Fused azepinones with antitumor activity

Based on the observation that some simple [1]benzazepin-2-ones exhibit in vivo antitumor activity, studies directed to several new structure classes with this partial motif have been reported recently, comprising 7,12-dihydro-indolo[3, 2-d][1]benzazepin-6(5H)-ones (paullones), 5H-qui nolino[3, 2-d][1]benzazepin-6(7H)-ones, 2,4-diaryl-5H-pyrido[3, 2-d][1]benzazepin-6(7H)-ones, spiro[1-benzazepine-4,1 -cyclohexane] deriva-tives, and naphthannelated benzazepinones. For the syntheses of these heterocyclic compounds, 1H-[1]benzazepine-2,5(3H,4H)-diones were employed as readily available starting materials. In each of the mentioned series, entities with in vitro antitumor activity have been detected. Considering potency and in vitro cell line selectivity, both the 2,4-diaryl-5H-pyrido[3, 2-d][1]benzazepin-6(7H)-ones and the paullones are apparently suitable for a further development. A biological mechanism probably related to the anti proliferative activity has been established only for the paullones. These compounds represent a novel class of selective inhibitors of cyclin-dependent kinases, a family of enzymes whose function seems to be deregulated in many human tumors.