Novel 4-Amino Bis-pyridinium and Bis-quinolinium Derivatives as Choline Kinase Inhibitors with Antiproliferative Activity against the Human Breast Cancer SKBR-3 Cell Line
Novel 4-Amino Bis-pyridinium and Bis-quinolinium Derivatives as Choline Kinase Inhibitors with Antiproliferative Activity against the Human Breast Cancer SKBR-3 Cell Line
复制标题
DOI：
10.1002/cmdc.201100505
复制
发表时间：
2012-04-01
期刊：
影响因子：
3.4
通讯作者：
Campos, Joaquin M.
中科院分区：
文献类型：
--
作者：
Gomez-Perez, Veronica;McSorley, Theresa;Campos, Joaquin M.
胆碱激酶（Choline kinase, ChoK）是真核生物细胞膜上主要的磷脂——磷脂酰胆碱的第一个合成酶。人类ChoK有三种异构体：ChoKa1、a2和β。据报道，特异性抑制ChoKa可选择性杀死肿瘤细胞。本研究合成了10个新的对称双吡啶和双喹啉衍生物，并测试了它们对人ChoKa2的抑制能力。这些化合物在吡啶或喹啉环的第4位有电子释放基团。1,1'-[(丁烷-1,3-二基双（苯-1,4-二基亚甲基）]二溴[4-（4-溴- n -甲基苯胺）吡啶]]和1,1'-（联苯-3,3'-二基亚甲基）二溴[7-氯-4-（过氢氮卓-1-基）喹啉]二溴被鉴定为高效的ChoK抑制剂，IC50值为80 nM。动力学酶分析表明，这些化合物对人乳腺癌SKBR3细胞系具有较强的抗增殖活性（EC50 1 μ M），其抑制机制是混合的，主要是竞争性的。
Choline kinase (ChoK) is the first enzyme in the CDP-choline pathway that synthesizes phosphatidylcholine, the major phospholipid in eukaryotic cell membranes. Human ChoK has three isoforms: ChoKa1, a2, and beta. Specific inhibition of ChoKa has been reported to selectively kill tumor cells. In this study, ten new symmetrical bis-pyridinium and bis-quinolinium derivatives were synthesized and tested for their ability to inhibit human ChoKa2. These compounds have electron-releasing groups at position 4 of the pyridinium or quinolinium rings. 1,1'-[(Butane-1,3-diylbis(benzene-1,4-diylmethylene)]bis[4-(4-bromo-N-methylanilino)pyridinium)] dibromide and 1,1'-(biphenyl-3,3'-diylmethylene)bis[7-chloro-4-(perhydroazepine-1-yl)quinolinium] dibromide were identified as highly potent ChoK inhibitors with IC50 values of 80 nM. Kinetic enzymatic assays indicated a mixed and predominantly competitive mechanism of inhibition for these compounds, which exhibited strong antiproliferative activity (EC50 1 mu M) against the human breast cancer SKBR3 cell line.