Anticancer evaluation and molecular modeling of multi-targeted kinase inhibitors based pyrido[2,3-d]pyrimidine scaffold

Heba S A Elzahabi; Eman S Nossier; Nagy M Khalifa; Rania A Alasfoury; May A El-Manawaty

doi:10.1080/14756366.2018.1437729

Anticancer evaluation and molecular modeling of multi-targeted kinase inhibitors based pyrido[2,3-d]pyrimidine scaffold

J Enzyme Inhib Med Chem. 2018 Dec;33(1):546-557. doi: 10.1080/14756366.2018.1437729.

Authors

Heba S A Elzahabi¹, Eman S Nossier¹, Nagy M Khalifa², Rania A Alasfoury¹, May A El-Manawaty³

Affiliations

¹ a Department of Pharmaceutical Chemistry , Faculty of Pharmacy (Girls), Al-Azhar University , Cairo , Egypt.
² b Drug Exploration & Development Chair (DEDC), Department of Pharmaceutical Chemistry , College of Pharmacy, King Saud University , Riyadh , Saudi Arabia.
³ c Department of Pharmacognosy, Pharmaceutical Science Division , National Research Centre , Cairo , Egypt.

Abstract

An efficient synthesis of substituted pyrido[2,3-d]pyrimidines was carried out and evaluated for in vitro anticancer activity against five cancer cell lines, namely hepatic cancer (HepG-2), prostate cancer (PC-3), colon cancer (HCT-116), breast cancer (MCF-7), and lung cancer (A-549) cell lines. Regarding HepG-2, PC-3, HCT-116 cancer cell lines, 7-(4-chlorophenyl)-2-(3-methyl-5-oxo-2,3-dihydro-1H-pyrazol-1-yl)-5-(p-tolyl)- pyrido[2,3-d]pyrimidin-4(3H)-one (5a) exhibited strong, more potent anticancer (IC₅₀: 0.3, 6.6 and 7 µM) relative to the standard doxorubicin (IC₅₀: 0.6, 6.8 and 12.8 µM), respectively. Kinase inhibitory assessment of 5a showed promising inhibitory activity against three kinases namely PDGFR β, EGFR, and CDK4/cyclin D1 at two concentrations 50 and 100 µM in single measurements. Further, a molecular docking study for compound 5a was performed to verify the binding mode towards the EGFR and CDK4/cyclin D1 kinases.

Keywords: CDK4/cyclin D1; EGFR; Pyrido[2,3-d]pyrimidine derivatives; anticancer activity; molecular docking.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Cyclin-Dependent Kinase 4 / antagonists & inhibitors*
Cyclin-Dependent Kinase 4 / metabolism
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
ErbB Receptors / antagonists & inhibitors*
ErbB Receptors / metabolism
Humans
Models, Molecular
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Pyridines / chemical synthesis
Pyridines / chemistry
Pyridines / pharmacology*
Pyrimidines / chemical synthesis
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Receptor, Platelet-Derived Growth Factor beta / antagonists & inhibitors*
Receptor, Platelet-Derived Growth Factor beta / metabolism
Structure-Activity Relationship

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Pyridines
Pyrimidines
pyrido(3,2-d)pyrimidine
ErbB Receptors
Receptor, Platelet-Derived Growth Factor beta
CDK4 protein, human
Cyclin-Dependent Kinase 4

Grants and funding

The authors are grateful to the Deanship of Scientific Research, King Saud University for funding through Vice Deanship of Scientific Research Chairs.