(+)-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: Research - peer-reviewArticle

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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.

LanguageEnglish (US)
Pages1625-1628
Number of pages4
JournalJournal of Natural Products
Volume68
Issue number11
DOIs
StatePublished - Nov 2005
Externally publishedYes

Fingerprint

DNA Polymerase beta
DNA
DNA-directed DNA polymerase
Nucleic Acid Synthesis Inhibitors
Bleomycin
Bovine Serum Albumin
bovine serum albumin
extracts
assays
cells
Assays
Plant DNA
DNA Cleavage
Plant Extracts
Complex Mixtures
Biological Assay
DNA Damage
Cell Count
Enzymes
Surveys and Questionnaires

ASJC Scopus subject areas

  • Plant Science
  • Chemistry (miscellaneous)
  • Drug Discovery
  • Organic Chemistry
  • Pharmacology

Cite this

(+)-Myristinins A and D from Knema elegans, which inhibit DNA polymerase β and cleave DNA. / Deng, Jing Zhen; Starck, Shelley R.; Li, Shisheng; Hecht, Sidney M.

In: Journal of Natural Products, Vol. 68, No. 11, 11.2005, p. 1625-1628.

Research output: Research - peer-reviewArticle

Deng, Jing Zhen ; Starck, Shelley R. ; Li, Shisheng ; Hecht, Sidney M./ (+)-Myristinins A and D from Knema elegans, which inhibit DNA polymerase β and cleave DNA. In: Journal of Natural Products. 2005 ; Vol. 68, No. 11. pp. 1625-1628
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