Novel series of 6-(2-substitutedacetamido)-4-anilinoquinazolines as EGFR-ERK signal transduction inhibitors in MCF-7 breast cancer cells

Rania S M Ismail; Sahar M Abou-Seri; Wagdy M Eldehna; Nasser S M Ismail; Sara M Elgazwi; Hazem A Ghabbour; Mahmoud Salama Ahmed; Fathi T Halaweish; Dalal A Abou El Ella

doi:10.1016/j.ejmech.2018.06.024

Novel series of 6-(2-substitutedacetamido)-4-anilinoquinazolines as EGFR-ERK signal transduction inhibitors in MCF-7 breast cancer cells

Eur J Med Chem. 2018 Jul 15:155:782-796. doi: 10.1016/j.ejmech.2018.06.024. Epub 2018 Jun 19.

Authors

Rania S M Ismail¹, Sahar M Abou-Seri², Wagdy M Eldehna³, Nasser S M Ismail⁴, Sara M Elgazwi⁵, Hazem A Ghabbour⁶, Mahmoud Salama Ahmed⁷, Fathi T Halaweish⁵, Dalal A Abou El Ella⁸

Affiliations

¹ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City, P.O. Box 11829, Cairo, Egypt.
² Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, P.O. Box 11562, Cairo, Egypt. Electronic address: sahar.shaarawy@pharma.cu.edu.eg.
³ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, 33516, Egypt. Electronic address: wagdy2000@gmail.com.
⁴ Pharmaceutical Chemistry Department, Faculty of Pharmaceutical Sciences and Pharmaceutical Industries, Future University in Egypt, Cairo, Egypt.
⁵ Department of Chemistry and Biochemisty, South Dakota State University, Brookings, SD, 57007, USA.
⁶ Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh, 11451, Saudi Arabia; Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.
⁷ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, The British University in Egypt, Al-Sherouk City, Cairo, Egypt.
⁸ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ain Shams University, Cairo, Abbassia, P.O. Box 11566, Egypt; Faculty of Pharmacy, Nahda University, New Beni Suef (NUB), 62511, Egypt.

PMID: 30047410
DOI: 10.1016/j.ejmech.2018.06.024

Abstract

Epidermal growth factor receptor (EGFR) signaling pathway has been previously investigated for its significant role in the progression of different types of malignant tumors, where development of small molecules targeting EGFR is well known strategy for design of antitumor agents. Herein, we report the design and synthesis of two series of 6-(2-substitutedacetamido)-4-anilinoquinazolines (6a-x and 13a-d) as EGFR inhibitors. All the newly synthesized quinazoline derivatives were in vitro evaluated for their anti-proliferative activity towards MCF-7 (Breast Cancer) and HepG2 (Hepatocellular carcinoma) cell lines. In particular, compound 6n showed significant inhibitory activity against MCF-7 and HepG2 cell lines (IC₅₀ = 3 and 16 μM, respectively), compared to that of Erlotinib (IC₅₀ = 20 and 25 μM, respectively). Western blotting of 6n at MCF-7 cell line revealed the dual inhibitory activity of 6n towards diminishing the phosphorylated levels for EGFR and ERK. Also, ELISA assay confirmed the anti-EGFR activity of compound 6n (IC₅₀ = 0.037 μM). Finally, a molecular docking study showed the potential binding mode of 6n within the ATP catalytic binding site of EGFR, exhibiting similar binding mode to EGFR inhibitor Erlotinib.

Keywords: Anilinoquinazolines; Docking; EGFR; ERK; Synthesis.

MeSH terms

Aniline Compounds / chemical synthesis
Aniline Compounds / chemistry
Aniline Compounds / pharmacology*
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Proliferation / drug effects
Drug Screening Assays, Antitumor
ErbB Receptors / antagonists & inhibitors*
ErbB Receptors / biosynthesis
ErbB Receptors / metabolism
Hep G2 Cells
Humans
MAP Kinase Signaling System / drug effects*
MCF-7 Cells
Models, Molecular
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Quinazolines / chemical synthesis
Quinazolines / chemistry
Quinazolines / pharmacology*
Signal Transduction / drug effects*

Substances

Aniline Compounds
Antineoplastic Agents
Protein Kinase Inhibitors
Quinazolines
anilinoquinazoline
EGFR protein, human
ErbB Receptors