Compostos N,S-quelantes de paládio(II) contendo fosfinas:síntese, citotoxicidade e interação com biomoléculas

Abstract

Desde a descoberta da atividade anticâncer da cisplatina há 40 anos, tem havido um interesse crescente no campo da quimioterapia baseada em complexos metálicos, buscando novos compostos de coordenação com atividade antitumoral aprimorada e redução dos efeitos adversos da cisplatina. Entre os compostos à base de metal estudados, os derivados de paládio atraíram considerável atenção devido à semelhança com a química de coordenação da platina. Este trabalho descreve a síntese dos complexos [PdCl(TSCZ)(PPh3)]Cl(1), [PdBr(TSCZ)(PPh3)]Cl (2), [PdI(TSCZ)(PPh3)]Cl (3), [PdSCN(TSCZ)(PPh3)]Cl (4), [PdCl(FMTSC)(PPh3)]Cl (5), [PdCl(FMTSC)(tfpp)]Cl (6), [PdCl(FMTSC)(tmf)]Cl (7), [PdCl(FMTSC)(tpf)]Cl (8), [PdCl(FMTSC)(dpt)]Cl (9), [PdCl(FMTSC)(PCy3)]Cl (10) e PdCl(FMTSC)(PPh2Pr)]Cl (11), em que TSCZ = tiossemicarbazida; FMTSC = N-metil-2-[4-(4-hidroxifenil)butan-2-ilideno]hidrazina-1-carbotioamida, PPh3= trifenilfosfina; tfpp = tris(4-fluorofenil)fosfina; tmf = tris(4-metoxifenil)fosfina, tpf = tris(4-metil)fosfina, dpt = 4-metildifenilfosfina, PPh2Pr = difenilpropilfosfina, PCy3= triciclohexilfosfina. Todos os complexos foram isolados e caracterizados por análise elementar, medidas de condutividade molar, espectroscopia no infravermelhoeressonância magnética nuclear 1D e 2D. Os resultados espectroscópicos evidenciaram a coordenação do liganteTSCZ ou FMTSC de modo neutro N,S-bidentado. A estrutura molecular e cristalina dos compostos 1 e 4 foi confirmada por difração de raio X de monocristal. A estabilidade química dos complexos nas soluções DMSO-d6, DMSO-d6:D2O e DMSO-d6:D2O:fosfato foi avaliada antes dos ensaios citotóxicos.Os complexos (1-10) tiveram sua atividade antiproliferativa,in vitro,investigada contra a linha celular de adenocarcinoma de mama humano (MCF-7), mostrandoresultados de IC50na faixa de 16,22-30,21 μM. Todos os complexos foramcerca de 2 vezes mais ativos que a cisplatina contra a linha celular MCF-7. Ensaios deinteraçãocom o DNA envolvendo alguns complexos representativos foram realizadas por espectroscopia UV-vis, dicroísmo circular e experimentosde ligação competitivas com Hoechst 33258. As propriedades de ligação doscompostos representativos na albumina sérica humana (HSA) foram estudadas por espectroscopia de fluorescênciae dicroísmo circular.

Since the discovery of the anticancer activity of cisplatin 40 years ago, there has been a growing interest in the field of chemotherapy based on metal complexes, searching for new coordination compounds with enhanced antitumor activity and reduced adverse effects than cisplatin. Among the metalbased compounds studied, palladium derivatives have attracted considerable attention due to the similarity with the coordination chemistry of platinum. This work describes the synthesis of the complexes [PdCl(TSCZ)(PPh3)]Cl (1), [PdBr(TSCZ)(PPh3)]Cl (2), [PdI(TSCZ)(PPh3)]Cl (3), [PdSCN(TSCZ)(PPh3)]Cl (4), [PdCl(FMTSC)(PPh3)]Cl (5), [PdCl(FMTSC)(tfpp)]Cl (6), [PdCl(FMTSC)(tmf)]Cl (7), [PdCl(FMTSC)(tpf)]Cl (8), [PdCl(FMTSC)(dpt)]Cl (9), [PdCl(FMTSC)(PCy3)]Cl (10) and PdCl(FMTSC)(PPh2Pr)]Cl (11), where TSCZ = thiosemicarbazide; FMTSC = N-methyl-2-[4-(4-hydroxyphenyl)butan-2-ylidene]hydrazine-1-carbothioamide, PPh3= triphenylphosphine; tfpp = tris(4-fluorophenyl)phosphine; tmf = tris(4-methoxyphenyl)phosphine, tpf = tris(4-methyl)phosphine, dpt = 4-methyldiphenylphosphine, PPh2Pr = diphenylpropylphosphine, PCy3= triciclohexylphosphine. All complexes were isolated, and characterized by elemental analysis, molar conductivity measurements, IR spectroscopy, 1D and 2D nuclear magnetic resonance. IR and NMR spectroscopic results evidenced the coordination of the TSCZ or FMTSC ligand in a neutral N,S-bidentate mode. The molecular and crystal structure of compounds 1 and 4 were confirmed by single crystal X-raydiffraction determination. The chemical stability of the complexes in DMSO-d6, DMSO-d6:D2O and DMSO-d6:D2O:phosphate buffer solutions was evaluated prior to cytotoxic assays. The complexes (1-10) had their in vitro antiproliferative activity investigatedagainst human breast adenocarcinoma (MCF-7) cell line, showing IC50results in the range of 16.22-30.21 μM.All complexes were about 2-fold more active than cisplatin against MCF-7 cell line. DNA binding experiments involving some representative palladiumcomplexes were carried out by means of UV-Vis spectroscopy, circular dichroism, and competitive binding experiments with Hoechst 33258. The binding properties of representative compounds on human serum albumin (HSA) were studied by fluorescence spectroscopyand circular dichroism.