Complexos de Ru(II) contendo ligantes h?bridos de cumarina: s?ntese e avalia??o das atividades citot?xica e antibacteriana

• Ano de defesa: 2019
• Autor(a) principal: Almeida, Patr?cia Saraiva Vilas Boas de
• Orientador(a): Neves, Amanda Porto
• Banca de defesa: Lima, ?urea Echevarria Aznar Neves, Silva, Gustavo Bezerra da, Vargas, Maria Domingues, Scarpellini, Marciela
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Federal Rural do Rio de Janeiro
• Programa de Pós-Graduação: Programa de P?s-Gradua??o em Qu?mica
• Departamento: Instituto de Qu?mica
• País: Brasil
• Palavras-chave em Português: complexos de rut?nio; h?bridos de cumarina; atividade antitumoral; atividade antibacteriana
• Palavras-chave em Inglês: ruthenium complexes; coumarin; antitumor activity; antibacterial activity
• Área do conhecimento CNPq: Qu?mica
• Link de acesso: https://tede.ufrrj.br/jspui/handle/jspui/5210

Cancer and bacterial infections are diseases that cause a large number of deaths, and despite the existing treatments, drugs being less harmful to the patients and more active against resistant cells are still needed. Coumarin derivatives and several classes of Ru(II) complexes have been studied for their potential as antimicrobial and antitumor agents. For this reason, four novel coumarin-N-acylhydrazone hybrid ligands of the type (E)-7-(diethylamino)-N'-(4-R-benzylidene)-2-oxo-2H-chromene-3-carbohydrazide (HL2: R=H; HL3: R=Cl, HL4: R=Br, HL5: R= OCH3), were obtained from condensation reactions, using one hydrazide (7-(diethylamine)-2-oxo-2H-chromone-3-carbohydrazide, HL1) and different p-substituted aldehydes. Reactions between HL2-5 and cis-[RuCl2(DMSO)4] afforded the complexes trans-cis-[RuCl2(DMSO)2(HL2-5)], C2-5 (Ru(II)-Cl-DMSO class). Concomitantly, hydrolysis of the ligand occurred, resulting in the formation of the complex trans-cis-[RuCl2(DMSO)2(HL1)] C1, containing the hydrazide as ligand. Crystal structures of HL2, HL3 and the complexes C2-5 were determined by single crystal XRD, that revealed an E to Z isomerization of the coumarin-N-acylhydrazones upon coordination. Complexes C2-5 exhibited the Ru(II) atom in a distorted octahedral geometry, where the coumarin ligand is coordinated in the keto form through the hydrazone carbonyl and the iminic nitrogen. In an attempt to synthesize a second class of complexes, containing bipyridine as auxiliary ligand and charged, ([Ru(bipy)2(HLn)]PF6 -Ru(II)-bipy class), the reaction between HL2 and cis-[Ru(bipy)2Cl2] was carried out. However, possible hydrolysis of the ligand precluded the isolation of the desired complex. A similar methodology using cumarin-?-ketoester hybrids HL6-8 yielded the complexes of the Ru(II)-bipy class, [Ru(bipy)2(HL6-8)]PF6 C6-8. The XRD analysis of C7 shows the Ru(II) ion in a distorted octahedral environment with the ligand coordinated through the deprotonated ?-ketoester portion and two bypiridines in the coordination sphere. Antiproliferative evaluation of the compounds against tumor cell lines (4T1: murine mammary carcinoma and B16-F10: murine melanoma metastatic) and a non-tumor cell line (BHK-21: hamster kidney) showed that overall, the coumarin-N-acylhydrazone and coumarin-hydrazyde hybrids HL1-5 were more active than the complexes C1-5, where the IC50 (half of the maximum inhibitory concentration) values for the ligands were found in the range of 10.6 to 50.4 ?M and between 17.7, and 97.8 ?M for the complexes. On the other hand, the coumarin-?-ketoester ligands HL6-8 were inactive (IC50 > 100 ?M), yet the complexes C6-8 presented high cytotoxicity, with IC50 values ranging from 2.0 and 12.8 ?M. For the antimicrobial assays, HL1 was the only ligand active against one gram-negative bacteria strain, however its MIC was not determined within the studied concentrations. Among the complexes, all demonstrated activity only against gram-positive bacteria strains. Within the Ru(II)-Cl-DMSO series, only C3 and C4 (R = Cl and Br) exhibited MIC at the concentrations used (40.5 and 86 ?M). On the other hand, the complexes of the Ru(II)-bipy class C6-8 presented MIC between 2.20 and 9.22 ?M. Comparing the classes of complexes, Ru(II)-bipy and Ru(II)-DMSO, the higher activities presented by the former in both biological studies was attributed to the presence of charge and of bipyridine ligands. The investigation of DNA interaction of the complexes [Ru(bipy)2(HLn)]PF6 (C6-8) are in progress.