Discovery of dihydroxylated 2,4-diphenyl-6-thiophen-2-yl-pyridine as a non-intercalative DNA-binding topoisomerase II-specific catalytic inhibitor
| Autor: | Eung-Seok Lee, Jun Ho Lee, Eunyoung Lee, So Eun Park, Youngjoo Kwon, Kyu Yeon Jun, Pritam Thapa, Radha Karki, Hanbyeol Kwon |
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| Rok vydání: | 2013 |
| Předmět: |
Models
Molecular Stereochemistry Protein Conformation Pyridines Quantitative Structure-Activity Relationship Apoptosis Ring (chemistry) chemistry.chemical_compound Cell Line Tumor Drug Discovery Pyridine medicine Hydroxides Humans Topoisomerase II Inhibitors Viability assay Cytotoxicity Pharmacology biology Chemistry Topoisomerase Organic Chemistry General Medicine DNA In vitro DNA Topoisomerases Type II Mechanism of action Drug Design biology.protein Biocatalysis medicine.symptom |
| Zdroj: | European journal of medicinal chemistry. 80 |
| ISSN: | 1768-3254 |
| Popis: | We describe our rationale for designing specific catalytic inhibitors of topoisomerase II (topo II) over topoisomerase I (topo I). Based on 3D-QSAR studies of previously published dihydroxylated 2,4-diphenyl-6-aryl pyridine derivatives, 9 novel dihydroxylated 2,4-diphenyl-6-thiophen-2-yl pyridine compounds were designed, synthesized, and their biological activities were evaluated. These compounds have 2-thienyl ring substituted on the R(3) group on the pyridine ring and they all showed excellent specificity toward topo II compared to topo I. In vitro experiments were performed for compound 13 to determine the mechanism of action for this series of compounds. Compound 13 inhibited topoisomerase II specifically by non-intercalative binding to DNA and did not stabilize enzyme-cleavable DNA complex. Compound 13 efficiently inhibited cell viability, cell migration, and induced G1 arrest. Also from 3D-QSAR studies, the results were compared with other previously published dihydroxylated 2,4-diphenyl-6-aryl pyridine derivatives to explain the structure-activity relationships. |
| Databáze: | OpenAIRE |
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