Design, synthesis, molecular modeling and anti-proliferative evaluation of novel quinoxaline derivatives as potential DNA intercalators and topoisomerase II inhibitors
| Autor: | Mohamed M. Radwan, Ahmed B.M. Mehany, Ahmed M. Metwaly, Mostafa A. Elhendawy, Abdelrahman M. Yassin, Mahmoud A. ElSohly, Mohamed-Kamal Ibrahim, Ibrahim H. Eissa, Elsayed E. Hafez, Nehal M. El-Deeb, Amany Belal, Mohammed S Taghour |
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| Rok vydání: | 2018 |
| Předmět: |
Models
Molecular Molecular model Stereochemistry Antineoplastic Agents 01 natural sciences Structure-Activity Relationship chemistry.chemical_compound Quinoxaline Cell Line Tumor Quinoxalines Drug Discovery medicine Humans Topoisomerase II Inhibitors Doxorubicin DNA Cleavage Cytotoxicity IC50 Cell Proliferation Pharmacology Dose-Response Relationship Drug Molecular Structure biology 010405 organic chemistry Topoisomerase Organic Chemistry DNA General Medicine 0104 chemical sciences 010404 medicinal & biomolecular chemistry DNA Topoisomerases Type II chemistry Drug Design biology.protein Topoisomerase-II Inhibitor medicine.drug |
| Zdroj: | European Journal of Medicinal Chemistry. 155:117-134 |
| ISSN: | 0223-5234 |
| DOI: | 10.1016/j.ejmech.2018.06.004 |
| Popis: | New series of [1,2,4]triazolo [4,3-a]quinoxaline and bis([1,2,4]triazolo)[4,3-a:3′,4′-c]quinoxaline derivatives have been designed, synthesized and biologically evaluated for their cytotoxic activities against three tumor cell lines (HePG-2, Hep-2 and Caco-2). Compounds 16e, 21, 25a and 25b exhibited the highest activities against the examined cell lines with IC50 values ranging from 0.29 to 0.90 μM comparable to that of doxorubicin (IC50 ranging from 0.51 to 0.73 μM). The most active members were further evaluated for their topoisomerase II (Topo II) inhibitory activities and DNA intercalating affinities as potential mechanisms for their anti-proliferative activities. Interestingly, the results of Topo II inhibition and DNA binding assays were consistent with that of the cytotoxicity data, where the most potent anti-proliferative derivatives exhibited good Topo II inhibitory activities and DNA binding affinities, comparable to that of doxorubicin. Moreover, the most active compound 25a caused cell cycle arrest at G2/M phase and induced apoptosis in Caco-2 cells. In addition, Furthermore, molecular docking studies were performed for the novel compounds against DNA-Topo II complex to investigate their binding patterns. Based on these studies, it was concluded that DNA binding and/or Topo II inhibition may contribute to the observed cytotoxicity of the synthesized compounds. |
| Databáze: | OpenAIRE |
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