Nitric oxide donating anilinopyrimidines: Synthesis and biological evaluation as EGFR inhibitors

• NO donating anilinopyrimidines were synthesized and evaluated as EGFR inhibitors.
• Compounds 10f–h exhibited potent inhibitory activity against EGFR L858R/T790M.
• Compounds 10f–h displayed antiproliferative activity as potent as WZ4002.
• 10h produced high levels of NO in H1975 cells but not in normal human cells.
• 10h inhibited the EGFR activation and downstream signaling in H1975 cells.

To search for potent nitric oxide (NO) donating epidermal growth factor receptor (EGFR) inhibitors, a series of phenylsulfonylfuroxan-based anilinopyrimidines 10a–h were synthesized and biologically evaluated. Compounds 10f–h exhibited potent inhibitory activity against EGFR L858R/T790M and were as potent as WZ4002 in inhibition of H1975 cells harboring EGFR L858R/T790M. Additionally, 10h produced high levels of NO in H1975 cells but not in normal human cells, and its antiproliferative activity was diminished by hemoglobin, an NO scavenger. Furthermore, 10h inhibited EGFR activation and downstream signaling in H1975 cells. These results suggest that the strong antiproliferative activity of 10h could be attributed to the synergic effects of high levels of NO production and inhibition of EGFR and downstream signaling in the cancer cells.

Compound 10h exhibited potent inhibitory activity against EGFR mutant L858R/T790M and antiproliferative effects on both gefitinib-resistant H1975 (harboring EGFR L858R/T790M) and gefitinib-sensitive HCC827 (bearing EGFR del E746_A750) cells.Figure optionsDownload as PowerPoint slide