作者: Divina, Federico ; Jimeno-González, Silvia ; Martínez-García, Pedro Manuel ; Delgado-Chaves, Fernando M ; Gómez-Vela, Francisco ; Cortés-Ledesma, Felipe ; Herrero-Ruiz, Andrés

Type II DNA topoisomerases relax topological stress by transiently gating DNA passage in a controlled cut-and-reseal mechanism that affects both DNA strands. Therefore, they are essential to overcome topological problems associated with DNA metabolism. Their aberrant activity results in the generation of DNA double-strand breaks, which can seriously compromise cell survival and genome integrity. Here, we profile the transcriptome of human-telomerase-immortalized retinal pigment epithelial 1 (RPE-1) cells when treated with merbarone, a drug that catalytically inhibits type II DNA topoisomerases. We performed RNA-Seq after 4 and 8 h of merbarone treatment and compared transcriptional profiles versus untreated samples. We report raw sequencing data together with lists of gene counts and differentially expressed genes.

2020-04-09·Journal of Medicinal Chemistry1区 · 医学

Design, Synthesis, Dynamic Docking, Biochemical Characterization, and in Vivo Pharmacokinetics Studies of Novel Topoisomerase II Poisons with Promising Antiproliferative Activity

1区 · 医学

Article

作者: Franco-Ulloa, Sebastian ; Brindani, Nicoletta ; Bertozzi, Sine Mandrup ; De Vivo, Marco ; Nigro, Michela ; Girotto, Stefania ; Summa, Maria ; Ottonello, Giuliana ; Bertorelli, Rosalia ; Armirotti, Andrea ; Kuriappan, Jissy Akkarapattiakal ; Arencibia, Jose M.

We previously reported a first set of hybrid topoisomerase II (topoII) poisons whose chemical core merges key pharmacophoric elements of etoposide and merbarone, which are two well-known topoII blockers. Here, we report on the expansion of this hybrid molecular scaffold and present 16 more hybrid derivatives that have been designed, synthesized, and characterized for their ability to block topoII and for their overall drug-like profile. Some of these compounds act as topoII poison and exhibit good solubility, metabolic (microsomal) stability, and promising cytotoxicity in three cancer cell lines (DU145, HeLa, A549). Compound 3f (ARN24139) is the most promising drug-like candidate, with a good pharmacokinetics profile in vivo. Our results indicate that this hybrid new chemical class of topoII poisons deserves further exploration and that 3f is a favorable lead candidate as a topoII poison, meriting future studies to test its efficacy in in vivo tumor models.

2019-10-01·Journal of Inorganic Biochemistry2区 · 生物学

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

2区 · 生物学

Article

作者: Garrido, Saulo S ; Farias, Renan L ; Goto, Renata N ; Nascimento-Júnior, Nailton M ; Oliveira, Adriano B ; Rocha, Fillipe V ; Mauro, Antônio E ; Netto, Adelino V G ; Landvogt, Christian ; Lima, Mauro A ; Beck, Johannes ; Leopoldino, Andréia M ; Batista, Victor S

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 (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.

100 项与 Merbarone 相关的药物交易

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