Study On Design, Synthesis And Biological Activities Of The N- [3-(2- Pyrimidinyl) Phenyl] Acrylamide

Epidermal growth factor receptor(EGFR, ErbB), an cell surface receptor of extracellular protein ligand classifiedⅠepidermal growth factor family, is an important transmembrane receptor with tyrosine kinase activity. High expression of EGFR can promote tumor cell proliferation, angiogenesis, adhesion, invasion and metastasis. So the EGFR tyrosine kinase inhibitors have become a research hotpoint of anticancer drugs.Based on studies that mutation of EGFR T790 M is the marjor cause of tumor resistance to thses drugs, this paper modificatied the EGFR inhibitor AZD-9291 in order to discover more potent and selective EGFR inhibitor to resistant tumor.Under the guidance of signal transduction mechanism of EGFR inhibitors, we modified the structure of the lead compound AZD-9291, according to the structure-activity relationships of tyrosine kinase inhibitor pyrimidine acrylamides, the structure characteristics of AZD-9291, and the sites analysis of AZD-9291 combined with EGFR crystals. Three series of target compounds were designed based on the structure N-[3-(2-pyrimidinyl) phenyl] acrylamide of AZD-9291. Serie A were designed by replacing the indole ring with a small molecule of heterocyclic, and series B and C were designed by replacing the indole ring with a chain of aromatic rings. Referencing the synthesis method of AZD-9291, 11 target compounds were synthesized and their experimental conditions were optimized. All the compounds haven’t been reported in the literature, and were confirmed by 1HNMR and LCMS.All these compounds were assayed with mutated EGFRT790 M, while AZD-9291 were used as control. Pharmacological screening results showed that the compound A1, A2 and C2 have better inhibitory activity of EGFRT790 M, with their IC50 among 2.5nM- 2.9nM. Then these three compounds were assayed in EGFRWT with their IC50 between 18.4nM-154 nM. The IC50 of the positive control drug AZD-9291 were 0.6nM with EGFRT790 M and 1.7nM with EGFRWT respectively. The results showed the selectivity of A1, A2 and C2 were 20.1, 20.7 and 2.2 folds higher than AZD-9291 respectively.Tumor cell perliferation inhibitory activity of compound A1 and A2 were further assayed with mutated NCI-H1975T790 M cells and wild A431 WT cells. The IC50 of compound A1 was 71.3nM for NCI-H1975T790 M, and 2138.5n M for A431 WT, respectively. The IC50 of compound A2 was 142.8nM for NCI-H1975T790 M, and 2578 n M for A431 WT. The selectiveities of compound A1 and A2 were 30 folds and 18 folds higher for the NCI-H1975T790 M cells than for the A431 WT cells. The selectivity of compound A1 is 1.7 times higher than that of AZD-9291.Conclusion: Target compound A1, A2 and C2 had better EGFRT790 M inhibitory activity and selectivity, and compound A1 was more potenct and selective to mutated NCI-H1975T790 Mcells. Compound A1 may be a candidate compound for further structural modification and research.