Isolation and biochemical characterization of a new topoisomerase I inhibitor from Ocotea leucoxylon

Bing Nan Zhou, Randall K. Johnson, Michael R. Mattern, Xiangyang Wang, Sidney M. Hecht, Hans T. Beck, Alonzo Ortiz, David G.I. Kingston

Research output: Contribution to journalArticle

55 Scopus citations

Abstract

In a continuation of our search for potential tumor inhibitors from plants, we found that a crude extract from Ocotea leucoxylon showed selective activity typical of inhibitors of the enzyme topoisomerase I in a yeast assay for DNA-damaging agents. Using a bioassay-directed fractionation approach, the major bioactive compound was isolated and identified as the known aporphine alkaloid dicentrinone (4); the inactive alkaloid dicentrine (3) was also isolated. Compound 4 showed selective bioactivity against the rad52 repair-deficient yeast strain RS322 (IC12 49 μg/mL) and was inactive against the rad52- and topo1-deficient strain RS321 (IC12 > 2000 μg/mL) and against the repair-proficient strain RJ03 (IC12 > 2000 μg/mL). Biochemical studies with recombinant human topoisomerase I indicated that dicentrinone (4) is an inhibitor of the human enzyme. Colony formation studies suggest that it is weakly cytotoxic, but that its mechanism of toxicity differs from that of camptothecin and its derivatives.

Original languageEnglish (US)
Pages (from-to)217-221
Number of pages5
JournalJournal of Natural Products
Volume63
Issue number2
DOIs
StatePublished - Feb 1 2000
Externally publishedYes

ASJC Scopus subject areas

  • Analytical Chemistry
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Drug Discovery
  • Complementary and alternative medicine
  • Organic Chemistry

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  • Cite this

    Zhou, B. N., Johnson, R. K., Mattern, M. R., Wang, X., Hecht, S. M., Beck, H. T., Ortiz, A., & Kingston, D. G. I. (2000). Isolation and biochemical characterization of a new topoisomerase I inhibitor from Ocotea leucoxylon. Journal of Natural Products, 63(2), 217-221. https://doi.org/10.1021/np990442s