Avaliação das propriedades química e citotóxicas de novos compostos organometálicos de Ru(II) com aciltioureias

Abstract

This thesis shows a study based on the synthesis, characterization and biological evaluation of 19 new organometallic Ru(II) complexes with acylthioureas. The complexes have general formula Ru(6-p-cymene)Cl(PPh3)Tu]PF6 e [Ru(6-p-cymene)(PPh3)Tu]PF6 where PPh3= triphenylphosphine and Tu= N-(methylfuroyl)-N’-2-furoylthiourea (1 e 1a); N-(methyltiophenyl)-N-2-tiophenylthiourea (2); N-(methylfuroyl)-N’-2-furoyltiourea; N-(methylfuroyl)-N’-2-tiophenylthiourea (3); N-(methyl-1,3-benzodioxolyl)-N’-2-furoylthiourea (4 e 4a); N-(methyl-1,3-benzodioxolyl)-N’-2-tiophenylthiourea (5); N,N-(dimethyl)-N’-benzoylthiourea (1m e 1b); N,N-(diethyl)-N’-benzoyltiourea (2m e 2b); N,N-(dimethyl)-N’-2-furoyltiourea (3m e 3b); N,N-(diethyl)-N’-2-furoyltiourea (4m e 4b); N,N-(dimethyl)-N’-2-tiophenylthiourea (5m e 5b); N,N-(diethyl)-N’-2-tiophenylthiourea (6m e 6b). Complexes characterization was carried out by elemental analysis, molar conductivity, absorption spectroscopy in infrared region, 31P {1H}, 1H e 13C {1H} nuclear magnetic resonance and single crystal X-ray diffraction. Three different coordination modes of the acylthiourea ligands, monodentate via S atom (1-5 e 1m-6m), bidentate via S and O atoms (1b-6b) or via S and N atoms (1a e 4a), were obtained from different synthetic routes. One of the synthetic routes base on hydrolysis reaction of monodentate complexes, which promotes the conversion of coordination mode of acylthioureas to bidentate. The cytotoxicity of the complexes was evaluated in breast (MDA-MB-231), lung (A549) and prostate (DU-145) human tumor cell lines and breast (MCF-10A) and lung (MRC-5) human nontumorigenic cell lines. IC50 values of the complexes 1-5, 1a e 4a, in A549 cells, which correspond the range from 0.25 to 0.61 M, after 48 h incubation, indicate a considerable cytotoxicity with values significantly lower than the reference drug, cisplatin (11.84 M). For the complexes 1m-6m e 1b-6b, the IC50 values in the prostate cell line (2.89-7.49 M), despite indicating cell proliferative inhibition, showed lower cytotoxicity than cisplatin (2.00 M). For breast (2.89-7.49 M), and lung (IC50= 0.51-1.83 M) cell lines, the complexes 1m-6m e 1b-6b were notably more active than cisplatin, as also showed expressive selectivity (IS= 4.66-19.34) toward breast tumor cell line. Base on both activity and selectivity, the complexes 1a, 5b e 6b, as well as their respective analogous complexes in monodentate coordination 1, 5m e 6m, were chosen to continuity of biological investigations in the breast (5m, 6m, 5b e 6b) and lung (1 e 1a) tumor cell lines. These complexes induced morphology changes in their respective cell lines, were able to inhibit the colony formation, and cell migration. In addition, the complexes promoted cell cycle arrest at Sub-G1 phase and induced apoptosis cell death. Interaction studies carried out by viscosity measurements, electrophoretic mobility and competitive assays suggest the interaction between the complexes and DNA is via minor groove. The complexes also showed high HSA protein affinity (Kb= 104-106). The competitive assay using dansylglycine indicates complexes interaction with HSA site II (subdomain IIIA).