title: Screening organometallic binuclear thiosemicarbazone ruthenium complexes as potential anti-tumour agents: cytotoxic activity and human serum albumin binding mechanism.
abstract: Four complexes combining the {Ru(p-cym)} moiety (p-cym = para-cymene) with thiosemicarbazone (TSC) ligands containing the 5-nitrofuryl pharmacophore were investigated in vitro for their properties as prospective anti-tumour agents. The compounds are dimeric structures of general formula [Ru2(p-cym)2(L)2]X2 where X = Cl(-), PF6(-) and L = deprotonated 5-nitrofuraldehyde TSC (L1), and the N-methyl (L2), N-ethyl (L3) and N-phenyl (L4) derivatives. The precursor [RuCl2(p-cym)]2, all TSC ligands L1-L4and their corresponding complexes 1-4 were screened in vitro for their cytotoxicity against a range of human cancer cell lines (HL-60 acute promyelocytic leukemia, A2780 ovarian adenocarcinoma, MCF7 breast adenocarcinoma and PC3 grade IV prostate carcinoma). While the precursor complex was found to be inactive and L4 exhibited moderate activity only in the MCF7 cell line, the coordination of L4 to the {Ru(p-cym)} moiety remarkably enhanced the activity of the whole complex. In fact, complex 4 [Ru2(p-cym)2(L4)2]Cl2 was found to be the most active agent of the whole series, and was studied further (as well as complex 1 for comparison). Concerning the mode of action, the mechanism of cell death for both 1 and 4 seemed to be related to apoptotic processes, and they strongly interacted with tubulin (involved in the cell cycle) and with integrin (involved in the cytoskeleton formation). As an approach to their pharmacokinetics, the interaction of 1 and 4 with human serum albumin (HSA) was assessed. A quantitative model for the binding of 4 to HSA is proposed from Circular Dichroism data, and validated by fluorescence results. Models of Förster resonance energy transfer and fluorescence quenching afforded the distance of 4 to the lone Trp214 residue. Importantly, HSA binding enhanced the cytotoxicity of 4 and correlated well with the HSA binding data. Our results consistently indicate that [Ru2(p-cymene)2(L4)2]Cl2 is quite promising as a prospective metallodrug for cancer chemotherapy.
authors.affiliation: Cátedra de Química Inorgánica, Facultad de Química, Universidad de la República, 11800 Montevideo, Uruguay.
authors.forename: Bruno
authors.initials: B
authors.lastname: Demoro
authors.forename: Rodrigo F M
authors.initials: RF
authors.lastname: de Almeida
authors.forename: Fernanda
authors.initials: F
authors.lastname: Marques
authors.forename: Cristina P
authors.initials: CP
authors.lastname: Matos
authors.forename: Lucía
authors.initials: L
authors.lastname: Otero
authors.forename: João
authors.initials: J
authors.lastname: Costa Pessoa
authors.forename: Isabel
authors.initials: I
authors.lastname: Santos
authors.forename: Alejandra
authors.initials: A
authors.lastname: Rodríguez
authors.forename: Virtudes
authors.initials: V
authors.lastname: Moreno
authors.forename: Julia
authors.initials: J
authors.lastname: Lorenzo
authors.forename: Dinorah
authors.initials: D
authors.lastname: Gambino
authors.forename: Ana Isabel
authors.initials: AI
authors.lastname: Tomaz
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002942:Circular Dichroism; D056831:Coordination Complexes / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D019281:Dimerization; D018922:HL-60 Cells; D006801:Humans; D061986:MCF-7 Cells; D011485:Protein Binding; D012428:Ruthenium / Q000737:chemistry*; D012709:Serum Albumin / Q000737:chemistry / Q000378:metabolism*; D013882:Thiosemicarbazones / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D012709:Serum Albumin; D013882:Thiosemicarbazones; D012428:Ruthenium