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J Inorg Biochem. 2015 Dec;153:306-314. doi: 10.1016/j.jinorgbio.2015.06.018. Epub 2015 Jun 30.

Novel ruthenium(II) cyclopentadienyl thiosemicarbazone compounds with antiproliferative activity on pathogenic trypanosomatid parasites.

Author information

1
Cátedra de Química Inorgánica, Facultad de Química, Universidad de la República, Montevideo, Uruguay.
2
Centro de Química Estrutural, Faculdade de Ciências da Universidade de Lisboa, Portugal.
3
Departamento de Química Inorgánica y Analítica, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile.
4
Programa de Farmacología Molecular y Clínica, ICBM, Facultad de Medicina, Universidad de Chile, Santiago, Chile.
5
Institut Pasteur de Montevideo, Group Redox Biology of Trypanosomes, Montevideo, Uruguay; Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay.
6
Institut Pasteur de Montevideo, Group Redox Biology of Trypanosomes, Montevideo, Uruguay.
7
Cátedra de Química Inorgánica, Facultad de Química, Universidad de la República, Montevideo, Uruguay. Electronic address: luotero@fq.edu.uy.
8
Cátedra de Química Inorgánica, Facultad de Química, Universidad de la República, Montevideo, Uruguay. Electronic address: dgambino@fq.edu.uy.

Abstract

Searching for new prospective antitrypanosomal agents, three novel Ru(II)-cyclopentadienyl compounds, [Ru(η(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] (L2=N-methyl derivative of 5-nitrofuryl containing thiosemicarbazone and Cp=cyclopentadienyl) as the most promising compound for further developments (IC50T. cruzi=0.41μM; IC50T. brucei brucei=3.5μM). 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.

KEYWORDS:

Ruthenium cyclopentadienyl compounds; Thiosemicarbazones; Trypanosoma brucei; Trypanosoma cruzi

PMID:
26275470
DOI:
10.1016/j.jinorgbio.2015.06.018
[Indexed for MEDLINE]

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