Novel ruthenium(II) cyclopentadienyl thiosemicarbazone compounds with antiproliferative activity on pathogenic trypanosomatid parasites.
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.
Cátedra de Química Inorgánica, Facultad de Química, Universidad de la República, Montevideo, Uruguay.
Mariana
M
Fernández
Cátedra de Química Inorgánica, Facultad de Química, Universidad de la República, Montevideo, Uruguay.
Esteban Rodríguez
ER
Arce
Cátedra de Química Inorgánica, Facultad de Química, Universidad de la República, Montevideo, Uruguay.
Cynthia
C
Sarniguet
Centro de Química Estrutural, Faculdade de Ciências da Universidade de Lisboa, Portugal.
Tânia S
TS
Morais
Centro de Química Estrutural, Faculdade de Ciências da Universidade de Lisboa, Portugal.
Ana Isabel
AI
Tomaz
Departamento de Química Inorgánica y Analítica, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile.
Claudio Olea
CO
Azar
Departamento de Química Inorgánica y Analítica, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile.
Roberto
R
Figueroa
Programa de Farmacología Molecular y Clínica, ICBM, Facultad de Medicina, Universidad de Chile, Santiago, Chile.
J
J
Diego Maya
Institut Pasteur de Montevideo, Group Redox Biology of Trypanosomes, Montevideo, Uruguay; Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay.
Andrea
A
Medeiros
Institut Pasteur de Montevideo, Group Redox Biology of Trypanosomes, Montevideo, Uruguay.
Marcelo
M
Comini
Centro de Química Estrutural, Faculdade de Ciências da Universidade de Lisboa, Portugal.
M
M
Helena Garcia
Cátedra de Química Inorgánica, Facultad de Química, Universidad de la República, Montevideo, Uruguay. Electronic address: luotero@fq.edu.uy.
Lucía
L
Otero
Cátedra de Química Inorgánica, Facultad de Química, Universidad de la República, Montevideo, Uruguay. Electronic address: dgambino@fq.edu.uy.
Dinorah
D
Gambino
D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002522:Chlorocebus aethiops; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D009942:Organometallic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D012428:Ruthenium / Q000737:chemistry*; D013882:Thiosemicarbazones / Q000737:chemistry; D014346:Trypanosoma brucei brucei / Q000187:drug effects; D014349:Trypanosoma cruzi / Q000187:drug effects; D014709:Vero Cells
D000981:Antiprotozoal Agents; D009942:Organometallic Compounds; D013882:Thiosemicarbazones; D012428:Ruthenium
Ruthenium cyclopentadienyl compounds; Thiosemicarbazones; Trypanosoma brucei; Trypanosoma cruzi