Pyrimidine Containing Epidermal Growth Factor Receptor Kinase inhibitors: Synthesis and Biological Evaluation

Abstract

Structure based design and synthesis of pyrimidine containing reversible epidermal growth factor receptor (EGFR) inhibitors 1a-d are reported. The compounds (1a-d) inhibited the EGFR kinase activity in vitro with IC₅₀ range 740 nM to 3 μM. mRNA expression of EGFR downstream target genes i.e. twist, c-fos and aurora were found to be altered upon treatment with compounds 1a-d. The compounds 1a-d exhibited excellent anticancer activity at low micromolar level (3.2-9 μM) in lung, colon and breast cancer cell lines. Furthermore, compounds induced the alteration in mitochondrial membrane potential and reactive oxygen species level and. Selected compound 1b was found to increase sub-G1 population indicative of cell death, the mode of cell death was apoptotic as evident from Annexin V verses propidium iodide assay. Molecular modelling further helped investigating the binding recognition pattern of the compounds in ATP-binding EGFR domain similar to erlotinib and dissimilar to WZ4002.

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We have designed, synthesised, and evaluated the pyrimidine based compounds (1a-1d) for their potential to exhibit anti-EGFR kinase activity at nanomolar range and anticancer activity at low micromolar range.

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