Síntese, caracterização e atividade biológica de ciclopaladados contendo o metil-éster da L-fenilalanina
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Data
2022-12-16
Autores
Badaró, Wladimir Pereira Duarte
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Editor
Universidade Estadual Paulista (Unesp)
Resumo
O câncer é uma das enfermidades que causam um grande número de mortes no mundo. De acordo com o INCA, o Brasil terá mais de 2 milhões de novos casos de câncer no triênio 2023-2025. Apesar dos grandes avanços no diagnóstico e tratamento da doença, o desenvolvimento de resistência frente aos fármacos continua sendo o principal fator limitante para a eficácia do tratamento de pacientes com câncer. Particularmente, os complexos metálicos surgem naturalmente como candidatos muito promissores pois são capazes de atuar em múltiplos alvos. Entretanto, os complexos de paládio (II) têm atraído considerável interesse pela sua ação citotóxica in vitro e in vivo contra vários tipos de células tumorais. Neste sentido, o presente trabalho objetiva sintetizar e caracterizar um novo complexo contendo o metil-éster da L-fenilalanina (L-Fame) ciclometalada de fórmula [Pd(C2,N-L-Fame)(Br)(L)] (L = 2,6-lutidina). O ciclopaladado foi preparado a partir da reação de clivagem do dímero precursor [Pd(C2,N-L-Fame)(Br)]2 e a 2,6-lutidina. Os compostos sintetizados foram caracterizados por análise elementar (CHN), espectroscopia vibracional no infravermelho (IV), ressonância magnética nuclear (RMN) de 1H e espectrometria de massas. O comportamento do complexo [Pd(C2,N-L-Fame)(Br)(L)] em solução foi estudado por RMN de ¹H, visando analisar se sua estrutura sofre alteração em condições semelhantes ao meio biológico. A ação citotóxica do complexo [Pd(C2,N-L-Fame)(Br)(L)] foi avaliada em um painel de linhagens de células tumorais humanas. Particularmente, o ciclopaladado demonstrou ser ativo contra células tumorais de ovário resistentes à cisplatina (A2780cis) e de mama triplo-negativo (MDA-MB-231), com valores de IC50 igual à 9,13 ± 0,25 e 6,04 ± 0,40 M, respectivamente. Considerando que o DNA é um alvo clássico dos fármacos à base de platina (II), estudos de interação entre o ciclopaladado e o ctDNA foram conduzidos. As bandas, negativa (244 nm) e positiva (276 nm) do espectro de dicroísmo circular do ctDNA não sofreram alterações com o aumento da concentração do ciclopaladado, sugerindo que a conformação do ctDNA sofre pouca ou nenhuma alteração na presença do complexo. Além disso, o aumento da concentração do ciclopaladado não foi capaz de causar a supressão da fluorescência do aduto Hoescht 33258-ctDNA, indicando que as forças que mantém o Hoescht 33258 ligado ao DNA são significativamente mais fortes em relação àquelas estabelecidas pelo ciclopaladado.
Cancer is one of the diseases that cause a large number of deaths in the world. According to INCA, Brazil will have more than 2 million new cases of cancer in the three-year period 2023-2025. Despite the great advances in the diagnosis and treatment of the disease, the development of drug resistance remains the main limiting factor for the effectiveness of the treatment of cancer patients. Particularly, metal complexes emerge as very promising candidates, as they are capable of acting on multiple targets. Particularly, palladium(II) complexes have attracted considerable interest due to their in vitro and in vivo cytotoxic action against various types of tumor cells. In this sense, the present work aims to synthesize and characterize a new complex containing the cyclometallated L-phenylalanine (L-Fame) methyl ester with formula [Pd(C2,N-L-Fame)(Br)(L)] (L = 2 ,6-lutidine). The cyclopalladated compound was obtained from the reaction between the precursor [Pd(C2,N-L-Fame)(Br)]2 and 2,6- lutidine. The synthesized compound was characterized by elemental analysis (CHN), vibrational infrared (IR) spectroscopy, ¹H nuclear magnetic resonance (NMR) and mass spectrometry. The behavior of the complex [Pd(C2,N-L-Fame)(Br)(L)] in solution was studied by ¹H NMR aiming at analyzing structure changes under conditions similar to the biological environment. The cytotoxicity of the [Pd(C2,N-L-Fame)(Br)(L)] complex was evaluated in a panel of human tumor cell lines. Complex [Pd(C2,N-L- Fame)(Br)(L)] demonstrated to be active against cisplatin-resistant ovarian (A2780cis) and triple-negative breast (MDA-MB-231) tumor cells, with IC50 values equal to 9.13 ± 0.25 and 6.04 ± 0.40 M, respectively. Considering that DNA is a classic target of platinum(II)-based drugs, studies between [Pd(C2,N-L-Fame)(Br)(L)] and ctDNA were carried out. Circular dichroism spectrum showed that the negative (244 nm) and positive (276 nm) bands of the ctDNA did not change with increasing [Pd(C2,N-L- Fame)(Br)(L)] concentration, suggesting that the ctDNA conformation undergoes little or no change in the presence of the complex. Furthermore, increasing the concentration of [Pd(C2,N-L-Fame)(Br)(L)] was able to induce a fluorescence quenching of the Hoescht 33258-ctDNA adduct, indicating that the [Pd(C2,N-L- Fame)(Br)(L)] interacts weakly with DNA.
Cancer is one of the diseases that cause a large number of deaths in the world. According to INCA, Brazil will have more than 2 million new cases of cancer in the three-year period 2023-2025. Despite the great advances in the diagnosis and treatment of the disease, the development of drug resistance remains the main limiting factor for the effectiveness of the treatment of cancer patients. Particularly, metal complexes emerge as very promising candidates, as they are capable of acting on multiple targets. Particularly, palladium(II) complexes have attracted considerable interest due to their in vitro and in vivo cytotoxic action against various types of tumor cells. In this sense, the present work aims to synthesize and characterize a new complex containing the cyclometallated L-phenylalanine (L-Fame) methyl ester with formula [Pd(C2,N-L-Fame)(Br)(L)] (L = 2 ,6-lutidine). The cyclopalladated compound was obtained from the reaction between the precursor [Pd(C2,N-L-Fame)(Br)]2 and 2,6- lutidine. The synthesized compound was characterized by elemental analysis (CHN), vibrational infrared (IR) spectroscopy, ¹H nuclear magnetic resonance (NMR) and mass spectrometry. The behavior of the complex [Pd(C2,N-L-Fame)(Br)(L)] in solution was studied by ¹H NMR aiming at analyzing structure changes under conditions similar to the biological environment. The cytotoxicity of the [Pd(C2,N-L-Fame)(Br)(L)] complex was evaluated in a panel of human tumor cell lines. Complex [Pd(C2,N-L- Fame)(Br)(L)] demonstrated to be active against cisplatin-resistant ovarian (A2780cis) and triple-negative breast (MDA-MB-231) tumor cells, with IC50 values equal to 9.13 ± 0.25 and 6.04 ± 0.40 M, respectively. Considering that DNA is a classic target of platinum(II)-based drugs, studies between [Pd(C2,N-L-Fame)(Br)(L)] and ctDNA were carried out. Circular dichroism spectrum showed that the negative (244 nm) and positive (276 nm) bands of the ctDNA did not change with increasing [Pd(C2,N-L- Fame)(Br)(L)] concentration, suggesting that the ctDNA conformation undergoes little or no change in the presence of the complex. Furthermore, increasing the concentration of [Pd(C2,N-L-Fame)(Br)(L)] was able to induce a fluorescence quenching of the Hoescht 33258-ctDNA adduct, indicating that the [Pd(C2,N-L- Fame)(Br)(L)] interacts weakly with DNA.
Descrição
Palavras-chave
Câncer, Paládio, Fenilalanina, DNA, Citotoxicidade