Synthesis and biological evaluation of bis(methoxymethyl)-7,8-dihydro-[14]dioxino[2,3-g]quinazolines as EGFR tyrosine kinase inhibitors

A series of 7,8-bis(methoxymethyl)-7,8-dihydro-[1,4]dioxino[2,3-g]quinazolines were prepared and evaluated for their inhibition of phosphorylation of the isolated epidermal growth factor receptor (EGFR) enzyme and for their growth inhibition of the A431 cell line. Among them, compound 3C having a 3-iodophenyl ring was most potent (IC50 = 1.66 nM) against the isolated EGFR enzyme and also showed meaningful potency (GI(50) = 1.99 mu M) against the A431 cell line, although less than PD153035 (GI(50) = 1.03 mu M). However, compound 3e as the exact rigidified analogue of Erlotinib (Tarceva (TM)) was inferior to the original compound when compared to its reported data.