title: Cytotoxicity and DNA topoisomerase inhibitory activity of benz[f]indole-4,9-dione analogs.
abstract: A series of benz[f]indole-4,9-diones, based on the antitumor activity of 1,4-naphthoquinone, were synthesized and evaluated for their cytotoxic activity in cultured human cancer cell lines A549 (lung cancer), Col2 (colon cancer), and SNU-638 (stomach cancer), and also for the inhibition of human DNA topoisomerases I and II activity in vitro. Several compounds including 2-amino-3-ethoxycarbonyl-N-methyl-benz[f]indole-4,9-dione showed a potential cytotoxic activity judged by IC50<20.0 microg/ml in the panel of cancer cell lines. Especially, 2-hydroxy-3-ethoxycarbonyl-N-(3,4-dimethylphenyl)-benz[f]indole-4,9-dione had potential selective cytotoxicity against lung cancer cells (IC50=0.4 microg/ml)) compared to colon (IC50>20.0 microg/ml) and stomach (IC50>20.0 microg/ml) cancer cells. To further investigate the cytotoxic mechanism, the effects of test compounds on DNA topoisomerase I and II activities were used. In a topoisomerase I-mediated relaxation assay using human placenta DNA topoisomerase I and supercoiled pHOTI plasmid DNA, 2-amino-3-ethoxycarbonyl-N-(4-fluorophenyl)-benz[f]indole-4,9-dione had the most potent inhibitory activity among the compounds tested. However, most of the compounds showed only weak inhibition of the DNA topoisomerase II-mediated KDNA (Kinetoplast DNA) decatenation assay, except for 2-amino-3-ethoxycarbonyl-N-(4-methylphenyl)-benz[f]indole-4,9-dione and 2-amino-3-ethoxycarbonyl-N-(2-bromoehtyl)-benz[f]indole-4,9-dione with a moderate inhibitory activity. These results suggest that several active compounds had relatively selective inhibitory activity against toposiomearse I compared to toposiomerase II. No obvious correlation was observed between the cytotoxicity of the individual compound and the inhibitory activity of DNA relaxation and decatenation by topoisomerase I and II, respectively, in vitro.
authors.affiliation: College of Pharmacy, Ewha Womans University, Seoul, Korea.
authors.forename: Hyen Joo
authors.initials: HJ
authors.lastname: Park
authors.forename: Hyun-Jung
authors.initials: HJ
authors.lastname: Lee
authors.forename: Eun-Jin
authors.initials: EJ
authors.lastname: Lee
authors.forename: Hye Jin
authors.initials: HJ
authors.lastname: Hwang
authors.forename: Sang-Hee
authors.initials: SH
authors.lastname: Shin
authors.forename: Myung-Eun
authors.initials: ME
authors.lastname: Suh
authors.forename: Choonmi
authors.initials: C
authors.lastname: Kim
authors.forename: Hwa Jung
authors.initials: HJ
authors.lastname: Kim
authors.forename: Eun-Kyung
authors.initials: EK
authors.lastname: Seo
authors.forename: Sang Kook
authors.initials: SK
authors.lastname: Lee
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D026942:DNA Topoisomerases / Q000378:metabolism; D018105:DNA, Kinetoplast / Q000378:metabolism; D004278:DNA, Superhelical / Q000187:drug effects / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D009285:Naphthoquinones / Q000737:chemistry* / Q000494:pharmacology*; D009690:Nucleic Acid Conformation; D013329:Structure-Activity Relationship; D059003:Topoisomerase Inhibitors
chemical_list: D000970:Antineoplastic Agents; D018105:DNA, Kinetoplast; D004278:DNA, Superhelical; D004791:Enzyme Inhibitors; D007211:Indoles; D009285:Naphthoquinones; D059003:Topoisomerase Inhibitors; D005047:Etoposide; D026942:DNA Topoisomerases