Synthesis of novel pyrimido[4,5-b]quinoline derivatives as dual EGFR/HER2 inhibitors as anticancer agents

A series of novel N-aryl-5-aryl-6,7,8,9-tetrahydropyrimido[4,5-b]quinolin-4-amines 4a-4l was synthesized as potential anticancer agents through Dimroth rearrangement reaction of intermediates 3a-3c. Pyrimido[4,5-b]quinolines 4a-4l showed promising activity against the Michigan Cancer Foundation-7 (MCF-7) cell line, compared with lapatinib as the reference drug. Compounds 4d, 4h, 4i, and 4l demonstrated higher cytotoxic activity than lapatinib, with IC₅₀ values of 2.67, 6.82, 4.31, and 1.62 µM, respectively. Compounds 4d, 4i, and 4l showed promising epidermal growth factor receptor (EGFR) inhibition with IC₅₀ values of 0.065, 0.116, and 0.052 µM, respectively. These compounds were subjected to human epidermal growth factor receptor 2 (HER2) inhibition and showed IC₅₀ values of 0.09, 0.164, and 0.055 µM, respectively. Compounds 4d, 4i, and 4l are good candidates as dual EGFR/HER2 inhibitors. The most active compound, 4l, was subjected to cell-cycle analysis and induced cell-cycle arrest at the S phase. Compound 4l induced apoptosis 60-fold compared with control untreated MCF-7 cells. 4l can inhibit cancer metastasis. It reduced MCF-7 cell infiltration and metastasis by 45% compared with control untreated cells.