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.