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

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.

Newly Synthesized Heteronuclear Ruthenium(II)/Ferrocene Complexes Suppress the Growth of Mammary Carcinoma in 4T1-Treated BALB/c Mice by Promoting Activation of Antitumor Immunity

“…Tumor volumes (mm 3 ) were calculated as LW 2 /2, where L represents the major axis of the tumor, while W represents the minor axis. 57 Isolation of Tumor-Infiltrating Leukocytes. Primary 4T1 tumors were minced and placed in 5 mL of DMEM containing 1 mg/mL of collagenase I, 1 mM ethylenediaminetetraacetic acid (EDTA), and 2% FBS (all from Sigma-Aldrich) for enzymatic digestion.…”

“…Then, cells were pelleted by centrifuging 10 min at 450g, at 4 °C. 57 Isolation of Splenocytes. The isolation of splenocytes was conducted as previously described.…”

Cellular and Molecular Targets of Nucleotide-Tagged Trithiolato-Bridged Arene Ruthenium Complexes in the Protozoan Parasites Toxoplasma gondii and Trypanosoma brucei

“…Previously published in vitro studies have revealed that trithiolato-bridged dinuclear ruthenium(II)–arene complexes were effective against T. gondii [ 14 , 15 , 16 , 17 ], Neospora caninum [ 17 , 18 ], and T. brucei [ 19 ]. To improve the effectivity of these ruthenium complexes, their organic substituents have attracted special attention [ 20 ]. Since many parasites lack de novo synthesis pathways of essential metabolites and have therefore become auxotrophic [ 21 ], it is tempting to conjugate Ru(II) complexes with such metabolites.…”

Induction of Early Autophagic Process on Leishmania amazonensis by Synergistic Effect of Miltefosine and Innovative Semi-synthetic Thiosemicarbazone

“…Thiosemicarbazones derivatives have been exhibited a wide spectrum biological activity, such as antibacterial ( Viñuelas-Zahínos et al, 2011 ), antiprotozoa ( Chellan et al, 2010 ; Britta et al, 2012 , 2014 ; Fernández et al, 2015 ); and antitumor ( Ferraz et al, 2011 ). Triapine ® , the most famous thiosemicarbazone, have been studied in clinical trials for treat different diseases using distinct strategies, including the combination with another drug, according to U.S. National Institutes of Health 1 .…”