Design, synthesis, and anti-cancer evaluation of new pyrido[2,3-d]pyrimidin-4(3H)-one derivatives as potential EGFRWT and EGFRT790M inhibitors and apoptosis inducers

Heba S A Elzahabi; Eman S Nossier; Rania A Alasfoury; May El-Manawaty; Sara M Sayed; Eslam B Elkaeed; Ahmed M Metwaly; Mohamed Hagras; Ibrahim H Eissa

doi:10.1080/14756366.2022.2062752

Design, synthesis, and anti-cancer evaluation of new pyrido[2,3-d]pyrimidin-4(3H)-one derivatives as potential EGFRWT and EGFRT790M inhibitors and apoptosis inducers

J Enzyme Inhib Med Chem. 2022 Dec;37(1):1053-1076. doi: 10.1080/14756366.2022.2062752.

Authors

Heba S A Elzahabi¹, Eman S Nossier¹, Rania A Alasfoury¹, May El-Manawaty², Sara M Sayed³, Eslam B Elkaeed⁴, Ahmed M Metwaly^{5

6}, Mohamed Hagras⁷, Ibrahim H Eissa⁸

Affiliations

¹ Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt.
² Pharmacognosy Department, National Research Centre, Dokki, Cairo, Egypt.
³ Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt.
⁴ Department of Pharmaceutical Sciences, College of Pharmacy, AlMaarefa University, Riyadh, Saudi Arabia.
⁵ Pharmacognosy and Medicinal Plants Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt.
⁶ Biopharmaceutical Products Research Department, Genetic Engineering and Biotechnology Research Institute, City of Scientific Research and Technological Applications (SRTA-City), Alexandria, Egypt.
⁷ Pharmaceutical Organic Chemistry, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt.
⁸ Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt.

Abstract

A new series of pyrido[2,3-d]pyrimidin-4(3H)-one derivatives having the essential pharmacophoric features of EGFR inhibitors has been designed and synthesised. Cell viability screening was performed for these compounds against A-549, PC-3, HCT-116, and MCF-7 cell lines at a dose of 100 μM. The highest active derivatives (8a, 8 b, 8d, 9a, and 12b) were selected for IC₅₀ screening. Compounds 8a, 8 b, and 9a showed the highest cytotoxic activities and were further investigated for wild EGFR^WT and mutant EGFR^T790M inhibitory activities. Compound 8a showed the highest inhibitory activities against EGFR^WT and EGFR^T790M with IC₅₀ values of 0.099 and 0.123 µM, respectively. In addition, it arrested the cell cycle at pre-G1 phase and induced a significant apoptotic effect in PC-3 cells. Furthermore, compound 8a induced a 5.3-fold increase in the level of caspase-3 in PC-3 cells. Finally, docking studies were carried out to examine the binding mode of the synthesised compounds against both EGFR^WT and EGFR^T790M.

Keywords: Anti-proliferative; EGFR inhibitors; apoptosis; docking studies; pyrido[2,3-d]pyrimidin-4(3H)-one.

MeSH terms

Apoptosis
Cell Line, Tumor
Cell Proliferation
ErbB Receptors* / metabolism
Humans
Lung Neoplasms*
Molecular Structure
Mutation
Protein Kinase Inhibitors
Structure-Activity Relationship

Substances

Protein Kinase Inhibitors
ErbB Receptors

Grants and funding

This paper is based upon work supported by Science, Technology & Innovation Funding Authority (STIFA) under [grant number 43327].