Molecular design, synthesis and docking study of benz[b]oxepines and 12-oxobenzo[c]phenanthridinones as topoisomerase 1 inhibitors.
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.
Lee
Suh-Hee
SH
College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, Republic of Korea.
Van
Hue Thi My
HT
Yang
Su Hui
SH
Lee
Kyung-Tae
KT
Kwon
Youngjoo
Y
Cho
Won-Jea
WJ
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D001584:Benzoxepins / Q000138:chemical synthesis* / Q000494:pharmacology; D002166:Camptothecin / Q000737:chemistry; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004264:DNA Topoisomerases, Type I / Q000737:chemistry; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D008956:Models, Chemical; D008968:Molecular Conformation; D010616:Phenanthrenes / Q000138:chemical synthesis* / Q000494:pharmacology; D011485:Protein Binding; D059004:Topoisomerase I Inhibitors
D000970:Antineoplastic Agents; D001584:Benzoxepins; D004791:Enzyme Inhibitors; D010616:Phenanthrenes; D059004:Topoisomerase I Inhibitors; C040601:phenanthridone; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin