New series of fluoroquinolone derivatives as potential anticancer Agents: Design, Synthesis, in vitro biological Evaluation, and Topoisomerase II Inhibition

Article

作者: Adly, Mina E ; Taher, Azza T ; Mahmoud, Ashraf M ; El-Masry, Rana M ; Ahmed, Fakher M ; Salem, Mohamed A

A series of fluoroquinolone analogs (II, III_a-g) derived from Ciprofloxacin hydrazide were designed, and synthesized. The NCI-60 Human Tumor Cell Line Screening assay indicated that compounds II, III_b, and III_f are the most potent among the series and were further selected for five-dose evaluation, where they exhibited potent cytotoxicity with mean GI₅₀ values of 3.30, 2.45, and 9.06 µM, respectively, where they reduced the cell proliferation of most of the tested cell lines with IC₅₀ values significantly lower than the reference drug Etoposide. A selectivity study demonstrated the high selective cytotoxicity of III_f towards cancerous cells over normal mammalian Vero cells, presenting it as a potent and selective antitumor agent. Cell cycle analysis revealed that treatment with II, III_b, or III_f induced cell cycle arrest at the G2/M phase in MCF-7 cells. Topoisomerase II enzyme inhibition assay showed that the three tested compounds are potent topo II inhibitors where compound II (IC₅₀ = 51.66 µM) displayed more potent inhibitory activity compared to the well-known topo II inhibitor Etoposide (IC₅₀ = 58.96 µM), while compounds III_b and III_f showed comparable activity to the reference drug. Molecular modeling study suggested that the topoisomerase inhibitory activity may be attributed to the binding to the Merbarone binding site and chelation with Mg²⁺_.

2022-10-01·Molecular Neurobiology

TOP2B Is Required to Maintain the Adrenergic Neural Phenotype and for ATRA-Induced Differentiation of SH-SY5Y Neuroblastoma Cells

Article

作者: Khazeem, Mushtaq M ; Austin, Caroline A ; Sumbung, Nielda K ; McGow, Jade F ; Cowell, Ian G ; Casement, John W ; Kenneth, Niall S ; Chan, Janice Yuen Tung ; Schlossmacher, George

AbstractThe neuroblastoma cell line SH-SY5Y is widely used to study retinoic acid (RA)-induced gene expression and differentiation and as a tool to study neurodegenerative disorders. SH-SY5Y cells predominantly exhibit adrenergic neuronal properties, but they can also exist in an epigenetically interconvertible alternative state with more mesenchymal characteristics; as a result, these cells can be used to study gene regulation circuitry controlling neuroblastoma phenotype. Using a combination of pharmacological inhibition and targeted gene inactivation, we have probed the requirement for DNA topoisomerase IIB (TOP2B) in RA-induced gene expression and differentiation and in the balance between adrenergic neuronal versus mesenchymal transcription programmes. We found that expression of many, but not all genes that are rapidly induced by ATRA in SH-SY5Y cells was significantly reduced in the TOP2B null cells; these genes include BCL2, CYP26A1, CRABP2, and NTRK2. Comparing gene expression profiles in wild-type versus TOP2B null cells, we found that long genes and genes expressed at a high level in WT SH-SY5Y cells were disproportionately dependent on TOP2B. Notably, TOP2B null SH-SY5Y cells upregulated mesenchymal markers vimentin (VIM) and fibronectin (FN1) and components of the NOTCH signalling pathway. Enrichment analysis and comparison with the transcription profiles of other neuroblastoma-derived cell lines supported the conclusion that TOP2B is required to fully maintain the adrenergic neural-like transcriptional signature of SH-SY5Y cells and to suppress the alternative mesenchymal epithelial-like epigenetic state.

2022-10-01·Data in Brief

Data of transcriptional effects of the merbarone-mediated inhibition of TOP2

Article

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.

100 项与 Merbarone 相关的药物交易

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