title: Activity of indenoisoquinolines against African trypanosomes.
abstract: African trypanosomiasis (sleeping sickness), caused by protozoan Trypanosoma brucei species, is a debilitating disease that is lethal if untreated. Available drugs are antiquated, toxic, and compromised by emerging resistance. The indenoisoquinolines are a class of noncamptothecin topoisomerase IB poisons that are under development as anticancer agents. We tested a variety of indenoisoquinolines for their ability to kill T. brucei. Indenoisoquinolines proved trypanocidal at submicromolar concentrations in vitro. Structure-activity analysis yielded motifs that enhanced potency, including alkylamino substitutions on N-6, methoxy groups on C-2 and C-3, and a methylenedioxy bridge between C-8 and C-9. Detailed analysis of eight water-soluble indenoisoquinolines demonstrated that in trypanosomes the compounds inhibited DNA synthesis and acted as topoisomerase poisons. Testing these compounds on L1210 mouse leukemia cells revealed that all eight were more effective against trypanosomes than against mammalian cells. In preliminary in vivo experiments one compound delayed parasitemia and extended survival in mice subjected to a lethal trypanosome challenge. The indenoisoquinolines provide a promising lead for the development of drugs against sleeping sickness.
authors.affiliation: Department of Medicine, Division of Clinical Pharmacology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. rbakshi@jhmi.edu
authors.forename: Rahul P
authors.initials: RP
authors.lastname: Bakshi
authors.forename: Dongpei
authors.initials: D
authors.lastname: Sang
authors.forename: Andrew
authors.initials: A
authors.lastname: Morrell
authors.forename: Mark
authors.initials: M
authors.lastname: Cushman
authors.forename: Theresa A
authors.initials: TA
authors.lastname: Shapiro
mesh_terms: D000818:Animals; D016054:DNA, Protozoan / Q000235:genetics; D007546:Isoquinolines / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000737:chemistry / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism
chemical_list: D016054:DNA, Protozoan; D007546:Isoquinolines; D014344:Trypanocidal Agents