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A novel series of 4-anilinoquinazoline analogues, <b>DW (1–10)</b>, were evaluated for anticancer efficacy in human breast cancer (BT-20) and human colorectal cancer (CRC) cell lines (HCT116, HT29, and SW620). The compound, <b>DW-8</b>, had the highest anticancer efficacy and selectivity in the colorectal cancer cell lines, HCT116, HT29, and SW620, with IC₅₀ values of 8.50 ± 2.53 µM, 5.80 ± 0.92 µM, and 6.15 ± 0.37 µM, respectively, compared to the non-cancerous colon cell line, CRL1459, with an IC₅₀ of 14.05 ± 0.37 µM. The selectivity index of <b>DW-8</b> was >2-fold in colon cancer cells incubated with vehicle. We further determined the mechanisms of cell death induced by <b>DW-8</b> in SW620 CRC cancer cells. <b>DW-8</b> (10 and 30 µM) induced apoptosis by (1) producing cell cycle arrest at the G2 phase; (2) activating the intrinsic apoptotic pathway, as indicated by the activation of caspase-9 and the executioner caspases-3 and 7; (3) nuclear fragmentation and (4) increasing the levels of reactive oxygen species (ROS). Overall, our results suggest that <b>DW-8</b> may represent a suitable lead for developing novel compounds to treat CRC.