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Insight into eukaryotic topoisomerase II-inhibiting fused heterocyclic compounds in human cancer cell lines by molecular docking

Etoposide is effective as an anti-tumour drug by inhibiting eukaryotic DNA topoisomerase II via establishing a covalent complex with DNA. Unfortunately, its wide therapeutic application is often hindered by multidrug resistance (MDR), low water solubility and toxicity. In our previous study, new der... Full description

Journal Title: SAR and QSAR in environmental research 2012-04-01, Vol.23 (3-4), p.345-355
Main Author: Taskin, T
Other Authors: Yilmaz, S , Yildiz, I , Yalcin, I , Aki, E
Format: Electronic Article Electronic Article
Language: English
Subjects:
Publisher: England: Taylor & Francis Group
ID: ISSN: 1062-936X
Link: https://www.ncbi.nlm.nih.gov/pubmed/22490049
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recordid: cdi_crossref_citationtrail_10_1080_1062936X_2012_664560
title: Insight into eukaryotic topoisomerase II-inhibiting fused heterocyclic compounds in human cancer cell lines by molecular docking
format: Article
creator:
  • Taskin, T
  • Yilmaz, S
  • Yildiz, I
  • Yalcin, I
  • Aki, E
subjects:
  • benzimidazoles
  • benzothiazoles
  • benzoxazoles
  • DNA Topoisomerases, Type II - chemistry
  • DNA Topoisomerases, Type II - metabolism
  • Etoposide - chemistry
  • Etoposide - pharmacology
  • Heterocyclic Compounds - chemistry
  • Heterocyclic Compounds - pharmacology
  • Humans
  • Ligands
  • Models, Molecular
  • molecular docking
  • Structure-Activity Relationship
  • topoisomerase II
  • Topoisomerase II Inhibitors - chemistry
  • Topoisomerase II Inhibitors - pharmacology
ispartof: SAR and QSAR in environmental research, 2012-04-01, Vol.23 (3-4), p.345-355
description: Etoposide is effective as an anti-tumour drug by inhibiting eukaryotic DNA topoisomerase II via establishing a covalent complex with DNA. Unfortunately, its wide therapeutic application is often hindered by multidrug resistance (MDR), low water solubility and toxicity. In our previous study, new derivatives of benzoxazoles, benzimidazoles and related fused heterocyclic compounds, which exhibited significant eukaryotic DNA topoisomerase II inhibitory activity, were synthesized and exhibited better inhibitory activity compared with the drug etoposide itself. To expose the binding interactions between the eukaryotic topoisomerase II and the active heterocyclic compounds, docking studies were performed, using the software Discovery Studio 2.1, based on the crystal structure of the Topo IIA-bound G-segment DNA (PDB ID: 2RGR). The research was conducted on a selected set of 31 fused heterocyclic compounds with variation in structure and activity. The structural analyses indicate coordinate and hydrogen bonding interactions, van der Waals interactions and hydrophobic interactions between ligands and the protein, as Topo IIA-bound G-segment DNA are responsible for the preference of inhibition and potency. Collectively, the results demonstrate that the compounds 1a, 1c, 3b, 3c, 3e and 4a are significant anti-tumour drug candidates that should be further studied.
language: eng
source:
identifier: ISSN: 1062-936X
fulltext: no_fulltext
issn:
  • 1062-936X
  • 1029-046X
url: Link


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titleInsight into eukaryotic topoisomerase II-inhibiting fused heterocyclic compounds in human cancer cell lines by molecular docking
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descriptionEtoposide is effective as an anti-tumour drug by inhibiting eukaryotic DNA topoisomerase II via establishing a covalent complex with DNA. Unfortunately, its wide therapeutic application is often hindered by multidrug resistance (MDR), low water solubility and toxicity. In our previous study, new derivatives of benzoxazoles, benzimidazoles and related fused heterocyclic compounds, which exhibited significant eukaryotic DNA topoisomerase II inhibitory activity, were synthesized and exhibited better inhibitory activity compared with the drug etoposide itself. To expose the binding interactions between the eukaryotic topoisomerase II and the active heterocyclic compounds, docking studies were performed, using the software Discovery Studio 2.1, based on the crystal structure of the Topo IIA-bound G-segment DNA (PDB ID: 2RGR). The research was conducted on a selected set of 31 fused heterocyclic compounds with variation in structure and activity. The structural analyses indicate coordinate and hydrogen bonding interactions, van der Waals interactions and hydrophobic interactions between ligands and the protein, as Topo IIA-bound G-segment DNA are responsible for the preference of inhibition and potency. Collectively, the results demonstrate that the compounds 1a, 1c, 3b, 3c, 3e and 4a are significant anti-tumour drug candidates that should be further studied.
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subjectbenzimidazoles ; benzothiazoles ; benzoxazoles ; DNA Topoisomerases, Type II - chemistry ; DNA Topoisomerases, Type II - metabolism ; Etoposide - chemistry ; Etoposide - pharmacology ; Heterocyclic Compounds - chemistry ; Heterocyclic Compounds - pharmacology ; Humans ; Ligands ; Models, Molecular ; molecular docking ; Structure-Activity Relationship ; topoisomerase II ; Topoisomerase II Inhibitors - chemistry ; Topoisomerase II Inhibitors - pharmacology
ispartofSAR and QSAR in environmental research, 2012-04-01, Vol.23 (3-4), p.345-355
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abstractEtoposide is effective as an anti-tumour drug by inhibiting eukaryotic DNA topoisomerase II via establishing a covalent complex with DNA. Unfortunately, its wide therapeutic application is often hindered by multidrug resistance (MDR), low water solubility and toxicity. In our previous study, new derivatives of benzoxazoles, benzimidazoles and related fused heterocyclic compounds, which exhibited significant eukaryotic DNA topoisomerase II inhibitory activity, were synthesized and exhibited better inhibitory activity compared with the drug etoposide itself. To expose the binding interactions between the eukaryotic topoisomerase II and the active heterocyclic compounds, docking studies were performed, using the software Discovery Studio 2.1, based on the crystal structure of the Topo IIA-bound G-segment DNA (PDB ID: 2RGR). The research was conducted on a selected set of 31 fused heterocyclic compounds with variation in structure and activity. The structural analyses indicate coordinate and hydrogen bonding interactions, van der Waals interactions and hydrophobic interactions between ligands and the protein, as Topo IIA-bound G-segment DNA are responsible for the preference of inhibition and potency. Collectively, the results demonstrate that the compounds 1a, 1c, 3b, 3c, 3e and 4a are significant anti-tumour drug candidates that should be further studied.
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doi10.1080/1062936X.2012.664560