Ellis, S and Sexton, DW and Steverding, D (2015) Trypanotoxic activity of thiosemicarbazone iron chelators. Experimental Parasitology, 150. pp. 7-12. ISSN 1090-2449
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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.
|Uncontrolled Keywords:||0605 Microbiology, 0707 Veterinary Sciences|
|Subjects:||Q Science > QR Microbiology
S Agriculture > SF Animal culture
|Divisions:||Pharmacy & Biomolecular Sciences|
|Date Deposited:||05 Nov 2015 10:57|
|Last Modified:||13 Jan 2016 00:50|
|DOI or Identification number:||10.1016/j.exppara.2015.01.004|
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Trypanotoxic activity of thiosemicarbazone iron chelators. (deposited 22 May 2015 13:28)
- Trypanotoxic activity of thiosemicarbazone iron chelators. (deposited 05 Nov 2015 10:57) [Currently Displayed]
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