Dinitrosilos de ferro contendo tiadiazol ou tiossemicarbazona derivada do cinamaldeído: síntese, caracterização e potencial aplicação antitumoral
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Data
2018-02-27
Autores
Zanetti, Renan Diego [UNESP]
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Universidade Estadual Paulista (Unesp)
Resumo
O câncer é, atualmente, uma das principais causas de morte no mundo. Além disto, tem-se observado crescente resistência celular à forma de tratamento utilizando radioterapia com uso de drogas. O sistema enzimático glutationa S transferases (GSTs), um dos responsáveis por essa resistência, catalisa a conjugação da glutationa com a cisplatina, que é um dos fármacos mais aplicados na terapia do câncer, restringindo sua ação. Neste contexto, foi proposto a utilização de dinitrosilos de ferro (DNIC – dinitrosyl iron complex) [(Fe(NO)2Ligante] como alternativa para diminuição da resistência celular à agentes antineoplásicos. DNICs são geralmente formados em células expostas a óxido nítrico (NO) e ligam-se às enzimas da família GST inibindo seu efeito contra drogas anticâncer. Assim, propôs-se desenvolver complexos do tipo [Fe(NO)2X] (X = tiossemicarbazona), em que X seria um ligante com potencial atividade antineoplásica. Estes ligantes seriam facilmente substituídos por grupos da cadeia lateral de aminoácidos da GSTs, proporcionando um possível sinergismo de inibição da enzima e liberação de agentes antineoplásicos. As tiossemicarbazonas foram sintetizadas a partir de cinamaldeído e tiossemicarbazidas correspondentes em meio etanólico e caracterizados por espectroscopia de absorção na região do infravermelho (IV), UV-Vis, ressonância magnética nuclear (RMN) de ¹H e ¹³C, espectrometria de massas e análise elementar, assim como seus produtos de ciclização testados. Os complexos foram obtidos a partir do precursor [Fe(CO)2(NO)2], preparado previamente, e as tiossemicarbazonas, em tetrahidrofurano (THF) e caracterizados por espectroscopia de absorção na região do infravermelho (IV) condutância molar e espectrometria de massas (MS).
Cancer is currently one of the leading causes of death in the world. In addition, increased cellular resistance to the form of treatment using radiation therapy with drug use has been observed. The enzymatic system glutathione S transferases (GSTs), one of the responsible for this resistance, catalyzes the conjugation of glutathione with cisplatin, which is one of the drugs most applied in cancer therapy, restricting its action. In this context, has been proposed the use of iron dinitrosyls (DNIC - dinitrosyl iron complex) [(Fe (NO ) 2 Ligand ] as an alternative to decrease the cellular resistance to antineopl astic agents. DNICs are generally formed in cells exposed to nitric oxide (NO) and bind to the enzymes of the GST f amily inhibiting their effect against anticancer drugs. Thus, it was proposed t o develop complexes of type [Fe(NO) 2 X] (X = thiosemicarbazone), where X would be a ligand with potential antineoplastic activity. These linkers would be readily substituted by GSTs amino acid side chain groups, providing a possible synergism of enzyme inhibition and release of antineoplastic agents. Thiosemicarbazones were synthesized from cinnamaldehyde and corresponding thiosemicarbazides in ethanolic medium and characterized by absorption spectroscopy in the infrared (IR), UV - Vis region, ¹H and ¹ ³C nuclear magnetic resonance (NMR), mass sp ectrometry and elemental analysis , as well as their tested cyclization products. The complexes were obtained from the pr eviously prepared precursor [Fe(CO) 2 (NO) 2 ] and the thiosemicarbazones, in tetrahydrofuran (THF) and characterized by absorption spectros copy in the infrared (IR) r egion molar conductance and mass spectrometry (MS).
Cancer is currently one of the leading causes of death in the world. In addition, increased cellular resistance to the form of treatment using radiation therapy with drug use has been observed. The enzymatic system glutathione S transferases (GSTs), one of the responsible for this resistance, catalyzes the conjugation of glutathione with cisplatin, which is one of the drugs most applied in cancer therapy, restricting its action. In this context, has been proposed the use of iron dinitrosyls (DNIC - dinitrosyl iron complex) [(Fe (NO ) 2 Ligand ] as an alternative to decrease the cellular resistance to antineopl astic agents. DNICs are generally formed in cells exposed to nitric oxide (NO) and bind to the enzymes of the GST f amily inhibiting their effect against anticancer drugs. Thus, it was proposed t o develop complexes of type [Fe(NO) 2 X] (X = thiosemicarbazone), where X would be a ligand with potential antineoplastic activity. These linkers would be readily substituted by GSTs amino acid side chain groups, providing a possible synergism of enzyme inhibition and release of antineoplastic agents. Thiosemicarbazones were synthesized from cinnamaldehyde and corresponding thiosemicarbazides in ethanolic medium and characterized by absorption spectroscopy in the infrared (IR), UV - Vis region, ¹H and ¹ ³C nuclear magnetic resonance (NMR), mass sp ectrometry and elemental analysis , as well as their tested cyclization products. The complexes were obtained from the pr eviously prepared precursor [Fe(CO) 2 (NO) 2 ] and the thiosemicarbazones, in tetrahydrofuran (THF) and characterized by absorption spectros copy in the infrared (IR) r egion molar conductance and mass spectrometry (MS).
Descrição
Palavras-chave
Complexos metálicos de transição, Câncer, Bases de Schif, Glutationa, Óxido nítrico