发现4-氨基喹唑啉-脲衍生物作为具有抗增殖活性的Aurora激酶抑制剂。
Discovery of 4-aminoquinazoline--urea derivatives as Aurora kinase inhibitors with antiproliferative activity.
作者信息
Cai Jin, Li Lili, Hong Kwon Ho, Wu Xiaoqing, Chen Junqing, Wang Peng, Cao Meng, Zong Xi, Ji Min
机构信息
School of Chemistry and Chemical Engineering, Institute of Pharmaceutical Engineering, Southeast University, 87 Dingjiaqiao, Nanjing, Jiangsu 210096, PR China.
Department of Medicinal Chemistry and The Institute for Therapeutics Discovery and Development, University of Minnesota, 717 Delaware Street SE, Minneapolis, MN 55414, USA.
出版信息
Bioorg Med Chem. 2014 Nov 1;22(21):5813-23. doi: 10.1016/j.bmc.2014.09.029. Epub 2014 Sep 19.
Two series of 20 novel 4-aminoquinazoline-urea derivatives have been designed and synthesized. The entire target compounds were investigated for their in vitro antiproliferative activity against six human cancer cell lines (K562, U937, A549, NCI-H661, HT29 and LoVo) using the MTT-based assay. Most compounds showed significant antiproliferative activities against four solid tumor cell lines, but no or poor activities against two leukemia cell lines. Furthermore, the target compounds were screened for Aurora A/B kinases inhibitory activity. Among them, 7c, 7d, 8c, and 8d are more potent against Aurora A kinase than ZM447439. Docking study of compounds 7d and ZM447439 revealed that they bound strongly to the ATP-binding sites of Aurora A and B. Thus, they may be promising lead compounds for the development of novel anti-tumor drug potentially via inhibiting Aurora kinases.
设计并合成了两个系列共20种新型4-氨基喹唑啉-脲衍生物。使用基于MTT的检测方法，研究了所有目标化合物对六种人类癌细胞系（K562、U937、A549、NCI-H661、HT29和LoVo）的体外抗增殖活性。大多数化合物对四种实体瘤细胞系显示出显著的抗增殖活性，但对两种白血病细胞系无活性或活性较差。此外，对目标化合物进行了Aurora A/B激酶抑制活性筛选。其中，7c、7d、8c和8d对Aurora A激酶的活性比ZM447439更强。化合物7d和ZM447439的对接研究表明，它们与Aurora A和B的ATP结合位点紧密结合。因此，它们可能是通过抑制Aurora激酶开发新型抗肿瘤药物的有前景的先导化合物。
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