Publication Type Journal Article
Title Novel ruthenium(II) cyclopentadienyl thiosemicarbazone compounds with antiproliferative activity on pathogenic trypanosomatid parasites
Authors Mariana Fernandez Esteban Rodriguez Arce Cynthia Sarniguet Tânia S. Morais Ana Isabel Tomaz Claudio Olea Azar Roberto Figueroa J. Diego Maya Andrea Medeiros Marcelo Comini M. Helena Garcia Lucia Otero Dinorah Gambino
Groups BIOIN
Journal JOURNAL OF INORGANIC BIOCHEMISTRY
Year 2015
Month December
Volume 153
Number
Pages 306-314
Abstract Searching for new prospective antitrypanosomal agents, three novel Ru(II)-cyclopentadienyl compounds, [Ru(eta(5)-C5H5)(PPh3)L], with HL = bioactive 5-nitrofuryl containing thiosemicarbazones were synthesized and characterized in the solid state and in solution. The compounds were evaluated in vitro on the blood circulating trypomastigote form of Trypanosoma cruzi (Dm28c strain), the infective form of Trypanosoma brucei brucei (strain 427) and on J774 murine macrophages and human-derived EA.hy926 endothelial cells. The compounds were active against both parasites with IC50 values in the micromolar or submicromolar range. Interestingly, they are much more active on T. cruzi than previously developed Ru(II) classical and organometallic compounds with the same bioactive ligands. The new compounds showed moderate to very good selectivity towards the parasites in respect to mammalian cells. The global results point at [RuCp(PPh3)L2] (12 = N-methyl derivative of 5-nitrofuryl containing thiosemicarbazone and Cp = cyclopentadienyl) as the most promising compound for further developments (IC50 T. cruzi = 0.41 mu M; IC50 T. brucei brucei = 3.5 mu M). Moreover, this compound shows excellent selectivity towards T. cruzi (SI > 49) and good selectivity towards T. brucei brucei (SI > 6). In order to get insight into the mechanism of antiparasitic action, the intracellular free radical production capacity of the new compounds was assessed by ESR. DMPO (5,5-dimethyl-1-pirroline-N-oxide) spin adducts related to the bioreduction of the complexes and to redox cycling processes were characterized. In addition, DNA competitive binding studies with ethidium bromide by fluorescence measurements showed that the compounds interact with this biomolecule. (C) 2015 Elsevier Inc. All rights reserved.
DOI http://dx.doi.org/10.1016/j.jinorgbio.2015.06.018
ISBN
Publisher ELSEVIER SCIENCE INC
Book Title
ISSN 0162-0134
EISSN 1873-3344
Conference Name
Bibtex ID ISI:000367563200035
Observations
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