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Cytotoxicity and DNA topoisomerase inhibitory activity of benz[f]indole-4,9-dione analogs

Title
Cytotoxicity and DNA topoisomerase inhibitory activity of benz[f]indole-4,9-dione analogs
Authors
Park H.J.Lee H.-J.Lee E.-J.Hwang H.J.Shin S.-H.Suh M.-E.Kim C.Kim H.J.Seo E.-K.Lee S.K.
Ewha Authors
김춘미김화정이상국서은경
SCOPUS Author ID
김춘미scopus; 김화정scopus; 서은경scopus
Issue Date
2003
Journal Title
Bioscience, Biotechnology and Biochemistry
ISSN
0916-8451JCR Link
Citation
vol. 67, no. 9, pp. 1944 - 1949
Indexed
SCI; SCIE; SCOPUS WOS scopus
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 IC 50 < 20.0 μg/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 (IC 50= 0.4 μg/ml)) compared to colon (IC 50 > 20.0 μg/ml) and stomach (IC 50 > 20.0 μg/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.
DOI
10.1271/bbb.67.1944
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약학대학 > 약학과 > Journal papers
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