title: Ruthenium(II) complexes of 1,3-thiazolidine-2-thione: Cytotoxicity against tumor cells and anti-Trypanosoma cruzi activity enhanced upon combination with benznidazole.
abstract: Three new mixed and mononuclear Ru(II) complexes containing 1,3-thiazolidine-2-thione (tzdtH) were synthesized and characterized by spectroscopic analysis, molar conductivity, cyclic voltammetry, high-resolution electrospray ionization mass spectra and X-ray diffraction. The complexes presented unique stereochemistry and the proposed formulae are: [Ru(tzdt)(bipy)(dppb)]PF6 (1), cis-[Ru(tzdt)2(PPh3)2] (2) and trans-[Ru(tzdt)(PPh3)2(bipy)]PF6 (3), where dppb=1,4-bis(diphenylphosphino)butane and bipy=2,2'-bipyridine. These complexes demonstrated strong cytotoxicity against cancer cell lines when compared to cisplatin. Specifically, complex 2 was the most potent cytotoxic agent against MCF-7 breast cells, while complexes 1 and 3 were more active in DU-145 prostate cells. Binding of complexes to ctDNA was determined by UV-vis titration and viscosity measurements and revealed binding constant (Kb) values in range of 1.0-4.9×10(3)M(-1), which are characteristic of compounds possessing weak affinity to ctDNA. In addition, these complexes presented antiparasitic activity against Trypanosoma cruzi. Specifically, complex 3 demonstrated strong potency, moderate selectivity index and acted in synergism with the approved antiparasitic drug, benznidazole. Additionally, complex 3 caused parasite cell death through a necrotic process. In conclusion, we demonstrated that Ru(II) complexes have powerful pharmacological activity, while the metal-free tzdtH does not provoke the same outcome.
authors.affiliation: Departamento de Química, Universidade Federal de São Carlos, CP 676, CEP 13565-905 São Carlos, SP, Brazil; Departamento de Química, ICEB, Universidade Federal de Ouro Preto, CEP 35400-000 Ouro Preto, MG, Brazil. Electronic address: rodrigocorrea@iceb.ufop.br.
authors.forename: Rodrigo S
authors.initials: RS
authors.lastname: Corrêa
authors.affiliation: Departamento de Química, Universidade Federal de São Carlos, CP 676, CEP 13565-905 São Carlos, SP, Brazil.
authors.forename: Monize M
authors.initials: MM
authors.lastname: da Silva
authors.affiliation: Departamento de Química, Universidade Federal de São Carlos, CP 676, CEP 13565-905 São Carlos, SP, Brazil.
authors.forename: Angelica E
authors.initials: AE
authors.lastname: Graminha
authors.affiliation: Centro de Pesquisas Gonçalo Moniz, Fiocruz, CEP:40296-710 Salvador, BA, Brazil.
authors.forename: Cássio S
authors.initials: CS
authors.lastname: Meira
authors.affiliation: Centro de Pesquisas Gonçalo Moniz, Fiocruz, CEP:40296-710 Salvador, BA, Brazil.
authors.forename: Jamyle A F Dos
authors.initials: JA
authors.lastname: Santos
authors.affiliation: Centro de Pesquisas Gonçalo Moniz, Fiocruz, CEP:40296-710 Salvador, BA, Brazil.
authors.forename: Diogo R M
authors.initials: DR
authors.lastname: Moreira
authors.affiliation: Centro de Pesquisas Gonçalo Moniz, Fiocruz, CEP:40296-710 Salvador, BA, Brazil; Centro de Biotecnologia e Terapia Celular, Hospital São Rafael, Avenida São Rafael, 2152, São Marcos, CEP 41253-190 Salvador, BA, Brazil.
authors.forename: Milena B P
authors.initials: MB
authors.lastname: Soares
authors.affiliation: Instituto de Química, Universidade Federal de Uberlândia, CP 593, CEP 38400-902 Uberlândia, MG, Brazil.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Von Poelhsitz
authors.affiliation: Instituto de Física, Universidade de São Paulo, CP 369, CEP 13560-970 São Carlos, SP, Brazil.
authors.forename: Eduardo E
authors.initials: EE
authors.lastname: Castellano
authors.affiliation: Centro Nacional de Pesquisa de Recursos Genéticos e Biotecnologia, EMBRAPA, Estação Parque Biológico, CEP 70910-900 Brasília, DF, Brazil.
authors.forename: Carlos
authors.initials: C
authors.lastname: Bloch
authors.affiliation: Departamento de Gerontologia, Universidade Federal de São Carlos, CP 676, CEP 13565-905 São Carlos, SP, Brazil.
authors.forename: Marcia R
authors.initials: MR
authors.lastname: Cominetti
authors.affiliation: Departamento de Química, Universidade Federal de São Carlos, CP 676, CEP 13565-905 São Carlos, SP, Brazil. Electronic address: daab@ufscar.br.
authors.forename: Alzir A
authors.initials: AA
authors.lastname: Batista
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D061986:MCF-7 Cells; D017975:Ruthenium Compounds / Q000737:chemistry*; D053778:Thiazolidines / Q000737:chemistry*; D014349:Trypanosoma cruzi / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D000981:Antiprotozoal Agents; D017975:Ruthenium Compounds; D053778:Thiazolidines; C005104:2-mercaptothiazoline
keywords: 1,3-Thiazolidine-2-thione; Cytotoxicity; Ru(II) complexes; Trypanosoma cruzi; ctDNA-binding