• Proceedings of the PSK Conference
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• 2003.04a
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• pp.236.2-237
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• 2003

Several studies of terbenzimidazoles and bibenzimidazoles suggested that benzimidazoles, especially 5-nitro-2-(para-methoxyphenyl)benzimidazole. possess topoisomerase I inhibition activities. In order to find out the structure activity relationship of 5-nitro-2-phenyl-benzimidazoles. eight derivatives that are substituted at the para position of 2-phenyl moiety were selected, synthesized ＆ evaluated considering their electronic or lipophilic parameters. (omitted)

• Bulletin of the Korean Chemical Society
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• v.32 no.10
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• pp.3566-3570
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• 2011

A series of 2,4,6-tripyridyl pyridines were synthesized, and evaluated for their antitumor cytotoxicity, topoisomerase I and II inhibitory activity. From the eighteen prepared compounds, compounds 10-12 have shown better or similar cytotoxicity against several human cancer cell lines as compared to 2,2':6',2"-terpyridine and doxorubicin. Especially, compound 10 exhibited the most potent cytotoxicity better than positive controls. Structure-activity relationship study indicated that 2,2':6',2"-terpyridine skeleton has an important role in displaying significant cytotoxicity against several human cancer cell lines.

• Natural Product Sciences
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• v.17 no.3
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• pp.245-249
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• 2011

Eight compounds, squalene (1), friedelin (2), ${\beta}$-sitosterol (3), ${\beta}$-sitosterol-3-O-glucoside (4), ${\alpha}$-tocopherol (5), betulinic acid (6), trilinolein (7) and 1-O-(9Z,12Z-Octadecadienoyl)-3-nonadecanoyl glycerol (8), were isolated from the barks of Tilia amurensis. Their chemical structures were identified by comparing their physicochemical and spectral data with those published in the literature. These isolated compounds were examined for their inhibitory activities against topoisomerase I and II. Compound 7 showed significant inhibition of DNA topoisomerase I and II activities, with percent decreases in activity of 87 and 95%, respectively at a concentration of $100\;{\mu}M$. Compound 6 exhibited cytotoxicity against the human colon adenocarcinoma cell line (HT-29), the human breast adenocarcinoma cell line (MCF-7) and the human liver hepatoblastoma cell line (HepG-2), with $IC_{50}$ values of 20, 59 and $16\;{\mu}M$, respectively.

• Proceedings of the PSK Conference
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• 2003.10b
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• pp.180.1-180.1
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• 2003

Eukaryotic DNA topoisomerase I (top I) is an essential enzyme that act to relax supercoiled DNA during the transcription, replication and mitosis. Intracellular levels of top I are elevated in a number of human solid tumors, relative to the respective normal tissues, suggesting that controlling the topI level is important to treat cancer. Top I poisons show their antitumor activities by stabilizing the cleavable ternary complex consisting of top I enzyme, DNA, and drug. Thus, top I is a promising target for the development of new cancer chemotherapeutics against a number of solid tumors. (omitted)

• Archives of Pharmacal Research
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• v.27 no.1
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• pp.77-82
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• 2004

DA-125, a novel derivative of adriamycin, is known for its anti-cancer activity. In this study, the inhibitory mechanism of DA-125 on topoisomerase was investigated in the simian virus 40 (SV40) replicating CV-1 cell by studying the SV40 DNA replication intermediates and DNA-topoisomerase complexes. DNA-protein complexes that were formed in the drug-treated cells were quantitated by using a glass filter assay. SV40 DNA replication intermediates that were accumulated in the drug-treated CV-1 cell were analyzed in a high resolution gel. DA-125 did not accumulate B-dimers of SV40 DNA replication intermediates which were found in the adriamycin-treated CV-1 cells. DA-125 induced a dose-dependent formation of the DNA-protein complexes, while adriamycin did not. When adriamycin and etoposide (VP16) were added to the SV40-infected cells at the same time, adriamycin blocked the formation of the DNA-protein complexes induced by VP16 in a dose-dependent manner. However, DA-125 blocked the formation of the DNA-protein complexes induced by VP16 up to the maximum level of the DNA-protein complexes that were induced by DA-125 alone. Adriamycin and DA-125 did not inhibit the formation of the DNA-protein complexes that were caused by camptothecin, a known topoisomerase I poison. DA-125 is bifunctional in inhibiting topoisomerase II because it simultaneously has the properties of the topoisomerase II poison and the DNA intercalator. As a topoisomerase II poison, DA-125 alone induced dose-dependent formation of the DNA-protein complexes. However, as a DNA intercalator, it quantitatively inhibited the formation of the DNA-protein complexes induced by a strong topoisomerase II poison VP16. Furthermore considering that the levels of the DNA-protein complex induced by VP16 were decreased by DA-125 in terms of the topoisomerase II poison, we suggest that DA-125 has a higher affinity to the drug-binding sites of DNA than VP16 has.

• Natural Product Sciences
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• v.16 no.4
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• pp.223-227
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• 2010

The DNA Topoisomerase I (DNA Topo I) inhibitory effect of ten isolated compounds (1.10) from the leaf and stem of Vitis amurensis were examined. Among them, amurensin G (5) and r-2-viniferin (7) showed high potent inhibitory activity against DNA Topo I. DNA Topo I, an important target for anticancer drugs, can cause DNA breaks and play a key role during cell proliferation, transcription and repair. Thus, the results suggest that the selected compounds (5 and 7) from Vitis amurensis have a possibility as DNA Topo I-targeting anticancer agents.

• Proceedings of the PSK Conference
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• 2003.10b
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• pp.159.1-159.1
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• 2003

Human Topoisomerase I (topo I) helps the control of DNA supercoiling in cells by assisting breaking and religation of DNA strand. It is essential for cellular metabolism and survival, hence, a good target for a novel class of anticancer drugs. As topo I inhibitor binds to the DNA-topo I complex, the religation of DNA strand is suppressed which results in the death of the target cell. Seven compounds of H-Imidazo［4, 5-g］phthalazing-4, 9-dione derivatives with $IC_50$ in the range of 0.001 and 6.27 $\mu$M in 5 different cancer cells and four compounds of 7-chloro-6-quinazoline-5, 8-dione derivatives with positive and negative topo I inhibition activities were studied. (omitted)

• Archives of Pharmacal Research
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• v.21 no.5
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• pp.581-590
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• 1998

We developed a novel water-soluble camptothecin analobue, CKD602, and evaluated the inhibition of topoisomerase I and the antitumor activities against mammalian tumor cells and human tumor xenografts. CKD602 was a nanomolar inhibitor of the topoisomerase I enzyme in the cleavable complex assay. CKD602 was found to be 3 times and slightly more potent than topotecan and camptothecin as inhibitors of topoisomerase, respecitively. In tumor cell cytotoxicity, CKD602 was more potent than topotecan in 14 out of 26 human cancer cell lines tested, while it was comparable to camptothecin. CKD602 was tested for the in vivo antitumor activity against the human tumor xenograft models. CKD602 was able to imduce regression of established HT-29, WIDR and CX-1 colon tumors, LX-1 lung tumor, MX-1 breast tumor and SKOV-3 ovarian tumor as much as 80, 94, 76, 67, 87% and 88%, respectively, with comparable body weight changes to those of topotecan. Also the therapeutic margin (R/Emax: maximum tolerance dose/$ED-{58}$) of CKD602 was significantly higher than that of topotecan by 4 times. Efficacy was determined at the maximal tolerated dose levels using schedule dependent i.p. administration in mice bearing L1210 leukemia. On a Q4dx4 (every 4 day for 4 doses) schedule, the maximum tolerated dose (MTD) was 25 mg/kg per administration, which caused great weight loss and lethality in <5% tumor bearing mouse. this schedule brought significant increase in life span (ILS), 212%, with 33% of long-term survivals. The ex vivo antitumor activity of CKD602 was compared with that of topotecan and the mean antitumor index (ATI) values recorded for CKD602 were significantly higher than that noted for topotecan. From these results, CKD602 warrants further clinical investigations as a potent inhibitor of topoisomerase I.

• Proceedings of the PSK Conference
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• 2002.10a
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• pp.314.2-314.2
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• 2002

DNA topoisomerases catalyze changes in DNA topology through cycles of transient DNA strand breakage and religation. During this process. the active site tyrosine in human DNA topoisomerase Ⅰ(Top Ⅰ) becomes covalently linked to the 3'-ends of a single-stranded nick in the DNA duplex, Stabilization of the Top Ⅰ-DNA cleavable complex is the common initial event leading to the cytotoxicity of top 1 inhibitors. (omitted)

• Bulletin of the Korean Chemical Society
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• v.25 no.4
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• pp.539-544
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• 2004

The ability of protoberberine alkaloids, berberine and berberrubine, to act as topoisomerase II poisons is linked to the anti-cancer activity. Minor alterations in structure have a significant effect on their relative activity. Berberine, which has methoxy group at the 19-position, is significantly less potent than berberrubine. Several observations support non-specific binding to HP14 by the berberine: (i) nonspecific upfield changes in $^1H$ chemical shift for protons of the berberine; (ii) the broadening of imino protons of HP14 upon binding of the berberine; (iii) very small increases in duplex melting temperature in the presence of the berberine. Our results reveal that substitution of a hydroxyl group to a methoxy group on the 19-position, thereby converting the berberrubine to the berberine is associated with a non-specific DNA binding affinity and a reduced topoisomerase II poisoning. The presence of a bulky 19-methoxy substituent decreases intercalating properties of berberine and makes it inactive as topoisomerase II poison.