title: Cleavable complex formation in Leishmania chagasi treated with anilinoacridines.
abstract: Anilinoacridines have recently been found to possess antiparasitic activity toward Leishmania, Trypanosoma, and Plasmodium species. These compounds have been examined for their ability to generate cleavable complex, the protein-associated DNA lesion characteristic of topoisomerase II involvement, in intact L. chagasi promastigotes. At cytotoxic concentrations, anilinoacridine compounds give cleavable complex in a whole cell assay which suggests that the drugs affect a nuclear topoisomerase II in the parasite. Linearization of kinetoplast DNA minicircles also occurs in parasites treated with anilinoacridines at similar concentrations. Exonuclease digestions reveal that the linearized minicircles are blocked at the 5' end but not at the 3' end, further implicating a kinetoplast topoisomerase II in the cleavage process. Interestingly, cytotoxic alkylaminoacridines did not stimulate the production of cleaved DNA in the same experiments. DNA binding experiments showed no apparent correlation between the affinity of the compounds for DNA and antileishmanial activity. Although multiple cytotoxic mechanisms are likely at work, these experiments suggest that topoisomerase II enzyme(s) are affected by antileishmanial anilinoacridines.
authors.affiliation: Department of Chemistry, University of Virginia, Charlottesville 22901.
authors.forename: K A
authors.initials: KA
authors.lastname: Werbovetz
authors.forename: P G
authors.initials: PG
authors.lastname: Spoors
authors.forename: R D
authors.initials: RD
authors.lastname: Pearson
authors.forename: T L
authors.initials: TL
authors.lastname: Macdonald
mesh_terms: D000585:Aminacrine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D004249:DNA Damage; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D018105:DNA, Kinetoplast / Q000187:drug effects / Q000378:metabolism*; D005092:Exonucleases / Q000494:pharmacology; D018314:Leishmania infantum / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D015800:Protozoan Proteins / Q000378:metabolism*; D014344:Trypanocidal Agents / Q000378:metabolism / Q000494:pharmacology
chemical_list: D018105:DNA, Kinetoplast; D009687:Nuclear Proteins; D015800:Protozoan Proteins; D014344:Trypanocidal Agents; D000585:Aminacrine; D005092:Exonucleases; D004250:DNA Topoisomerases, Type II