Nitric oxide donating anilinopyrimidines: Synthesis and biological evaluation as EGFR inhibitors

被引：18

作者：

Han, Chun ^{[1
,2
]}

Huang, Zhangjian ^{[1
,2
]}

Zheng, Chao ^{[3
]}

Wan, Ledong ^{[1
,2
]}

Lai, Yisheng ^{[1
,2
]}

Peng, Sixun ^{[1
,2
]}

Ding, Ke ^{[4
,5
]}

Ji, Hongbin ^{[3
]}

Zhang, Yihua ^{[1
,2
]}

机构：

[1] China Pharmaceut Univ, State Key Lab Nat Med, Nanjing 210009, Jiangsu, Peoples R China

[2] China Pharmaceut Univ, Ctr Drug Discovery, Nanjing 210009, Jiangsu, Peoples R China

[3] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, State Key Lab Cell Biol, Shanghai 200030, Peoples R China

[4] Chinese Acad Sci, Guangzhou Inst Biomed & Hlth, Key Lab Regenerat Biol, Guangzhou 510530, Guangdong, Peoples R China

[5] Chinese Acad Sci, Guangzhou Inst Biomed & Hlth, Inst Chem Biol, Guangzhou 510530, Guangdong, Peoples R China

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2013年 / 66卷

关键词：

Nitric oxide; EGFR inhibitor; Anilinopyrimidine; Antiproliferative activity; WZ4002; GROWTH-FACTOR RECEPTOR; CELL LUNG-CANCER; ANTIHEPATOCELLULAR CARCINOMA ACTIVITY; TYROSINE KINASE INHIBITOR; PAN-ERBB INHIBITOR; PHASE-II TRIAL; DRUG-RESISTANCE; DERIVATIVES; GEFITINIB; FUROXANS;

D O I：

10.1016/j.ejmech.2013.05.026

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

To search for potent nitric oxide (NO) donating epidermal growth factor receptor (EGFR) inhibitors, a series of phenylsulfonylfuroxan-based anilinopyrimidines 10a-h were synthesized and biologically evaluated. Compounds 10f-h exhibited potent inhibitory activity against EGFR L858R/T790M and were as potent as WZ4002 in inhibition of H1975 cells harboring EGFR L858R/T790M. Additionally, 10h produced high levels of NO in H1975 cells but not in normal human cells, and its antiproliferative activity was diminished by hemoglobin, an NO scavenger. Furthermore, 10h inhibited EGFR activation and downstream signaling in H1975 cells. These results suggest that the strong antiproliferative activity of 10h could be attributed to the synergic effects of high levels of NO production and inhibition of EGFR and downstream signaling in the cancer cells. (C) 2013 Elsevier Masson SAS. All rights reserved.

引用

页码：82 / 90

页数：9

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