Computational studies, design and synthesis of Pd(II)-based complexes: Allosteric inhibitors of the Human Topoisomerase-II alpha

Autor(es):Mostrar menos -

Rocha, Fillipe V. ^[1] ; Farias, Renan L. ^[2] ; Lima, Mauro A. ^[1] ; Batista, Victor S. ^[3] ; Nascimento-Junior, Nailton M. ^[3] ; Garrido, Saulo S. ^[4] ; Leopoldino, Andrea M. ^[5] ; Goto, Renata N. ^[5] ; Oliveira, Adriano B. ^[6] ; Beck, Johannes ^[7] ; Landvogt, Christian ^[7] ; Mauro, Antonio E. ^[2] ; Netto, Adelino V. G. ^[2]

Afiliação do(s) autor(es)

^[1] UFSCar Univ Fed Sao Carlos, Dept Quim, Sao Carlos, SP - Brazil

^[2] UNESP Univ Estadual Paulista, Inst Quim, Dept Quim Geral & Inorgan, Araraquara - Brazil

^[3] UNESP Univ Estadual Paulista, Inst Quim, Dept Quim Organ, Araraquara - Brazil

^[4] UNESP Univ Estadual Paulista, Inst Quim, Dept Bioquim & Tecnol Quim, Araraquara - Brazil

^[5] Univ Sao Paulo, Dept Clin Anal Toxicol & Food Sci, Ribeirao Preto - Brazil

^[6] Univ Fed Sergipe, Dept Quim, Sao Cristovao - Brazil

^[7] Rheinische Friedrich Wilhelms Univ Bonn, Inst Anorgan Chem, Bonn - Germany

• Tipo de documento: Artigo Científico
• Fonte: Journal of Inorganic Biochemistry; v. 199, OCT 2019.
• Citações Web of Science: 7

Resumo

Herein, a robust docking protocol was developed by using a low-cost workflow to highlight the modulation at ATPase domain from Human Topoisomerase-Ha (TOP2A) towards four novel Pd(II)-complexes bearing N,S-donor ligands. In vitro TOP2A inhibition assay confirmed the ability of them to prevent the enzyme functions into concentration ranging at 6.25-25 mu M. These results exhibited more effectivity than anticancer agent etoposide (35 mu M) and merbarone (40-50 mu M). The compounds were screened via Resazurin assay against MCF-7, MDA-MB-231 (Human breast), DU-145 (Human prostate), A549 (Human lung) and Ca127 (Human tongue) tumor cell lines revealing great cytotoxic effects, primarily to MCF-7 (IC50 = 1.81-4.46 mu M). As well, 1-4 exhibited their selectivity index (SI) higher than cisplatin against HEK-293 (human kidney) normal cells, at least 11.6-fold = (SI1.4 = 1.4-5.0; Sl(cis) = 0.12). Further, Red Blood Cell hemolytic test suggested in vitro non-toxic character for compound 4, previously evaluated as the most effective TOP2A inhibitor. (AU)

• Processo FAPESP: 12/15486-3 - Compostos de Pd(II): síntese, citotoxicidade e investigação espectrofotométrica da interação com o DNA
• Beneficiário: Regina Celia Galvao Frem
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 16/17711-5 - Investigação do potencial antitumoral de compostos de paládio(ii) contendo ligantes ligantes ortometalados ou n,s-doadores
• Beneficiário: Adelino Vieira de Godoy Netto
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 13/20156-5 - Planejamento de novas tiossemicarbazonas e seus complexos de Cu(II) e Pd(II) como inibidores da topoisomerase
• Beneficiário: Fillipe Vieira Rocha
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 16/04201-9 - Compostos de metais de transição contendo tiossemicarbazonas e fosfinas como ligantes: Investigação da citotoxicidade e mecanismo de ação
• Beneficiário: Fillipe Vieira Rocha
• Modalidade de apoio: Auxílio à Pesquisa - Regular