Discovery of dihydroxylated 2,4-diphenyl-6-thiophen-2-yl-pyridine as a non-intercalative DNA-binding topoisomerase II-specific catalytic inhibitor

Title
Discovery of dihydroxylated 2,4-diphenyl-6-thiophen-2-yl-pyridine as a non-intercalative DNA-binding topoisomerase II-specific catalytic inhibitor
Author(s)
이응석전규원[전규원]권한별[권한별]박소은[박소은]이은영[이은영]라다깔끼프리텀다빠이준호[이준호]권영주[권영주]
Keywords
ANALYSIS COMSIA; CANCER-CELLS; PYRIDINES; CYTOTOXICITY; DERIVATIVES; DESIGN; PROLIFERATION; CHALCONES; MOIETY; SERIES
Issue Date
201406
Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
Citation
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, v.80, pp.428 - 438
Abstract
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 2,4diphenyl-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. (C) 2014 Elsevier Masson SAS. All rights reserved.
URI
http://hdl.handle.net/YU.REPOSITORY/31920http://dx.doi.org/10.1016/j.ejmech.2014.04.066
ISSN
0223-5234
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약학대학 > 약학부 > Articles
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