(+)-Myristinins A and D from Knema elegans, which inhibit DNA polymerase beta and cleave DNA.
A survey of crude plant extracts for DNA polymerase beta 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 beta, 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 microM, respectively, as inhibitors of DNA polymerase beta in the presence of bovine serum albumin (BSA), and 2.7 and 1.2 microM in the absence of BSA. As such, they are the most potent DNA polymerase beta 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 microM 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 beta inhibition and DNA damage.
Deng
Jing-Zhen
JZ
Department of Chemistry, University of Virginia, Charlottesville, Virginia 22903, USA.
Starck
Shelley R
SR
Li
Shisheng
S
Hecht
Sidney M
SM
D000818:Animals; D001761:Bleomycin / Q000494:pharmacology; D004249:DNA Damage; D019951:DNA Polymerase beta / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D005419:Flavonoids / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D007941:Leukemia P388; D015394:Molecular Structure; D026324:Myristicaceae / Q000737:chemistry*; D018547:Plant Stems / Q000737:chemistry; D010946:Plants, Medicinal / Q000737:chemistry*; D013237:Stereoisomerism; D013785:Thailand
D004791:Enzyme Inhibitors; D005419:Flavonoids; C500691:myristinin A; C506383:myristinin D; D001761:Bleomycin; D019951:DNA Polymerase beta