitizing Agents
Phenylpropanolamine
EGFR protein, human
ErbB Receptors