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

Author(s):Show less -

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]

Affiliation

^[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

• Document type: Journal article
• Source: Journal of Inorganic Biochemistry; v. 199, OCT 2019.
• Web of Science Citations: 7

Abstract

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)

• FAPESP's process: 16/04201-9 - Transition metal compounds bearinhg thiosemicarbazones and phosphines as ligand: investigation of cytotoxicity and mechanism of action
• Grantee: Fillipe Vieira Rocha
• Support type: Regular Research Grants
• FAPESP's process: 16/17711-5 - INVESTIGATION OF THE ANTITUMOR POTENTIAL OF PALLADIUM(II) COMPOUNDS CONTAINING ORTHOMETALLATED OR N,S-DONOR LIGANDS
• Grantee: Adelino Vieira de Godoy Netto
• Support type: Regular Research Grants
• FAPESP's process: 13/20156-5 - Design of new thiosemicarbazones and their Cu(II) and Pd(II) complexes as topoisomerase inhibitors
• Grantee: Fillipe Vieira Rocha
• Support type: Scholarships in Brazil - Post-Doctorate
• FAPESP's process: 12/15486-3 - Pd(II) compounds: synthesis, cytotoxicity, and DNA binding studies
• Grantee: Regina Celia Galvao Frem
• Support type: Regular Research Grants