Synthesis and anticancer activities of 4-(4-substituted piperazin)-5,6,7-trialkoxy quinazoline derivatives

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• 作者：Ying Zhang^a ; ¹ ; Yin-Jiu Huang^b ; ¹ ; Hong-Mei Xiang^a ; Pei-Yi Wang^a ; De-Yu Hu^a ; Wei Xue^a ; Bao-An Song^a ; ; Song Yang^a ; ^{jhzx.msm@gmail.com" class="auth_mail} ; ^{yangsdqj2002@yahoo.com" class="auth_mail}
• 关键词：Quinazoline ; Anticancer ; ERK1/2 ; P38 ; Antiphosphorylation ; Cell cycle
• 刊名：European Journal of Medicinal Chemistry
• 出版年：6 May, 2014
• 年：2014
• 卷：78
• 期：Complete
• 页码：23-34
• 全文大小：1056 K

文摘

A series of 4-(4-substituted piperazin)-5,6,7-trialkoxy quinazoline was prepared by conventional heating methods. Among these compounds, the crystal structure of compound 10o (CCDC: 916922) was determined by X-ray crystallography. Bioassay results showed that most target compounds had certain inhibition activities against proliferation of tumor cells, and some compounds even had good broad-spectrum inhibition activities. The ethoxyl series of compounds possessed higher inhibition activities against tumor cells than the methoxyl series of compounds. Bioactivity tests showed that the IC₅₀ values of compound 10s against PC3, MGC803, A375, and A549 cells were 1.8, 2.8, 1.3, and 2.9聽渭螠, respectively, which were much higher than those of commercial gefitinib (7.2, 7.6, 7.2, and 9.8聽渭M, respectively). Conversely, the IC₅₀ values of compound 10s were very low against NH3T3, indicating only weak effect on normal cells as also proven by lactate dehydrogenase and acridine orange/ethidium bromide staining. Analyses of cell configuration and cell cycle revealed that compound 10s possibly caused cells to remain at G0/G1 phase by inhibiting cell proliferation for 24聽h. Compound 10s also inhibited the phosphorylation of ERK1/2 and P38 with obvious concentration dependence. Thus, these compounds can inhibit the proliferation of A549 cells through the interruption of ERK1/2 and P38signaling pathways.