title: Lunacridine from Lunasia amara is a DNA intercalating topoisomerase II inhibitor.
abstract: An ethnobotanical survey of plants used to treat tropical ulcers in Papua New Guinea identified Lunasia amara as possessing anti-Staphylococcus aureus activity. Activity-guided fractionation of the aqueous bark extract resulted in the identification of the quinoline alkaloid lunacridine as the active principle. Lunacridine tends to cyslise at room temperature but the 2'-O-trifluoroacetyl derivative was found to be stable and therefore more suitable for biological assays. The compound exhibited a minimal inhibitory concentration (MIC) of 64 micro g/ml against Staphylococcus aureus NCTC 6571 and activity in the low micromolar range against HeLa and H226 cells; the latter showing signs of caspase-3/7 mediated apoptotic cell death. Experiments with drug resistant strains of Streptococcus pneumoniae suggested topoisomerase as a likely target for the drug in bacteria whilst decatenation assays with human topoisomerase II showed the compound to be a potent inhibitor of this isoform (IC(50)<5 micro M) thus explaining the drug's activity against human cell lines. Both lunacridine and 2'-O-trifluoroacetyl lunacridine exhibited mild DNA intercalation activity giving 50% decrease in ethidium DNA fluorescence at 0.22 and 0.6 mM, respectively, placing the drug amongst the DNA intercalating class of topoisomerase II inhibitors.
authors.affiliation: Centre for Integrative Physiology, College of Medicine, University of Edinburgh, Edinburgh, UK.
authors.forename: Thomas A K
authors.initials: TA
authors.lastname: Prescott
authors.forename: Ian H
authors.initials: IH
authors.lastname: Sadler
authors.forename: Robert
authors.initials: R
authors.lastname: Kiapranis
authors.forename: Sutherland K
authors.initials: SK
authors.lastname: Maciver
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D007364:Intercalating Agents / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D024301:Plant Bark / Q000737:chemistry; D011804:Quinolines / Q000494:pharmacology; D027821:Rutaceae / Q000737:chemistry*; D013211:Staphylococcus aureus / Q000187:drug effects; D013296:Streptococcus pneumoniae / Q000187:drug effects; D059005:Topoisomerase II Inhibitors
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D007364:Intercalating Agents; D011804:Quinolines; D059005:Topoisomerase II Inhibitors; C518539:lunacridine; D020169:Caspases