Compostos de paládio(II) contendo tetralonaoxima ortometalada, tiossemicarbazona e fosfinas terciárias: síntese, estudo estrutural e avaliação da ação antitumoral
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Data
2022-02-24
Autores
Velasques, Jecika Maciel [UNESP]
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Universidade Estadual Paulista (Unesp)
Resumo
Os metalofármacos baseados em platina indubitavelmente configuram a contribuição mais relevante da área de Química Bioinorgânica ao desenvolvimento de fármacos antitumorais aplicados a tratamentos quimioterápicos. Ainda assim, a resistência intrínseca e adquirida por algumas linhagens, a ação inespecífica e por consequência, pouco eficiente destes fármacos desencadeiam uma série de efeitos colaterais severos, representando problemáticas altamente relevantes e que tem impulsionado a busca por moléculas alternativas mais eficazes. Neste contexto, complexos de Pd(II) tem sido apontados como promissores pela similaridade deste íon metálico com o íon Pt(II) e por em geral apresentarem menor toxicidade em comparação aos fármacos baseados em platina. Visando contribuir para a pesquisa destes compostos, o presente trabalho apresenta a síntese, caracterização e avaliação do perfil antitumoral de 2 novas séries de compostos de Pt(II) com fosfinas terciárias aromáticas: monômeros ciclopaladados de fórmula geral [PdCl(C2,N-tetrox)PR3] (JC1-4) e os complexos de Pd(II) de fórmula geral [PdCl(L1)PR3]Cl (J1-4), onde tetrox = tetralonaoxima, L1 = vanilina-morfolinaetiltiossemicarbazona e PR3 = trifenilfosfina, tri(p-toluil)fosfina, tris(4-fluorofenil)fosfina, tris(4-metóxifenil)fosfina. Os compostos sintetizados foram caracterizados pelas técnicas espectroscópicas de IV e RMN 1H, 13C{1H} e 31P{1H}, análise elementar (CHN) e DRX. Ensaios de inibição do radical DPPH demonstraram que o ligante L1 apresenta ação antioxidante moderada [IC50 49,7 µM] enquanto os complexos não apresentam atividade. Espectros de RMN 1H e 31P{1H} coletados em 0, 24 e 48 h evidenciaram a estabilidade dos complexos obtidos. A avaliação da ação antiproliferativa dos compostos frente as linhagens tumorais de mama (MCF-7, MDA-MB-231), pulmão (A549), próstata (DU-145) e não tumoral de pulmão (MRC-5) demonstrou que a família de ciclopaladados (JC1-4) exibiu melhores resultados frente a linhagem MCF-7 [IC50 19,22 a 26,33 µM], apresentando-se mais ativos em comparação a cisplatina [IC50 >50 µM]. Já a série de complexos J1-4, bem como o ligante L1 apresentaram ação elevada e seletiva frente a linhagem A549 [IC50 19,22 a 26,33 µM; SI 3,64 a 54]. Estudos espectroscópicos de interação demonstraram que ambas as séries de compostos interagem fracamente com o DNA, através de ligações de natureza não covalente, preferencialmente nas regiões de sulco. Complementarmente, ensaios de interação com HSA por fluorescência e cálculos de docking molecular demonstraram a habilidade da série de compostos ciclopaladados poderem ser transportados pela proteína na região do sítio DS1. Foram obtidos os valores de log D para o ligante L1 de 1,61±0,05 e para o complexo J1 1,52±0,08, denotando o perfil lipofílico desta série de compostos. A partir dos resultados observados, os complexos J1-4 foram considerados como mais promissores em comparação a série de monômeros JC1-4, demonstrando o papel farmacofórico do ligante L1. Ainda, com a similaridade na atividade inibitória apresentada dentre os compostos de ambas as séries pôdese propor que as fosfinas terciárias atuam como ligantes auxiliares.
Platinum-based compounds undoubtedly represent the most relevant contribution in the Bioinorganic area to the development of antitumor drugs applied to chemotherapy treatments. Although, the intrinsic and acquired resistance by some tumor cells, the nonspecific and, consequently, inefficient action of these drugs trigger severe side effects, representing great problems and which have driven the research for more effective molecules. In this context, Pd(II) complexes have been pointed out as promising because of the similarity of this metal ion with Pt(II) and displaying lower toxicity compared to platinum drugs. Aiming to contribute to the research of these compounds, this work presents the synthesis, characterization and evaluation of the antitumor profile of 2 new series of Pd(II) compounds bearing tertiary phosphines: mononuclear cyclopalladated compounds of the type [PdCl(C2,N-tetrox)(PR3)] (JC1-4) and Pd(II) complexes of the type [PdCl(L1)PR3]Cl (J1-4) where tetrox = tetraloneoxime, L1 = vanillinmorpholine-ethylthiosemicarbazone and PR3 = triphenylphosphine; tris(4- methylphenyl)phosphine; tris(4-fluorophenyl)phosphine, tris(4- methoxyphenyl)phosphine. The compounds have been characterized by elemental analyses, infrared (FT-IR) and 1H, 13C{1H} and 31P{1H}-NMR spectroscopies and single crystal X-ray diffraction. DPPH radical inhibition assays showed that the L1 has moderate antioxidant action [IC50 49.7 µM] while the complexes have no activity. 1H and 31P{1H}-NMR spectra collected at 0, 24 and 48 h showed the stability of the obtained complexes. The evaluation of the antiproliferative action of the compounds against breast (MCF-7, MDA-MB-231), lung (A549), prostate (DU-145) and non-tumor lung cell (MRC-5) demonstrated that the family of cyclopalladated (JC1-4) showed better results against MCF-7 cells [IC50 19.22 a 26.33 µM], being more active compared to cisplatin [IC50 > 50 µM]. The J1-4 complexes, as well as the L1, showed high and selective action against the A549 cells [IC50 19.22 a 26.33 µM; SI 3.64 a 54]. Interaction spectroscopic studies demonstrated that both series of compounds interact weakly with DNA, through non-covalent bonds, preferentially in the minor groove region. In addition, fluorescence spectroscopy assays and molecular docking calculations demonstrated the ability of the cyclopalladated compounds to be transported by HSA protein in the DS1 site. Log D values for L1 of 1.61±0.05 and for J1 of 1.52±0.08 denoting the lipophilic profile of this series of compounds. From the observed results, J1-4 complexes were considered as more promising compared to the JC1-4 monomers, demonstrating the pharmacophoric role of the L1. With the similarity in the inhibitory activity presented among the compounds of both series, it was possible to propose that tertiary phosphines act as auxiliary ligands.
Platinum-based compounds undoubtedly represent the most relevant contribution in the Bioinorganic area to the development of antitumor drugs applied to chemotherapy treatments. Although, the intrinsic and acquired resistance by some tumor cells, the nonspecific and, consequently, inefficient action of these drugs trigger severe side effects, representing great problems and which have driven the research for more effective molecules. In this context, Pd(II) complexes have been pointed out as promising because of the similarity of this metal ion with Pt(II) and displaying lower toxicity compared to platinum drugs. Aiming to contribute to the research of these compounds, this work presents the synthesis, characterization and evaluation of the antitumor profile of 2 new series of Pd(II) compounds bearing tertiary phosphines: mononuclear cyclopalladated compounds of the type [PdCl(C2,N-tetrox)(PR3)] (JC1-4) and Pd(II) complexes of the type [PdCl(L1)PR3]Cl (J1-4) where tetrox = tetraloneoxime, L1 = vanillinmorpholine-ethylthiosemicarbazone and PR3 = triphenylphosphine; tris(4- methylphenyl)phosphine; tris(4-fluorophenyl)phosphine, tris(4- methoxyphenyl)phosphine. The compounds have been characterized by elemental analyses, infrared (FT-IR) and 1H, 13C{1H} and 31P{1H}-NMR spectroscopies and single crystal X-ray diffraction. DPPH radical inhibition assays showed that the L1 has moderate antioxidant action [IC50 49.7 µM] while the complexes have no activity. 1H and 31P{1H}-NMR spectra collected at 0, 24 and 48 h showed the stability of the obtained complexes. The evaluation of the antiproliferative action of the compounds against breast (MCF-7, MDA-MB-231), lung (A549), prostate (DU-145) and non-tumor lung cell (MRC-5) demonstrated that the family of cyclopalladated (JC1-4) showed better results against MCF-7 cells [IC50 19.22 a 26.33 µM], being more active compared to cisplatin [IC50 > 50 µM]. The J1-4 complexes, as well as the L1, showed high and selective action against the A549 cells [IC50 19.22 a 26.33 µM; SI 3.64 a 54]. Interaction spectroscopic studies demonstrated that both series of compounds interact weakly with DNA, through non-covalent bonds, preferentially in the minor groove region. In addition, fluorescence spectroscopy assays and molecular docking calculations demonstrated the ability of the cyclopalladated compounds to be transported by HSA protein in the DS1 site. Log D values for L1 of 1.61±0.05 and for J1 of 1.52±0.08 denoting the lipophilic profile of this series of compounds. From the observed results, J1-4 complexes were considered as more promising compared to the JC1-4 monomers, demonstrating the pharmacophoric role of the L1. With the similarity in the inhibitory activity presented among the compounds of both series, it was possible to propose that tertiary phosphines act as auxiliary ligands.
Descrição
Palavras-chave
Complexos de Pd(II), Ciclopaladados, Tiossemicarbazonas, Oximas, Atividade antitumoral, Biomoléculas, Fosfinas terciárias, Atividade biológica