Pyrimidine containing epidermal growth factor receptor kinase inhibitors: Synthesis and biological evaluation.
Gaurav JoshiHimanshu NayyarSourav KalraPraveen SharmaAnjana MunshiSandeep SinghRaj KumarPublished in: Chemical biology & drug design (2017)
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, that is 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 to investigate the binding recognition pattern of the compounds in ATP binding EGFR domain similar to erlotinib and dissimilar to WZ4002.
Keyphrases
- epidermal growth factor receptor
- cell death
- tyrosine kinase
- advanced non small cell lung cancer
- reactive oxygen species
- small cell lung cancer
- cell cycle arrest
- high throughput
- photodynamic therapy
- diabetic rats
- risk assessment
- dna methylation
- epithelial mesenchymal transition
- binding protein
- human health
- dna binding
- signaling pathway
- anti inflammatory