Investigação estrutural e potencialidades biológicas de espécies ciclopaladadas contendo o ligante 2,6-lutidina
Carregando...
Data
2017-03-03
Autores
Cunha, Gislaine Aparecida da [UNESP]
Título da Revista
ISSN da Revista
Título de Volume
Editor
Universidade Estadual Paulista (Unesp)
Resumo
O presente trabalho teve como objetivo sintetizar e caracterizar estruturalmente compostos ciclopaladados motivado pela possível aplicação dos mesmos como fármacos antitumorais. Os complexos foram sintetizados utilizando como precursores os compostos [Pd(S(-)-C2,N-dmpa)(Cl)]2 (1) {S(-)-C2,N-dmpa = S(-)N,N-dimetil-1-feniletilamina} e [Pd(C2,N-dmba)(Cl)]2, (6) {C2,N-dmba = N,N-dimetilbenzilamina) dos quais foram obtidos os dímeros [Pd(S(-)-C2,N-dmpa)(X)] (X = I 2, N3 3, NCS 4 e NCO 5) e [Pd(C2,N-dmba)(X)]2 (X = I 7, N3 8, e NCO 9) pela reação com os sais KI, NaN3, KNCS e KNCO, respectivamente. Estes dímeros foram clivados com o ligante 2,6-lutidina obtendo-se os compostos [Pd(S(-)-C2,N-dmpa)(X)(luti)] (X = Cl 10, I 11, N3 12 e NCO 13) e [Pd(C2,N-dmba)(X)(luti)] (X = Cl 14, I 15, N3 16, e NCO 17). As suas estruturas foram propostas com base em medidas de análise elementar, espectroscopia vibracional na região do infravermelho, espectroscopia de RMN e por difração de raios X em monocristal. As espécies 1-5, 10, 12, 13, 14, 15 e 17 tiveram seus comportamentos térmicos investigados por termogravimetria e análise térmica diferencial. Os ciclopaladados 10-13 tiveram seus efeitos citotóxicos avaliados frente às linhagens de glioblastomas U251 e T98G e de melanomas humanos HT144 e LB737 MEL. Os compostos 14-17 foram testados frente às linhagens celulares de melanoma murino B16F10-Nex2, melanoma humano A2058, Skmel-10 e Skmel-05, de carcinoma murino de mama 4T1. Estas linhagens de células representam modelos de tumores extremamente agressivos, evidenciando que os resultados da citotoxicidade in vitro dos compostos apresentam potencial para estudos biológicos mais aprofundados. A cisplatina — fármaco antitumoral inorgânico, empregado em aproximadamente 50% de todos os tratamentos de câncer — foi utilizada como padrão para fins de comparação. Os valores de IC50 (Concentração que inibe 50% do crescimento celular) mostraram que os compostos [Pd(S(-)-C2,N-dmpa)(X)(luti)] (X = Cl 10, I 11, N3 12 e NCO 13) foram tão citotóxicos quanto a cisplatina; e os compostos [Pd(C2,N-dmba)(X)(luti)] (X = Cl 14, I 15, N3 16, e NCO 17) foram mais citotóxicos que a cisplatina, sendo cerca de 100 vezes mais ativos que a cisplatina. Além disso, foi realizado ensaio hemolítico para verificar a capacidade dos compostos em provocar hemólise em células sanguíneas saudáveis. E o estudo de interação com DNA indicou que houve interação dos complexos 14-17 com a molécula do DNA. A capacidade dos complexos em inibir o crescimento dos bacilos Mycobacterium tuberculosis, foi avaliada e os valores de CIM (concentração inibitória mínima) obtidos indicaram que em relação a pirazinamida os complexos 10 - 13 foram aproximadamente 12 vezes mais ativo.
The presente study aimed to synthesize and characterize structurally cyclopalladated compounds motivated by their possible applications as antitumor drugs. The complexes were synthesized using as precursors the compounds [Pd(S(-)-C2,N-dmpa)(Cl)]2 (1) {S(-)-C2,N-dmpa = S(-)N,N-dimethyl-1-phenethylamine} e [Pd(C2,N-dmba)(Cl)]2, (6) {C2,N-dmba = N,N-dimethylbenzylamine} which were obtained [Pd(S(-)-C2,N-dmpa)(X)] (X = I 2, N3 3, NCS 4 e NCO 5) e [Pd(C2,N-dmba)(X)]2 (X = I 7, N3 8, e NCO 9) dimers by reaction with the salts KI, NaN3, KNCS e KNCO, respectivelly. These dimers were cleaved with 2,6-lutidine ligand producing [Pd(S(-)-C2,N-dmpa)(X)(luti)] (X = Cl 10, I 11, N3 12 e NCO 13) e [Pd(C2,N-dmba)(X)(luti)] (X = Cl 14, I 15, N3 16, e NCO 17). Their structures were proposed based on measurements of elemental analysis, infrared and NMR spectroscopy and X-ray diffraction on single crystal. The thermal behavior of compounds 1-5, 10, 12, 13, 14, 15 and 17 was studied by thermogravimetry and differential thermal analysis. The cytotoxicity effects of the cyclopalladated 10-13 were carried out using tumor cell lines glioblastoma (U251 and T98G) and human melanoma (HT144 and LB737 MEL). The compounds 14-17 were tested against tumor cell lines murine melanoma (B16F10-Nex2), human melanoma A2058, Skmel-10 and Skmel-05, and mammary carcinoma murine 4T1. These cell lines represent extremely aggressive tumor models, showing the in vitro cytotoxicity results of the compounds have potential for more detailed biological studies. The cisplatin — inorganic antitumor drug has been used in 50% of cancer tratament, were used as standart. The IC50 (concentration that inhibits 50% of cell growth) values showed that the compounds [Pd(S(-)-C2,N-dmpa)(X)(luti)] (X = Cl 10, I 11, N3 12 e NCO 13) are as cytotoxic as cisplatin; in contrast the compounds [Pd(C2,N-dmba)(X)(luti)] (X = Cl 14, I 15, N3 16, e NCO 17) are more cytotoxic than cisplatin, being about one hundred times more active. Forthermore, was investigated their ability to cause hemolysis in healthy blood cells. The interaction DNA study reveals interactions of the compounds 14-17 with DNA molecule. The ability of the complexes to inhibit the growth of Mycobacterium tuberculosis bacilli was evaluated and MIC (minimum inhibitory concentration) values obtained indicate that in relation to pyrazinamide the complexes 10-13 were approximately 12 times more active.
The presente study aimed to synthesize and characterize structurally cyclopalladated compounds motivated by their possible applications as antitumor drugs. The complexes were synthesized using as precursors the compounds [Pd(S(-)-C2,N-dmpa)(Cl)]2 (1) {S(-)-C2,N-dmpa = S(-)N,N-dimethyl-1-phenethylamine} e [Pd(C2,N-dmba)(Cl)]2, (6) {C2,N-dmba = N,N-dimethylbenzylamine} which were obtained [Pd(S(-)-C2,N-dmpa)(X)] (X = I 2, N3 3, NCS 4 e NCO 5) e [Pd(C2,N-dmba)(X)]2 (X = I 7, N3 8, e NCO 9) dimers by reaction with the salts KI, NaN3, KNCS e KNCO, respectivelly. These dimers were cleaved with 2,6-lutidine ligand producing [Pd(S(-)-C2,N-dmpa)(X)(luti)] (X = Cl 10, I 11, N3 12 e NCO 13) e [Pd(C2,N-dmba)(X)(luti)] (X = Cl 14, I 15, N3 16, e NCO 17). Their structures were proposed based on measurements of elemental analysis, infrared and NMR spectroscopy and X-ray diffraction on single crystal. The thermal behavior of compounds 1-5, 10, 12, 13, 14, 15 and 17 was studied by thermogravimetry and differential thermal analysis. The cytotoxicity effects of the cyclopalladated 10-13 were carried out using tumor cell lines glioblastoma (U251 and T98G) and human melanoma (HT144 and LB737 MEL). The compounds 14-17 were tested against tumor cell lines murine melanoma (B16F10-Nex2), human melanoma A2058, Skmel-10 and Skmel-05, and mammary carcinoma murine 4T1. These cell lines represent extremely aggressive tumor models, showing the in vitro cytotoxicity results of the compounds have potential for more detailed biological studies. The cisplatin — inorganic antitumor drug has been used in 50% of cancer tratament, were used as standart. The IC50 (concentration that inhibits 50% of cell growth) values showed that the compounds [Pd(S(-)-C2,N-dmpa)(X)(luti)] (X = Cl 10, I 11, N3 12 e NCO 13) are as cytotoxic as cisplatin; in contrast the compounds [Pd(C2,N-dmba)(X)(luti)] (X = Cl 14, I 15, N3 16, e NCO 17) are more cytotoxic than cisplatin, being about one hundred times more active. Forthermore, was investigated their ability to cause hemolysis in healthy blood cells. The interaction DNA study reveals interactions of the compounds 14-17 with DNA molecule. The ability of the complexes to inhibit the growth of Mycobacterium tuberculosis bacilli was evaluated and MIC (minimum inhibitory concentration) values obtained indicate that in relation to pyrazinamide the complexes 10-13 were approximately 12 times more active.
Descrição
Palavras-chave
Paládio, Química bioinorgânica, Síntese, Citotoxicidade, Tuberculose