(+)-Myristinins A and D from Knema elegans, which inhibit DNA polymerase β and cleave DNA

Jing Zhen Deng, Shelley R. Starck, Shisheng Li, Sidney M. Hecht

Research output: Contribution to journalArticle

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Abstract

A survey of crude plant extracts for DNA polymerase β inhibitors resulted in the identification of a methyl ethyl ketone extract prepared from Knema elegans that strongly inhibited the enzyme. Subsequent bioassay-guided fractionation of the extract, using an assay to monitor the activity of DNA polymerase β, led to the isolation of two potent inhibitors, (+)-myristinins A (1) and D (2), which are known flavans having unusual structures. (+)-Myristinins A and D exhibited IC50 values of 12 and 4.3 μM, respectively, as inhibitors of DNA polymerase β in the presence of bovine serum albumin (BSA), and 2.7 and 1.2 μM in the absence of BSA. As such, they are the most potent DNA polymerase β inhibitors reported to date. Compounds 1 and 2 potentiated the cytotoxicity of bleomycin toward cultured P388D1 cells, reducing the number of viable cells by at least 30% when employed at 9 μM concentration for 6 h in the presence of an otherwise nontoxic concentration of bleomycin (75 nM). Principles 1 and 2 also induced strong Cu2+-dependent DNA strand scission in a DNA cleavage assay. Accordingly, 1 and 2 exhibit two activities, namely, DNA polymerase β inhibition and DNA damage.

Original languageEnglish (US)
Pages (from-to)1625-1628
Number of pages4
JournalJournal of Natural Products
Volume68
Issue number11
DOIs
StatePublished - Nov 1 2005

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ASJC Scopus subject areas

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

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