Chemistry, School of Environmental & Life Science, The University of Newcastle, University Drive Callaghan, NSW 2308, Australia.
Eur J Med Chem. 2012 Nov;57:65-73. doi: 10.1016/j.ejmech.2012.09.019. Epub 2012 Sep 18.
We previously reported the discovery of a simple conjugated cyano pharmacophore which had led to the development of (Z)-2-(3,4-dichlorophenyl)-3-(4-nitrophenyl)acrylonitrile, as a selective inhibitor of oestrogen receptor positive (ER+ve) human breast cancer cell line, MCF-7. Further exploration though modification of the acrylonitrile and aromatic substituents has highlighted key structural components necessary for broad spectrum cytotoxicity. The acrylic acid derivates (Z)-2-(3,4-dichlorophenyl)-3-(4-nitrophenyl)acrylic acid and (Z)-2-(3,4-dichlorophenyl)-3-(4-methoxyphenyl)acrylic acid (9) were inactive; confirming the importance of the cyanide moiety. The most potent 2-phenylacrylonitriles synthesized were (Z)-2-(3,4-dichlorophenyl)-3-(1H-indol-3-yl)acrylonitrile and (Z)-2-(3,4-dichlorophenyl)-3-(1H-indol-5-yl)acrylonitrile (20) with an average GI(50) values of 1.4 and 0.53 μM respectively. Five additional (Z)-2-(3,4-dichlorophenyl)-3-(indolyl)acrylonitriles also displayed average GI(50) values of ≤8.4 μM. In the case of indole, this represents a 32-fold increase in broad spectrum cytotoxicity relative to the lead.
我们之前报道了一个简单的共轭氰基药效团的发现，这导致了（Z）-2-（3,4-二氯苯基）-3-（4-硝基苯基）丙烯腈的开发，作为雌激素受体阳性（ER+ve）人乳腺癌细胞系 MCF-7 的选择性抑制剂。通过对丙烯腈和芳基取代基的进一步修饰，突出了广泛细胞毒性所必需的关键结构成分。丙烯酸衍生物（Z）-2-（3,4-二氯苯基）-3-（4-硝基苯基）丙烯酸和（Z）-2-（3,4-二氯苯基）-3-（4-甲氧基苯基）丙烯酸（9）无活性；证实了氰化物部分的重要性。合成的最有效 2-苯基丙烯腈分别为（Z）-2-（3,4-二氯苯基）-3-（1H-吲哚-3-基）丙烯腈和（Z）-2-（3,4-二氯苯基）-3-（1H-吲哚-5-基）丙烯腈（20），平均 GI（50）值分别为 1.4 和 0.53 μM。另外五个（Z）-2-（3,4-二氯苯基）-3-（吲哚基）丙烯腈的平均 GI（50）值也≤8.4 μM。对于吲哚，这代表与先导化合物相比，广谱细胞毒性增加了 32 倍。
