Molecular design,synthesis and docking study of benz[b]oxepines and 12-oxobenzo[c]phenanthridinones as topoisomerase 1 inhibitors

Benzb]oxepines 4a–g and 12-oxobenzoc]phenanthridines 5a–d were designed and synthesized as constrained forms of 3-arylisoquinolines through an intramolecular radical cyclization reaction. Radical cyclization of O-vinyl compounds preferentially led to the 7-endo-trig cyclization pathway to the benzb]oxepines and 12-oxobenzoc]phenanthridines through 6-exo-trig path as minor products. Among the synthesized compounds, benzb]oxepine derivative 4e exhibited potent in vitro cytotoxicity against three different tumor cell lines, as well as topoisomerase 1 inhibitory activity. A Surflex–Dock docking study was performed to clarify the topoisomerase 1 activity of 4e.