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BIBTEX RIS

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

2019; Elsevier BV; Volume: 199; Linguagem: Inglês

10.1016/j.jinorgbio.2019.110725

ISSN

1873-3344

Autores

Fillipe V. Rocha, Renan Lira de Farias, Mauro A. Lima, Victor S. Batista, Nailton M. Nascimento-Júnior, Saulo Santesso Garrido, Andréia Machado Leopoldino, Renata N. Goto, Adriano Bof de Oliveira, Johannes Beck, Christian Landvogt, Antônio E. Mauro, Adelino V.G. Netto,

Tópico(s)

Synthesis and biological activity

Resumo

Herein, a robust docking protocol was developed by using a low-cost workflow to highlight the modulation at ATPase domain from Human Topoisomerase-IIα (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 6.25-25μM. These results exhibited more effectivity than anticancer agent etoposide (35μM) and merbarone (40-50μM). The compounds were screened via Resazurin assay against MCF-7, MDA-MB-231 (Human breast), DU-145 (Human prostate), A549 (Human lung) and Cal27 (Human tongue) tumor cell lines revealing great cytotoxic effects, primarily to MCF-7 (IC50=1.81-4.46μM). 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; SIcis=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.

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