Design and synthesis of pyrazolo[3,4-d]pyrimidines: Nitric oxide releasing compounds targeting hepatocellular carcinoma
Design and synthesis of pyrazolo[3,4-d]pyrimidines: Nitric oxide releasing compounds targeting hepatocellular carcinoma
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DOI：
10.1016/j.bmc.2017.03.002
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发表时间：
2017-06-15
影响因子：
3.5
通讯作者：
Halaweish, Fathi
中科院分区：
文献类型：
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作者：
Elshaier, Yaseen A. M. M.;Shaaban, Mohamed A.;Halaweish, Fathi
设计并合成了一系列新的含一氧化氮（NO）生成官能团的吡唑并[3，4-d]嘧啶类化合物。磺酰罗丹明B（SR B）蛋白质分析显示，合成的化合物中的NO释放部分比des-NO类似物更显著地抑制细胞生长。具有N-对位取代苯基的化合物7 C和7 G释放的NO浓度最高，分别为4.6%和4.7%。合成的化合物对HepG 2细胞系的抗增殖活性鉴定出化合物7 h、7 p、14 a和14 b分别是与作为参比药物的厄洛替尼（IC 50 = 25 μ M）相比在IC 50 = 3、5、3和5 μ M系列中最具细胞毒性的化合物。流式细胞仪检测显示，7 h使细胞阻滞于细胞周期的GO/G1期，而7 p使细胞阻滞于S期。此外，对所合成化合物与EGFR（PDB代码：1 M17）的对接研究和细胞毒性研究表明，N-1苯基帕拉取代、吡唑C-3烷基取代和通过丁基连接硝酸酯基团对活性有显著影响。(C)爱思唯尔有限公司出版
A new series of pyrazolo[3,4-dlpyrimidines tethered with nitric oxide (NO) producing functionality was designed and synthesized. Sulforhodamine B (SRB) protein assay revealed that NO releasing moiety in the synthesized compounds significantly decreased the cell growth more than the des-NO analogues. Compounds 7C and 7G possessing N-para-substituted phenyl group, released the highest NO concentration of 4.6% and 4.7% respectively. Anti-proliferative activity of synthesized compounds on HepG2 cell line identified compounds 7h, 7p, 14a and 14b as the most cytotoxic compounds in the series of IC50 = 3, 5, 3 and 5 mu M, respectively, compared to erlotinib as a reference drug (IC50 = 25 mu M). Flow cytometry studies revealed that 7 h arrested the cells in GO/G1 phase of cell cycle while 7p arrested the cells in S phase. Moreover, docking study of the synthesized compounds on EGFR (PDB code: 1M17) and cytotoxicity study indicated that N-1 phenyl para substitution, pyrazole C-3 alkyl substitution and tethering the nitrate moiety through butyl group had a significant impact on the activity. (C) Published by Elsevier Ltd.