Discovery of dihydroxylated 2,4-diphenyl-6-thiophen-2-yl-pyridine as a non-intercalative DNA-binding topoisomerase II-specific catalytic inhibitor
- 주제(키워드) Topoisomerase I , Topoisomerase II , Cytotoxicity , Anticancer agents , Dihydroxylated 2 , 4-diphenyl-6-thiophen-2-yl-pyridines , 3D-QSAR
- 등재 SCIE, SCOPUS
- 발행기관 ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
- 발행년도 2014
- 총서유형 Journal
- URI http://www.dcollection.net/handler/ewha/000000091635
- 본문언어 영어
- Published As http://dx.doi.org/10.1016/j.ejmech.2014.04.066
초록/요약
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.
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