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

Autor: Rocha FV; UFSCar - Univ Federal de São Carlos, Departamento de Química, São Carlos, Brazil. Electronic address: fillipe@ufscar.br., Farias RL; UNESP - Univ Estadual Paulista, Instituto de Química, Departamento de Química Geral e Inorgânica, Araraquara, Brazil., Lima MA; UFSCar - Univ Federal de São Carlos, Departamento de Química, São Carlos, Brazil., Batista VS; UNESP - Univ Estadual Paulista, Instituto de Química, Departamento de Química Orgânica, Araraquara, Brazil., Nascimento-Júnior NM; UNESP - Univ Estadual Paulista, Instituto de Química, Departamento de Química Orgânica, Araraquara, Brazil., Garrido SS; UNESP - Univ Estadual Paulista, Instituto de Química, Departamento de Bioquímica e Tecnologia Química, Araraquara, Brazil., Leopoldino AM; USP - Univ de São Paulo, Department of Clinical Analyses, Toxicology and Food Sciences, Ribeirão Preto, Brazil., Goto RN; USP - Univ de São Paulo, Department of Clinical Analyses, Toxicology and Food Sciences, Ribeirão Preto, Brazil., Oliveira AB; UFS - Univ Federal de Sergipe, Departamento de Química, São Cristóvão, Brazil., Beck J; Rheinische Friedrich-Wilhelms-Universität Bonn, Institut für Anorganische Chemie, Bonn, Germany., Landvogt C; Rheinische Friedrich-Wilhelms-Universität Bonn, Institut für Anorganische Chemie, Bonn, Germany., Mauro AE; UNESP - Univ Estadual Paulista, Instituto de Química, Departamento de Química Geral e Inorgânica, Araraquara, Brazil., Netto AVG; UNESP - Univ Estadual Paulista, Instituto de Química, Departamento de Química Geral e Inorgânica, Araraquara, Brazil.
Jazyk: angličtina
Zdroj: Journal of inorganic biochemistry [J Inorg Biochem] 2019 Oct; Vol. 199, pp. 110725. Date of Electronic Publication: 2019 Jun 06.
DOI: 10.1016/j.jinorgbio.2019.110725
Abstrakt: 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 (IC 50 =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 (SI 1-4 =1.4-5.0; SI 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.
(Copyright © 2019 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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