Novel amide analogues of quinazoline carboxylate display selective antiproliferative activity and potent EGFR inhibition
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Medicinal Chemistry Research https://doi.org/10.1007/s00044-020-02634-0
ORIGINAL RESEARCH
Novel amide analogues of quinazoline carboxylate display selective antiproliferative activity and potent EGFR inhibition Anjleena Malhotra1 Ranju Bansal 1 Clarissa Esmeralda Halim2 Celestial T. Yap2 Gautam Sethi3 Alan Prem Kumar3,4,5 Mahendra Bishnoi6 Kamalendra Yadav6 ●
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Received: 7 March 2020 / Accepted: 8 September 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract In the present study, a novel series of quinazoline derivatives is developed for cancer therapy. All the synthesised analogues were evaluated against a panel of 60 human cancer cell lines for the antiproliferative activity. Significant and selective growth inhibition of several solid tumour cell lines such as NCI-H322M, NCI-H522 (non-small cell lung cancer), IGROV1, SK-OV-3 (ovarian cancer), TK-10 (renal cancer) and MDA-MB-468 (breast cancer) was observed. Further, all the new amide analogues strongly inhibited EGFR in low nanomolar range with morpholino quinazoline 10 producing activity (IC50 = 6.12 nM) comparable to standard drugs erlotinib and gefitinib. In addition, western blot analysis depicted inhibition of phosphorylation of EGFR by compounds 10 and 11 in MDA-MB-468 cells at 10 µM. Molecular docking studies showed the strong binding interactions with the active site of the EGFR protein. The current investigation could be extremely helpful for the development of newer therapeutically useful quinazoline based molecules for cancer therapy. Keywords Quinazoline EGFR inhibitors Antiproliferative activity ●
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Introduction The epidermal growth factor receptor (EGFR) belongs to receptor tyrosine kinase group, which regulates several functions of cellular proliferation, adhesion, migration, survival and differentiation through various signal
Supplementary information The online version of this article (https:// doi.org/10.1007/s00044-020-02634-0) contains supplementary material, which is available to authorized users. * Ranju Bansal [email protected] 1
University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India
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Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
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Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
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Medical Science Cluster, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
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Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
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National Agri-Food Biotechnology Institute, Mohali, Punjab, India
transduction pathways [1, 2]. Overexpression of EGFR results not only in progression of wide variety of solid tumours including non-small cell lung, breast, colorectal, renal, head, neck, bladder, ovarian cancers but also decreases sensitivity of cells to conventional chemotherapeutic agents [3, 4]. Inhibition of EGFR has emer
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