Bioorganic & Medicinal Chemistry Letters 2009-05-01

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

Suh-Hee Lee, Hue Thi My Van, Su Hui Yang, Kyung-Tae Lee, Youngjoo Kwon, Won-Jea Cho

Index: Bioorg. Med. Chem. Lett. 19 , 2444-7, (2009)

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Abstract

Benz[b]oxepines 4a-g and 12-oxobenzo[c]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 benz[b]oxepines and 12-oxobenzo[c]phenanthridines through 6-exo-trig path as minor products. Among the synthesized compounds, benz[b]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.