TY - JOUR
T1 - Cytotoxicity and DNA topoisomerase inhibitory activity of benz[f]indole-4,9-dione analogs
AU - Park, Hyen Joo
AU - Lee, Hyun Jung
AU - Lee, Eun Jin
AU - Hwang, Hye Jin
AU - Shin, Sang Hee
AU - Suh, Myung Eun
AU - Kim, Choonmi
AU - Kim, Hwa Jung
AU - Seo, Eun Kyung
AU - Lee, Sang Kook
N1 - Funding Information:
This work was supported by a Korea Research Foundation Grant (KRF-2001-005-F00023).
PY - 2003/9
Y1 - 2003/9
N2 - 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 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 (IC50= 0.4 μg/ml)) compared to colon (IC50 > 20.0 μg/ml) and stomach (IC50 > 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.
AB - 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 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 (IC50= 0.4 μg/ml)) compared to colon (IC50 > 20.0 μg/ml) and stomach (IC50 > 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.
KW - Benz[f]indole-4,9-diones
KW - Cytotoxicity
KW - Topoisomerase I and II
UR - http://www.scopus.com/inward/record.url?scp=2842599309&partnerID=8YFLogxK
U2 - 10.1271/bbb.67.1944
DO - 10.1271/bbb.67.1944
M3 - Article
C2 - 14519980
AN - SCOPUS:2842599309
SN - 0916-8451
VL - 67
SP - 1944
EP - 1949
JO - Bioscience, Biotechnology and Biochemistry
JF - Bioscience, Biotechnology and Biochemistry
IS - 9
ER -