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

Autor: Fernández M; Cátedra de Química Inorgánica, Facultad de Química, Universidad de la República, Montevideo, Uruguay., Arce ER; Cátedra de Química Inorgánica, Facultad de Química, Universidad de la República, Montevideo, Uruguay., Sarniguet C; Cátedra de Química Inorgánica, Facultad de Química, Universidad de la República, Montevideo, Uruguay., Morais TS; Centro de Química Estrutural, Faculdade de Ciências da Universidade de Lisboa, Portugal., Tomaz AI; Centro de Química Estrutural, Faculdade de Ciências da Universidade de Lisboa, Portugal., Azar CO; Departamento de Química Inorgánica y Analítica, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile., Figueroa R; Departamento de Química Inorgánica y Analítica, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile., Diego Maya J; Programa de Farmacología Molecular y Clínica, ICBM, Facultad de Medicina, Universidad de Chile, Santiago, Chile., Medeiros A; Institut Pasteur de Montevideo, Group Redox Biology of Trypanosomes, Montevideo, Uruguay; Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay., Comini M; Institut Pasteur de Montevideo, Group Redox Biology of Trypanosomes, Montevideo, Uruguay., Helena Garcia M; Centro de Química Estrutural, Faculdade de Ciências da Universidade de Lisboa, Portugal., Otero L; Cátedra de Química Inorgánica, Facultad de Química, Universidad de la República, Montevideo, Uruguay. Electronic address: luotero@fq.edu.uy., Gambino D; Cátedra de Química Inorgánica, Facultad de Química, Universidad de la República, Montevideo, Uruguay. Electronic address: dgambino@fq.edu.uy.
Jazyk: angličtina
Zdroj: Journal of inorganic biochemistry [J Inorg Biochem] 2015 Dec; Vol. 153, pp. 306-314. Date of Electronic Publication: 2015 Jun 30.
DOI: 10.1016/j.jinorgbio.2015.06.018
Abstrakt: 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.
(Copyright © 2015 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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