title: Trypanotoxic activity of thiosemicarbazone iron chelators.
abstract: Only a few drugs are available for treating sleeping sickness and nagana disease; parasitic infections caused by protozoans of the genus Trypanosoma in sub-Saharan Africa. There is an urgent need for the development of new medicines for chemotherapy of these devastating diseases. In this study, three newly designed thiosemicarbazone iron chelators, TSC24, Dp44mT and 3-AP, were tested for in vitro activity against bloodstream forms of Trypanosoma brucei and human leukaemia HL-60 cells. In addition to their iron chelating properties, TSC24 and Dp44mT inhibit topoisomerase IIα while 3-AP inactivates ribonucleotide reductase. All three compounds exhibited anti-trypanosomal activity, with minimum inhibitory concentration (MIC) values ranging between 1 and 100 µM and 50% growth inhibition (GI50) values of around 250 nM. Although the compounds did not kill HL-60 cells (MIC values >100 µM), TSC24 and Dp44mT displayed considerable cytotoxicity based on their GI50 values. Iron supplementation partly reversed the trypanotoxic and cytotoxic activity of TSC24 and Dp44mT but not of 3-AP. This finding suggests possible synergy between the iron chelating and topoisomerase IIα inhibiting activity of the compounds. However, further investigation using separate agents, the iron chelator deferoxamine and the topoisomerase II inhibitor epirubicin, did not support any synergy for the interaction of iron chelation and topoisomerase II inhibition. Furthermore, TSC24 was shown to induce DNA degradation in bloodstream forms of T. brucei indicating that the mechanism of trypanotoxic activity of the compound is topoisomerase II independent. In conclusion, the data support further investigation of thiosemicarbazone iron chelators with dual activity as lead compounds for anti-trypanosomal drug development.
authors.affiliation: BioMedical Research Centre, Norwich Medical School, University of East Anglia, Norwich, United Kingdom.
authors.forename: Samuel
authors.initials: S
authors.lastname: Ellis
authors.affiliation: BioMedical Research Centre, Norwich Medical School, University of East Anglia, Norwich, United Kingdom.
authors.forename: Darren W
authors.initials: DW
authors.lastname: Sexton
authors.affiliation: BioMedical Research Centre, Norwich Medical School, University of East Anglia, Norwich, United Kingdom. Electronic address: dsteverding@hotmail.com.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Steverding
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D007501:Iron / Q000378:metabolism; D007502:Iron Chelating Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D013882:Thiosemicarbazones / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D014346:Trypanosoma brucei brucei / Q000187:drug effects*
chemical_list: C549333:2-(quinolin-2-ylmethylene)hydrazinecarbothioamide; D007502:Iron Chelating Agents; D011725:Pyridines; D013882:Thiosemicarbazones; C539263:di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone; C078157:3-aminopyridine-2-carboxaldehyde thiosemicarbazone; D007501:Iron
keywords: Sleeping sickness; Thiosemicarbazone iron chelators; Topoisomerase; Trypanosoma brucei