Synthesis and evaluation of 2-anilinopyrimidines bearing 3-aminopropamides as potential epidermal growth factor receptor inhibitors

• Compounds 12a–i were synthesized and biologically evaluated as EGFR inhibitors.
• Compounds 12a–h could be converted to WZ4002 (1) in the presence of arginine.
• NO donating compound 12i displayed stronger antiproliferative activity than 12a–h.
• 12i produced high levels of NO in H1975 cells but not in normal human cells.
• 12i inhibited the EGFR activation and downstream signaling in H1975 cells.

Novel compounds 12a–i were synthesized and biologically evaluated. Several ones exhibited stronger inhibitory activity than gefitinib against EGFR L858R/T790M and antiproliferative effects on H1975 and HCC827 cells. The 3-aminopropamide in compounds like 12h could be converted to the active acrylamide in the presence of arginine. Importantly, 12h showed improved stability relative to compound 1 whose structure is same to 12h excepting an acrylamide moiety. Interestingly, 12i, a NO donating compound of 12h, showed more potent and selective inhibition than 12h on H1975 cells. Significantly, 12i produced high levels of NO in H1975 cells but not in non-tumorous 16HBE cells, and its inhibition was diminished by NO scavenger. Furthermore, 12i dose-dependently produced inhibitory effects on EGFR downstream signaling in H1975 cells.

Compound 12h could be converted to the active compound 1 in the presence of arginine and NO donating compound 12i showed more potent and selective antiproliferative effects than 12h.Figure optionsDownload as PowerPoint slide