Novel Hybrids of (Phenylsulfonyl)furoxan and Anilinopyrimidine as Potent and Selective Epidermal Growth Factor Receptor Inhibitors for Intervention of Non-Small-Cell Lung Cancer

详细信息    查看全文

• 作者：Chun Han ; Zhangjian Huang ; Chao Zheng ; Ledong Wan ; Lianwen Zhang ; Sixun Peng ; Ke Ding ; Hongbin Ji ; Jide Tian ; Yihua Zhang
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：June 13, 2013
• 年：2013
• 卷：56
• 期：11
• 页码：4738-4748
• 全文大小：474K
• 年卷期：v.56,no.11(June 13, 2013)
• ISSN：1520-4804

文摘

A series of hybrids (12a鈥?b>k) from (phenylsulfonyl)furoxan and anilinopyrimidine were synthesized and biologically evaluated as epidermal growth factor receptor (EGFR) inhibitors for intervention of non-small-cell lung cancer (NSCLC). Compound 12k exhibited strong and selective EGFR L858R/T790M inhibitory activity (IC₅₀ = 0.047 渭M) and displayed antiproliferative effects on EGFR mutation NSCLC cell lines HCC827 (del E746_A750) and H1975 (L858R/T790M) with IC₅₀ values of 0.007 and 0.029 渭M, respectively. Additionally, 12k released high levels of NO in H1975 cells but not in normal human cells, and its activity was diminished by pretreatment with a NO scavenger. Furthermore, 12k induced apoptosis of H1975 and HCC827 cells more strongly than WZ4002 (1), inhibited EGFR downstream signaling in H1975 cells, and suppressed the nuclear factor-魏B activation in H1975 cells, while 1 had no significant effects under the same conditions. Finally, 12k substantially inhibited tumor growth in an H1975 xenograft mouse model. Overall, 12k might be a promising candidate for the treatment of NSCLC.