Development of novel bis-pyrazole derivatives as antitumor agents with potent apoptosis induction effects and DNA damage
Development of novel bis-pyrazole derivatives as antitumor agents with potent apoptosis induction effects and DNA damage
复制标题
开发新型双吡唑衍生物作为抗肿瘤剂，具有有效的细胞凋亡诱导作用和 DNA 损伤作用
DOI：
10.1016/j.ejmech.2017.11.098
复制
发表时间：
2018-01-01
影响因子：
6.7
通讯作者：
Shi, Yujun
中科院分区：
文献类型：
--
作者：
Dai, Hong;Ge, Shushan;Shi, Yujun
设计合成了一系列双吡唑衍生物，并对其体外和体内抗肿瘤作用进行了研究。几种化合物在体外对3种人类癌细胞表现出良好的抗增殖活性，IC50值在低微摩尔范围内，优于5-FU。最有效的化合物10M在体外选择性抑制人肝癌细胞而非肿瘤肝细胞的增殖，并通过裂解PARP和caspase-3显著诱导SMMC-7721细胞凋亡，且呈浓度依赖性。进一步研究发现，10M在抑制细胞生长和诱导细胞凋亡方面的强大活性与DNA损伤和p53信号通路的激活有关。此外，10M对小鼠的急性毒性较低，在体内对肝癌肿瘤有明显的生长抑制作用。(C) 2017 Elsevier Masson SAS。版权所有。
A series of bis-pyrazole derivatives were designed and synthesized, and their antitumor effects in vitro and in vivo were investigated. Several compounds displayed good antiproliferative activity with IC50 values in low-micromolar range against three human cancer cell lines in vitro, superior to 5-FU. The most potent compound 10M selectively inhibited human hepatocellular carcinoma cells but not non-tumor liver cell proliferation in vitro, and significantly triggered SMMC-7721 cell apoptosis by cleavage of both PARP and caspase-3 in a concentration-dependent manner. Further study revealed that the potent activity in the cell growth inhibition and apoptosis induction effects of 10M were related to DNA damage and activation of the p53 signaling pathway. Moreover, 10M showed low acute toxicity to mice and significant growth inhibition of the hepatoma tumor in vivo. (C) 2017 Elsevier Masson SAS. All rights reserved.