Luotonin A is a pyrroloquinazolinoquinoline alkaloid isolated from the Chinese herbal medicinal plant Peganum nigellastrum. Although previously shown to exhibit cytotoxicity against the murine leukemia P-388 cell line, the mechanism of action of luotonin A is unknown. Presently, we demonstrate that luotonin A stabilizes the human DNA topoisomerase I-DNA covalent binary complex, affording the same pattern of cleavage as the structurally related topoisomerase I inhibitor camptothecin. Luotonin A also mediated topoisomerase I-dependent cytotoxicity toward Saccharyomyces cerevisiae lacking yeast topoisomerase I, but harboring a plasmid having the human topoisomerase I gene under the control of a galactose promoter. This finding identifies a putative biochemical locus for the cytotoxic action of luotonin A and has important implications for the mechanism of action of camptothecin and the design of camptothecin analogues.
Bioassay-directed fractionation of a n-hexane extract of Couepia polyandra using an assay to detect inhibitors of the lyase activity of DNA polymerase beta resulted in the isolation of the new triterpene 3beta,16beta,23-triacetoxyolean-12-en-28-oic acid (1) and four known compounds, oleanolic acid, betulinic acid, stigmasterol, and beta-sitosterol. The structure of the new compound was established on the basis of extensive 1D and 2D NMR spectroscopic interpretation. All five compounds inhibited DNA polymerase beta lyase activity.
A crude extract prepared from roots of Mallotus resinosus exhibited significant Cu(2+)-dependent DNA strand scission activity and was thus selected for bioassay-guided fractionation. Scopoletin (1), a simple coumarin, was identified as the active principle responsible for DNA cleavage activity of the crude extract. The DNA strand scission activity of 1, as well as that of three structural analogues, is reported.
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