Design, synthesis, anticancer evaluation, and in silico studies of some thieno[2,3-d]pyrimidine derivatives as EGFR inhibitors

New series of 20 thieno[2,3-d]pyrimidine derivatives have been synthesized. The National Cancer Institute evaluated all the newly synthesized compounds for their antiproliferative activity against a panel of 60 cancer cell lines. Compound 7b exhibited a remarkable antineoplastic activity at 10 & mu;M dose and was therefore tested at five dose concentrations. The significant and broad-spectrum antineoplastic action of compound 7b was observed against 37 of the tested cancer cell lines with a dose that inhibits 50% of the growth compared to control values in the micromolar range of 1.95-9.6 & mu;M. The dose which inhibits the growth completely in the cytostatic range of 3.99-100 & mu;M was also observed. Compound 7b effectively inhibited epidermal growth factor receptor (EGFR) with 50% inhibition concentration value (IC50) = 0.096 & PLUSMN; 0.004 compared to erlotinib with IC50 = 0.037 & PLUSMN; 0.002. Moreover, compound 7b revealed a powerful downregulation effect on total EGFR concentration and its phosphorylation. In addition, compound 7b inhibited phosphatidylinositol 3-kinase, protein kinase B, and the mammalian target of rapamycin pathway phosphorylation. Furthermore, compound 7b raised total apoptosis by 21.93-fold in the ovarian cancer cell line (OVCAR-4) and caused an arrest in the cell cycle in the G1/S phase. It also raised the level of caspase-3 by 4.72-fold. Furthermore, to determine the binding manner of the most effective derivatives and validate their capacity to comply with the pharmacophoric properties necessary for EGFR inhibition, they were docked into the active site of the EGFR.

Automated summary

A series of 20 thieno[2,3-d]pyrimidine derivatives were synthesized and evaluated for their antiproliferative activity against 60 cancer cell lines. Compound 7b showed significant antineoplastic activity and inhibited the growth of 37 tested cancer cell lines at micromolar concentrations. It effectively inhibited EGFR and showed downregulation effects on total EGFR concentration and its phosphorylation. Compound 7b also increased apoptosis and arrested the cell cycle in the G1/S phase.