3′‐(4‐(Benzyloxy)phenyl)‐1′‐phenyl‐5‐(heteroaryl/aryl)‐3,4‐dihydro‐1′H,2H‐[3,4′‐bipyrazole]‐2‐carboxamides as EGFR kinase inhibitors: Synthesis, anticancer evaluation, and molecular docking studies
- 31 January 2020
- journal article
- research article
- Published by Wiley in Archiv der Pharmazie
- Vol. 353 (4), e1900262
- https://doi.org/10.1002/ardp.201900262
Abstract
Pyrazoline‐linked carboxamide derivatives were designed, synthesized, and evaluated for potential epidermal growth factor receptor (EGFR) kinase inhibition, anticancer activity, and apoptotic and cardiomyopathy toxicity. Compounds 6m and 6n inhibit EGFR kinase at a concentration of 6.5 ± 2.91 and 3.65 ± 0.54 µM, respectively. Some of these compounds showed effects on proliferation, which were also then evaluated against four different human cancer cell lines, that is, MCF‐7 (breast cancer), A549 (non‐small‐cell lung tumor), HCT‐116 (colon cancer), and SiHa cells (cancerous tissues of the cervix uteri). The results showed that certain synthetic compounds showed significant inhibitor activity; compounds 6m and 6n were more cytotoxic than doxorubicin against A549 cancer cells, with IC50 values of 10.3 ± 1.07 and 4.6 ± 0.57 µM, respectively. Additionally, compounds 6m and 6n induced apoptosis in A549 cancer cells, as evidenced by 4′,6‐diamidino‐2‐phenylindole (DAPI) staining and phase‐contrast microscopy. Potency to induce apoptosis by compound 6n was further confirmed by fluorescence‐activated cell sorting using Annexin V‐FITC and propidium iodide labeling. Compound 6n showed normal cardiomyocytes with no marked sign of pyknotic nuclei in cardiomyopathy and also normal histological appearance of the renal cortex when compared with that of control. Results of molecular docking studies suggested that compounds 6m and 6n can bind to the hinge region of the adenosine triphosphate‐binding site of EGFR kinase, like the standard drug erlotinib. Therefore, the present study suggests that compounds 6m and 6n have potent in vitro antitumor activities against the human non‐small‐cell lung tumor cell line A549, which can be further explored in other cancer cell lines and in animal studies.Keywords
Funding Information
- Department of Science and Technology, New Delhi, India (IF-131173)
This publication has 35 references indexed in Scilit:
- Fingerprint-based in silico models for the prediction of P-glycoprotein substrates and inhibitorsBioorganic & Medicinal Chemistry, 2012
- Design, synthesis and biological evaluation of pyrazolyl-thiazolinone derivatives as potential EGFR and HER-2 kinase inhibitorsBioorganic & Medicinal Chemistry, 2012
- Synthesis, molecular docking and evaluation of thiazolyl-pyrazoline derivatives as EGFR TK inhibitors and potential anticancer agentsBioorganic & Medicinal Chemistry Letters, 2011
- The Emergence of Drug Transporter-Mediated Multidrug Resistance to Cancer ChemotherapyMolecular Pharmaceutics, 2011
- Synthesis and in vitro anti-tumor activity of new oxadiazole thioglycosidesEuropean Journal of Medicinal Chemistry, 2011
- Cardiotoxicity Associated with Targeting Kinase Pathways in CancerToxicological Sciences, 2010
- Synthesis and biological evaluation of novel 2,4′-bis substituted diphenylamines as anticancer agents and potential epidermal growth factor receptor tyrosine kinase inhibitorsEuropean Journal of Medicinal Chemistry, 2010
- Design, synthesis and biological evaluation of thiazolidinone derivatives as potential EGFR and HER-2 kinase inhibitorsBioorganic & Medicinal Chemistry, 2010
- Cardiotoxicity induced by tyrosine kinase inhibitorsActa Oncologica, 2009
- Synthesis and biological evaluation of substituted 6-alkynyl-4-anilinoquinazoline derivatives as potent EGFR inhibitorsBioorganic & Medicinal Chemistry Letters, 2007