Design, synthesis and antitumor activity of 2-substituted quinazoline-4-amine derivatives

Werner (WRN) syndrome protein is a multifunctional enzyme with helicase, ATPase, and exonuclease activities that are necessary for numerous DNA-related transactions in the human cell. Recent studies identified WRN as a synthetic lethal target in cancers. In this study, a series of new N-arylquinazoline-4-amine analogs were designed and synthesized based on structure optimization of quinazoline. The structures of the thirty-two newly synthesized compounds were confirmed by ¹H NMR, ¹³C NMR and ESI-MS. The anticancer activity in vitro against chronic myeloid leukemia cells (K562), non-small cell lung cancer cells (A549), human prostate cancer cells (PC3), and cervical cancer cells (HeLa) of the target compounds was evaluated. Among them, the inhibition ratio of compounds 17d, 18a, 18b, 11 and 23a against four cancer cells at 5 μM concentration were more than 50 %. The IC₅₀ values of compounds 18a and 18b were 0.3 ± 0.01 μM and 0.05 ± 0.02 μM in K562 cells respectively, compared with HeLa and A549 cells, 18a and 18b were more sensitive to K562 cells. In addition, the PC3 cells with WRN overexpression (PC3-WRN) was constructed, 18a and 18b and 23a were more sensitive to PC3-WRN cells compared with the control group cells (PC3-NC). Then, the cell viability of the novel WRN inhibitors were further assessed by colony formation assay. Compared with PC3-NC cells, 18b and 23a had obvious inhibitory effect on PC3-WRN cell at 1000 nM. In summary, these results indicated that the compounds 18b and 23a could be WRN protein inhibitor with potent anticancer properties in vitro.