Archives of Pharmacal Research

, Volume 33, Issue 9, pp 1307–1315 | Cite as

Inhibition of DNA topoisomerases I and II and cytotoxicity of compounds from Ulmus davidiana var. japonica

  • Ming Shan Zheng
  • Yeun-Kyung Lee
  • Ying Li
  • Kyoung Hwangbo
  • Chong-Soon Lee
  • Jae-Ryong Kim
  • Sunny Kyung-Seon Lee
  • Hyun-Wook Chang
  • Jong-Keun Son
Research Articles Drug Discovery and Development


Twenty five compounds including ten triterpenes (1–3, 5–11), six flavonoids (12–15, 24, 25), five lignans (17, 18, 21–23), two butenyl clohexnone glycosides (19–20), one fructofuranoside (16) and one fatty acid (4) were isolated from the roots of Ulmus davidiana var. japonica. The structures of those compounds were identified by comparing their physicochemical and spectral data with those of published in literatures. All the compounds were evaluated for DNA topoisomerase inhibitory activities and cytotoxicities. Among the purified compounds, 4 and 19 showed more potent inhibitory acitivities (IC50: 39 and 19 μM, respectively) than camptothecin, as the positive control (IC50: 46 μM) against topoisomerase I. Compounds, 4, 10, 12, 19, 24 and 25 showed strong inhibitory activities toward DNA topoisomerase II (IC50: 0.1, 0.52, 0.47, 0.42, 0.17 μM and 17 nM, respectively), which were more potent than that of etoposide as positive control (IC50: 20 μM). In A549 cell line, 5 and 6 showed cytotoxicities (IC50: 4 μM and 3 μM, respectively, with IC50 of camptothecin as positive control: 10.3 μM). In the HepG2 cell line, 3, 5 and 7 showed cytotoxicity (IC50: 4, 3 and 4 μM, respectively, with IC50 of camptothecin: 0.3 μM). Compounds 6, 12 and 23 showed cytotoxicities in the HT-29 cell line (IC50: 19, 19 and 15 μM, respectively, with IC50 of camptothecin: 2 μM).

Key words

Ulmus davidiana var. japonica Topoisomerase Cytotoxicity 


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  1. Achenbach, H., Waibel, R., Raffelsberger, B., and Ivan, A. M., Iridoid and other constituents of Canthium subcordatum. Phytochemistry, 20, 1591–1595 (1981).CrossRefGoogle Scholar
  2. Aguirre, M. C., Delporte, C., Backhouse, N., Erazo, S., Letelier, M. E., Cassels, B. K., Silva, X., Alegria, S., and Negrete, R., Topical anti-inflammatory activity of 2alpha-hydroxy pentacyclic triterpene acids from the leaves of Ugni molinae. Bioorg. Med. Chem., 14, 5673–5677 (2006).CrossRefPubMedGoogle Scholar
  3. Ali, M. S., Mahmud, S., Perveen, S., Ahmad, V. U., and Rizwani, G. H., Epimers from the leaves of Calophyllum inophyllum. Phytochemistry, 50, 1385–1389 (1999).CrossRefGoogle Scholar
  4. Chang, C. W., Wu, T. S., Hsieh, Y. S., Kuo, S. C., and Chao, P. D., Terpenoids of Syzygium formosanum. J. Nat. Prod., 62, 327–328 (1999).CrossRefPubMedGoogle Scholar
  5. Chen, A. Y. and Liu, L. F., DNA topoisomerase: essential enzymes and lethal targets. Annu. Rev. Pharmacol. Toxicol., 34, 191–218 (1994).CrossRefPubMedGoogle Scholar
  6. Chung, I. M., Khanh, T. D., Lee, O. K., and Ahmad, A., Chemical constituents from ajwain seeds (Trachyspermum ammi) and inhibitory acitivity of thymol, lupeol and fatty acids on barnyard grass and radish seeds. Chem. Asian J., 19, 1524–1534 (2007).Google Scholar
  7. D’Arpa, P. and Liu, L. F., Topoisomerase-targeting antitumor drugs. Biochim. Biophys. Acta, 989, 163–177 (1989).PubMedGoogle Scholar
  8. De Marino, S., Borbone, N., Zollo, F., Ianaro, A., Di Meglio, P., and Iorizzi, M., Megastigmane and phenolic components from Laurus nobilis L. leaves and their inhibitory effects on nitric oxide production. J. Agric. Food Chem., 52, 7525–7531 (2004).CrossRefPubMedGoogle Scholar
  9. Foo, L. Y. and Karchesy, J. J., Polyphenolic glycosides from Douglas fir inner bark. Phytochemistry, 28, 1237–1240 (1989).CrossRefGoogle Scholar
  10. Fukuda, M., Nishio, K., Kanzawa, F., Ogasawara, H., Ishida, T., Arioka, H., Bojamowski, K., Oka, M., and Saijo, N., Synergism between cisplatin and topoisomerase I inhibitors, NB-506 and SN-38, in human small cell lung cancer cells. Cancer Res., 56, 789–793 (1996).PubMedGoogle Scholar
  11. Hisashi, K. and Haruo, O., Configurational studies on hydroxy groups at C-2, 3 and 23 or 24 of oleanene and ursene-type triterpenes by NMR spectroscopy. Phytochemistry, 28, 1703–1710 (1989).CrossRefGoogle Scholar
  12. Inoshiri, S., Sasaki, M., Kohda, H., Otsuka, H., and Yamasaki, K., Aromatic glycosides from Berchemia racemosa. Phytochemistry, 26, 2811–2814 (1987).CrossRefGoogle Scholar
  13. Ishimaru, K., Nonaka, G. I., and Nishioka, I., Flavan-3-ol and procyanidin glycosides from Quercus miyagii. Phytochemistry, 26, 1167–1170 (1987).CrossRefGoogle Scholar
  14. Jin, U. H., Lee, D. Y., Kim, D. S., Lee, I. S., and Kim, C. H., Induction of mitochondria-mediated apoptosis by methanol fraction of Ulmus davidiana Planch (Ulmaceae) in U87 glioblastoma cells. Environ. Toxicol. Pharmacol., 22, 136–141 (2006).CrossRefGoogle Scholar
  15. Jin, U. H., Suh, S. J., Park, S. D., Kim, K. S., Kwon, D. Y., and Kim, C. H., Inhibition of mouse osteoblast proliferation and prostaglandin E2 synthesis by Ulmus davidiana Planch (Ulmaceae). Food Chem. Toxicol., 46, 2135–2142 (2008).CrossRefPubMedGoogle Scholar
  16. Jun, C. D., Pae, H. O., Kim, Y. C., Jeong, S. J., Yoo, J. C., Lee, E. J., Choi, B. M., Chae, S. W., Park, R. K., and Chung, H. T., Inhibition of nitric oxide synthesis by butanol fraction of the methanol extract of Ulmus davidiana in murine macrophages. J. Ethnopharmacol., 62, 129–135 (1998).CrossRefPubMedGoogle Scholar
  17. Kang, S. K., Kim, K. S., Byun, Y. S., Suh, S. J., Jin, U. H., Kim, K. H., Lee, I. S., and Kim, C. H., Effects of Ulmus davidiana Planch on mineralization, bone morphogenetic protein-2, alkaline phosphatase type I collagen, and collagenase-1 in bone cells. In Vitro Cell. Dev. Biol. Anim., 42, 225–229 (2006).CrossRefPubMedGoogle Scholar
  18. Kohler, N., Wray, V., and Winterhalter, P., Preparative isolation of procyanidins from grap seed extracts by highspeed counter-current chromatography. J. Chromatogr. A, 1177, 114–125 (2008).CrossRefPubMedGoogle Scholar
  19. Lavaud, C., Massiot, G., Barrera, J. B., Moretti, C., and Le Men-Olivier, L., Triterpene saponins from Myrsine pellucida. Phytochemistry, 37, 1671–1677 (1994).CrossRefPubMedGoogle Scholar
  20. Lee, K. H., Lee, J. H., Cho, C. H., Noh, M. J., and Kim, Y. B., Radiosensitizing and topoisomerase I inhibitory effects of Aloe vera, Formitella fraxinea, and Ulmus davidiana extracts. Nat. Prod. Sci., 7, 60–62 (2001a).Google Scholar
  21. Lee, M. K., Sung, S. H., Lee, H. S., Cho, J. H., and Kim, Y. C., Lignan and neolignan glycosides from Ulmus davidiana var. japonica. Arch. Pharm. Res., 24, 198–201 (2001b).CrossRefPubMedGoogle Scholar
  22. Li, S., Chen, R. Y., and Yu, D. Q., Study on chemical constituents of Myricaria paniculata I. Zhongguo Zhong Yao Za Zhi, 32, 403–406 (2007).PubMedGoogle Scholar
  23. Liu, L. F., DNA topoisomerase poisons as antitumor drugs. Annu. Rev. Biochem., 58, 351–375 (1989).CrossRefPubMedGoogle Scholar
  24. Liu, P., Duan, H. Q., Pan, Q., Zhang, Y. W., and Yao, Z., Triterpenes from herb of Potentilla chinesis. Zhongguo Zhong Yao Za Zhi, 31, 1875–1879 (2006).PubMedGoogle Scholar
  25. Lundgren, L. N., Popoff, T., and Theander, O., Dilignol glycosides from needels of Picea abies. Phytochemistry, 20, 1967–1969 (1981).CrossRefGoogle Scholar
  26. Moon, Y. H. and Rim, G. R., Studies on the constituents of Ulmus parvifolia. Korean J. Pharmaco., 26, 1–7 (1995).Google Scholar
  27. Na, M. K., An, R. B., Lee, S. M., Min, B. S., Kim, Y. H., Bae, K. H., and Kang, S. S., Antioxidant compounds from the stem bark of Sorbus commixta. Nat. Prod. Sci., 8, 26–29 (2002).Google Scholar
  28. Nahrstedt, A., Proksch, P., and Conn, E. E., (-)-Catechin, flavonol glycosides and flavones from Chamaebatia foliolosa. Phytochemistry, 26, 1546–1547 (1987).CrossRefGoogle Scholar
  29. Pabst, A., Barron, D., Semon, E., and Schreier, P., Two diastereomeric 3-oxo-α-ionol-β-glucosides from raspberry fruit. Phytochemistry, 31, 1649–1652 (1992).CrossRefGoogle Scholar
  30. Pommier, Y., DNA topoisomerase I and II in cancer chemotherapy: update and perspectives. Cancer Chemother. Pharmacol., 32, 103–108 (1993).CrossRefPubMedGoogle Scholar
  31. Potmesil, M., Camptothecins: from bench research to hospital wards. Cancer Res., 54, 1431–1439 (1994).PubMedGoogle Scholar
  32. Rubinstein, L. V., Shoemaker, R. H., Paul, K. D., Simon, R. M., Tosini, S., Skehan, P., Scudiero, D. A., Monks, A., and Boyd, M. R., Comparison of in vitro anticancer-drug-screening data generated with a lines. J. Nat. Cancer Inst., 82, 1113–1118 (1990).CrossRefPubMedGoogle Scholar
  33. Sang, S., Kikuzaki, H., Lapsley, K., Rosen, R. T., Nakatani, N., and Ho, C. T., Sphingolipid and other constituents from almond nuts (Prunus amygdalus Batsch). J. Agric. Food Chem., 50, 4709–4712 (2002).CrossRefPubMedGoogle Scholar
  34. Seebacher, W., Simic, N., Weis, R., Saf, R., and Kunert, O., Complete assignments of 1H and 13C NMR resonances of oleanolic acid, 18-oleanolic acid, ursolic acid and their 11-oxo derivatives. Magn. Reson. Chem., 41, 636–638 (2003).CrossRefGoogle Scholar
  35. Siddiqui, A. A., Wani, S. M., Rajesh, R., and Alagarsamy, V., Phytochemical and pharmacological investigation of Hibiscus rosasinensis Linn. Indian J. Pharm. Sci., 68, 588–593 (2006).CrossRefGoogle Scholar
  36. Slichenmyer, W. J., Rowinsky, E. K., Donehower, R. C., and Kaufmann, S. H., The current status of camptothecin analogues as antitumor agents. J. Natl. Cancer Inst., 85, 271–291 (1993).CrossRefPubMedGoogle Scholar
  37. Smite, E., Pan, H., and Lundgren, L. N., Lignan glycosides from inner bark of Betula pendula. Phytochemistry, 40, 341–343 (1995).CrossRefGoogle Scholar
  38. Suh, S. J., Yun, W. S., Kim, K. S., Jin, U. H., Kim, J. K., Kim, M. S., Kwon, D. Y., and Kim, C. H., Stimulative effect of Ulmus davidiana Planch (Ulmaceae) on osteoblastic MC3T3-E1 cells. J. Ethnopharmacol., 109, 480–485 (2007).CrossRefPubMedGoogle Scholar
  39. Suzuki, K., Shono, F., Kai, H., Uno, T., and Uyeda, M., Inhibition of topoisomerases by fatty acids. J.Enzym. Inhib., 15, 357–366 (2000).CrossRefPubMedGoogle Scholar
  40. Tarascou, I., Barathieu, K., Andr, Y., Pianet, I., Dufourc, E. J., and Fouquet. E., An improved synthesis of procyanidin dimers: regio- and stereocontrol of the interflavan bond. European J. Org. Chem., 23, 5367–5377 (2006).CrossRefGoogle Scholar
  41. Umlauf, D., Zapp, J., Becker, H., and Adam, K. P., Biosynthesis of the irregular monoterpene artemisia ketone, the sesquiterpene germacrene D and other isoprenoids in Tanacetum vulgare L. (Asteraceae). Phytochemistry, 65, 2463–2470 (2004).CrossRefPubMedGoogle Scholar
  42. Wang, D., Xia, M., and Cui, Z., New triterpenoids isolated from the root bark of Ulmus pumila L. Chem. Pharm. Bull., 54, 775–778 (2006).CrossRefPubMedGoogle Scholar
  43. Wang, J. C., DNA topoisomerases. Annu. Rev. Biochem., 65, 635–692 (1996).CrossRefPubMedGoogle Scholar
  44. Xie, W. D., Gao, X., and Jia, Z. J., A new C-10 acetylene and a new triterpenoid from Conyza canadensis. Arch. Pharm. Res., 30, 547–551 (2007).CrossRefPubMedGoogle Scholar
  45. Yoo, S. W., Kim, J. S., Kang, S. S., Son, K. H., Chang, H. W., Kim, H. P., Bae, K., and Lee, C. O., Constituents of the fruits and leaves of Euodia daniellii. Arch. Pharm. Res., 25, 824–830 (2002).CrossRefPubMedGoogle Scholar
  46. Yoshinari, K., Sashida, Y., and Shimomura, H., Two new lignan xylosides from the barks of Prunus ssiori and Prunus padus. Chem. Pharm. Bull., 37, 3301–3303 (1989).Google Scholar
  47. Yumiko, K., Toshihiro, A., Ken, Y., Michio, T., and Toshitake, T., Structures of five hydroxylated sterols from the seeds of Trichosanthes kirilowii Maxim. Chem. Pharm. Bull., 43, 1813–1817 (1995).Google Scholar
  48. Zhang, C. Z., Xu, X. Z., and Li, C., Fructosides from Cynomorium songaricum. Phytochemistry, 41, 975–976 (1996).CrossRefGoogle Scholar

Copyright information

© The Pharmaceutical Society of Korea and Springer Netherlands 2010

Authors and Affiliations

  • Ming Shan Zheng
    • 1
    • 2
  • Yeun-Kyung Lee
    • 1
  • Ying Li
    • 1
  • Kyoung Hwangbo
    • 1
  • Chong-Soon Lee
    • 3
  • Jae-Ryong Kim
    • 4
  • Sunny Kyung-Seon Lee
    • 5
  • Hyun-Wook Chang
    • 1
  • Jong-Keun Son
    • 1
  1. 1.College of PharmacyYeungnam UniversityGyongsanKorea
  2. 2.Yanbian UniversityYanjiChina
  3. 3.Department of Biochemistry, College of ScienceYeungnam UniversityGyongsanKorea
  4. 4.Department of Biochemistry and Molecular Biology, Aging-associated Vascular Disease Research Center, College of MedicineYeungnam UniversityDaeguKorea
  5. 5.Department of Pathology and Laboratory MedicineUniversity of California DavisSacramentoUSA

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