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KMID : 0617320030120010153
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Journal of Pharmacetical Sceiences Ewha Womans University
2003 Volume.12 No. 1 p.153 ~ p.158
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Cytotoxicity and DNA Topoisomerase Inhibitory Activity of Benz［f］indole-4,9-dione Analogs
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PARK, Hyen Joo
LEE, Hyun-Jung/LEE, Eun-Jin/HWANG, Hye Jin/SHIN, Sang-Hee/SUH, Myung-Eun/KIM, Choonmi
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Abstract
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A series of benz[f]indole-4,9-diones, based on the antitumor activity of 1,4-naphthoqninone, were synthesized and evaluated for their cytotoxic activity in cultured human cancer cell lines A549 (lung cancer), Co12 (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-mcthyl-benz[f]indole-4,9-dione showed a potential cytotoxic activity judged by IC_(50)< 20.0 ㎍/㎖ in the panel of cancer cell lines. Especially, 2-hydroxy-3-ethoxycarbonyl-N-(3,4-dimethyl-phenyl)-benz[f]indole-4,9-dione had potential selective cytotoxicity against lung cancer cells (IC_(50)=0.4㎍/㎖)) compared to colon (IC_(50)>20.0㎍/㎖) and stomach (IC_(50)>20.0㎍/㎖) 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-ethoxycarboHyl-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-cthoxycarbonyl-N-(4-mcthylphcnyl)-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.
1,4-Naphthoquinone derivatives with an amino group at the 2-position have been reported to have good antineoplasmic, carcinostatic actions´ and bacterial growth inhibition. Based on the cytotoxic potential of 1,4-naphthoquinone derivatives, in our continuing efforts to develop novel antitumor agents, we have been synthesized benz[f]indole-4,9-dione analogs, heterocyclic pyrrole ring derivatives attached to 1,4-naphthoquinone. In this study we evaluated the cytotoxic potential of additional benz[f]indole-4,9-dione analogs in cultured human solid tumor cell lines including human lung (A549), colon (Col2), and stomach (SNU-638) cancer cells. Further, a variety of antitumor agents currently used in chemotherapy or evaluated in clinical trials are known to inhibit DNA topoisomerase Ⅰ (topo Ⅰ) or Ⅱ (topo Ⅱ). DNA topoisomerases are enzymes that catalyze the passage of individual DNA strands (type 1) or double helices (type Ⅱ) through one another, which is manifested in the interconversion between topological isomers of DNA. These enzymes have important roles in replication, recombination, transcription, chromosome condensation, and the maintenance of genome stability, and hence are good targets for antineoplastic drugs. The antitumor drugs camptothecin, doxorubicin, and etoposide are representative topo Ⅰ or topo Ⅱ inhibitors. Therefore, in this study, to investigate one possible mechanism of action of the cytotoxic activity of benz[f]indole-4,9-dione analogs, we evaluated their ability to inhibit topo Ⅰ or topo Ⅱ activities with DNA relaxation and a DNA decatenation assay, respectively. We report here that benz[f]-indole-4,9-dione analogs show potential cytotoxicity against cancer cell lines with topo Ⅰ or Ⅱ inhibitory activity.
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