Planejamento estrutural, modelagem molecular e síntese de complexos de cobre (ii) como potenciais inibidores da topoisomerase ii alfa humana
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Data
2021-03-05
Autores
Vieira, Marcelle Alcântara
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Universidade Estadual Paulista (Unesp)
Resumo
O câncer é considerado uma das principais causas de morte no mundo. É compreendido por mais de cem doenças que possuem características comuns, como a rápida proliferação celular e angiogênese. Embora haja fármacos disponíveis para o tratamento de diversos tipos de câncer, esses apresentam seletividade limitada e são consideravelmente tóxicos também para as células saudáveis. Compostos contendo platina, como cisplatina, estão entre os mais usados em quimioterapia, porém, podem resultar em resistência adquirida pelas células tumorais. Sendo assim, tem-se buscado o desenvolvimento de novos compostos que usem metais essenciais, que possam apresentar alto grau de seletividade, que não se liguem covalentemente ao DNA e com menor toxicidade para as células saudáveis. Neste contexto, o cobre, por estar presente no organismo, é biocompatível, o que pode o tornar potencialmente menos tóxico para as células saudáveis. Os complexos de cobre (II) com tiossemicarbazonas são investigados como metalofármacos para várias aplicações medicinais, incluindo seu uso como agentes anticâncer, onde seu mecanismo de ação é dado pela inibição da topoisomerase IIα humana. As topoisomerases são alvos das substâncias com atividade antitumoral, pois são enzimas essenciais que gerenciam o estado estrutural do DNA. A topoisomerase IIα humana (TOP IIα) é altamente expressa em muitas células tumorais, o que a torna um dos principais alvos das substâncias com atividade anticâncer. Neste projeto, foram planejados 180 complexos de cobre (II) tendo como ligantes tissemicarbazonas e isatinas. Inicialmente, foi realizada a validação de modelos in silico da topoisomerase IIα nos sítios do ATP e do etoposídeo, por redocagem. Em seguida, para ambos os sítios, foram ancorados compostos descritos na literatura encontradas no ChEMBL com atividade in vitro comprovada no sítio do ATP e no sitio do etoposídeo. As interações dos ligantes com os resíduos de aminoácidos do sítio ativo foram analisadas, sistematicamente com os resíduos de tirosina 805 (Y805), metionina 766 (M766) e a metionina 762 (M762) para o sitio do etoposídeo e lisina 378 (K378) e asparagina 150 (N150) para o sítio do ATP. Na sequência, através da triagem virtual por ancoragem molecular das estruturas planejadas, foi possível selecionar, dentre 180 complexos de cobre (II), os 20 mais promissores para a etapa de síntese. A rota de síntese foi aplicada para a obtenção de um dos complexos que apresentava maior viabilidade sintética, o complexo (426) obtido foi o (Z)-2-(1-(2- morfolinoetil)-2-oxoindolin-3-ilideno)-N-fenil-hidrazina-1- carbotioamidato)clorocobre(II), sendo que o não foi observado a troca de ligante entre o cloridro e a trifenilfosfina para obtenção do complexo 1 (70).
Cancer is one of the leading causes of death in the world. It comprises of more than one hundred diseases that have common characteristics, such as rapid cell proliferation and angiogenesis. Although drugs are available for the treatment of several types of cancer, they have limited selectivity and are toxic to healthy cells. Platinum compounds, such as cisplatin, are among the most used in chemotherapy, however, they can result in resistance acquired by tumor cells. Therefore, the development of novel compounds that use essential metals can present a high degree of selectivity, no covalently bond with DNA, and reduced toxicity in normal cells, has been researched. In this context, copper, as it is present in the body, is biocompatible, which can potentially make it less toxic to healthy cells. Copper (II) complexes with thiosemicarbazones are studied by medicinal chemists for several applications, including their use as anti-cancer agents, where their mechanism of action is given by the inhibition of human topoisomerase IIα. Topoisomerases are targets of compounds with antitumor activity, as they are essential enzymes that play a role in the structural state of DNA. Human topoisomerase IIα (TOP IIα) is highly expressed in many tumor cells, making it one of the main targets of substances with anticancer activity. In this project, 180 copper (II) complexes were designed with thiosemicarbazones and isatins as ligands. First of all, the validation of topoisomerase IIα through in silico models at the ATP and etoposide sites was carried out by redocking. Then, for both sites, compounds described in the literature found in the ChEMBL with proven in vitro activity at the ATP site and the etoposide site were docked. The analysis of the interactions between the ligands and the key amino acid residues of the active site were systematically performed, highlighting tyrosine 805 (Y805), methionine 766 (M766), and methionine 762 (M762) present in most of the interactions for the etoposide site. Also, lysine 378 (K378) and asparagine 150 (N150) were frequently observed in interactions for the ATP site. Subsequently, through the virtual screening by molecular docking, it was possible to select, among 180 copper (II) complexes, the 20 most promising for the synthesis step. The synthesis route was applied to obtain one of the complexes that had greater synthetic viability, the complex (426) obtained was (Z) -2- (1- (2-morpholinoethyl) -2-oxoindolin-3-ylidene) -N-phenylhydrazine-1-carbothioamidate) chlorocopper (II), and the ligand exchange between hydrochloride and triphenylphosphine was not observed to obtain complex 1 (70).
Cancer is one of the leading causes of death in the world. It comprises of more than one hundred diseases that have common characteristics, such as rapid cell proliferation and angiogenesis. Although drugs are available for the treatment of several types of cancer, they have limited selectivity and are toxic to healthy cells. Platinum compounds, such as cisplatin, are among the most used in chemotherapy, however, they can result in resistance acquired by tumor cells. Therefore, the development of novel compounds that use essential metals can present a high degree of selectivity, no covalently bond with DNA, and reduced toxicity in normal cells, has been researched. In this context, copper, as it is present in the body, is biocompatible, which can potentially make it less toxic to healthy cells. Copper (II) complexes with thiosemicarbazones are studied by medicinal chemists for several applications, including their use as anti-cancer agents, where their mechanism of action is given by the inhibition of human topoisomerase IIα. Topoisomerases are targets of compounds with antitumor activity, as they are essential enzymes that play a role in the structural state of DNA. Human topoisomerase IIα (TOP IIα) is highly expressed in many tumor cells, making it one of the main targets of substances with anticancer activity. In this project, 180 copper (II) complexes were designed with thiosemicarbazones and isatins as ligands. First of all, the validation of topoisomerase IIα through in silico models at the ATP and etoposide sites was carried out by redocking. Then, for both sites, compounds described in the literature found in the ChEMBL with proven in vitro activity at the ATP site and the etoposide site were docked. The analysis of the interactions between the ligands and the key amino acid residues of the active site were systematically performed, highlighting tyrosine 805 (Y805), methionine 766 (M766), and methionine 762 (M762) present in most of the interactions for the etoposide site. Also, lysine 378 (K378) and asparagine 150 (N150) were frequently observed in interactions for the ATP site. Subsequently, through the virtual screening by molecular docking, it was possible to select, among 180 copper (II) complexes, the 20 most promising for the synthesis step. The synthesis route was applied to obtain one of the complexes that had greater synthetic viability, the complex (426) obtained was (Z) -2- (1- (2-morpholinoethyl) -2-oxoindolin-3-ylidene) -N-phenylhydrazine-1-carbothioamidate) chlorocopper (II), and the ligand exchange between hydrochloride and triphenylphosphine was not observed to obtain complex 1 (70).
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Palavras-chave
Química medicinal, Inibidores enzimáticos, Câncer, Estudos de validação, Compostos de cobre