Link A, Kunick C
Institut für Pharmazie, Abteilung Pharmazeutische Chemie, Universität Hamburg, Bundesstrasse 45, D-20146 Hamburg, Germany.
J Med Chem. 1998 Apr 9;41(8):1299-305. doi: 10.1021/jm970675l.
The synthesis of novel quinolino[3,2-d][1]benzazepines and pyrido[3,2-d][1]benzazepines is described. The in vitro antitumor activity of the compounds has been tested in the antitumor screening of the National Cancer Institute (NCI). Several 2,4-diarylpyrido[3, 2-d][1]benzazepin-6-ones and -thiones turned out to exhibit considerable cytotoxicity for tumor cells. For studies of SAR within these series, substituents were introduced into the aromatic rings of the parent systems. Compounds from the thiolactam series tended to show higher potency than the corresponding lactams. Prominent compounds with noteworthy activity and remarkable selectivity for renal cancer cell lines are the lactams 10c, 10g, and 10h and the corresponding thiolactams 11c, 11g, and 11h. Methylation of the azepine nitrogen leads to complete loss of activity, whereas annelation of a triazolo ring at the lactam site or transformation of the thiolactam function to a thiolactim ether results in decreased antitumor activity and selectivity. Consequently, the secondary lactam or thiolactam structure of the seven-membered ring has to be regarded as essential for selective antitumor activity.
本文描述了新型喹啉并[3,2-d][1]苯并氮杂卓和吡啶并[3,2-d][1]苯并氮杂卓的合成。这些化合物的体外抗肿瘤活性已在美国国立癌症研究所（NCI）的抗肿瘤筛选中进行了测试。结果发现，几种2,4-二芳基吡啶并[3,2-d][1]苯并氮杂卓-6-酮和硫酮对肿瘤细胞表现出相当大的细胞毒性。为了研究这些系列中的构效关系，在母体系统的芳环中引入了取代基。硫内酰胺系列的化合物往往比相应的内酰胺显示出更高的活性。具有显著活性和对肾癌细胞系具有显著选择性的突出化合物是内酰胺10c、10g和10h以及相应的硫内酰胺11c、11g和11h。氮杂卓氮的甲基化导致活性完全丧失，而在内酰胺位点稠合一个三唑环或将硫内酰胺官能团转化为硫亚胺醚会导致抗肿瘤活性和选择性降低。因此，七元环的仲内酰胺或硫内酰胺结构必须被视为选择性抗肿瘤活性所必需的。
