부산대학교 도서관

New compounds of 4-anilino-6-substituted quinazoline were designed, synthesized, and tested for their EGFR-TK and tumor growth inhibitory activities. The synthesized compounds were appended with amides 6 and 7, dithiocarbamate ester 8a–f or urea/thiourea 9–12 moieties at C-6 of the quinazoline ring to work as extra hydrogen bond acceptors. All the synthesized compounds were effective against EGFR-TK activity, particularly derivatives 8a, 8f, and 9 with IC50 values of 0.14 ± 0.003, 0.119 ± 0.003, and 0.115 ± 0.002 μMrespectively showed the best activities. The three compounds were further assayed for their cytotoxicity against MCF-7, H-69, SKOV-3, and LS-174T cell lines. Multikinase enzyme inhibition activity of compound 9 was further screened including VEGFR-2, c-MER, c-MET, and Her-2. Compounds 8a, 8f, and 9 were docked into the ATP binding site of EGFR-TK, which also had a resemblance binding pattern to erlotinib with extra binding mode with Cys-773 at the gatekeeper of the enzyme. Cell-cycle analyses of MCF-7 cells treated with 8a and 9 were measured in addition to other related factors, such as Bax, Bcl-2, caspase-9, and PARP-1. Among the tested compounds, 8a and 8f (with the dithiocarbamate group) and 9 (with the urea group) were the most potent inhibitors against EGFR in comparison with erlotinib as a reference drug. Those three compounds tested against four cell lines MCF-7, H-69, SKOV-3 and LS-174T, where 8a showed the highest cytotoxic activity, among the three tested compounds, 8f exhibits the highest activity against LS-174T, and 9 exhibits the highest activity against the H-69 cell line. Moreover, compound 9 exhibited high multi-inhibitory activities against extra kinases such as VEGFR-2, HER2, c-MET, and c-MER. [ABSTRACT FROM AUTHOR]