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Rational design, synthesis, and evaluation of novel 2,4-Chloro- and Hydroxy-Substituted diphenyl Benzofuro[3,2-b]Pyridines: Non-intercalative catalytic topoisomerase I and II dual inhibitor

Title
Rational design, synthesis, and evaluation of novel 2,4-Chloro- and Hydroxy-Substituted diphenyl Benzofuro[3,2-b]Pyridines: Non-intercalative catalytic topoisomerase I and II dual inhibitor
Authors
Park, SeojeongMagar, Til Bahadur ThapaKadayat, Tara ManLee, Hwa JongBist, GaneshShrestha, AarajanaLee, Eung-SeokKwon, Youngjoo
Ewha Authors
이화정권영주
SCOPUS Author ID
이화정scopus; 권영주scopus
Issue Date
2017
Journal Title
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
ISSN
0223-5234JCR Link1768-3254JCR Link
Citation
vol. 127, pp. 318 - 333
Keywords
2,4-chloro- and hydroxy-substituteddiphenyl benzofuro[3,2-b]pyridinesDual topoisomerase I and II inhibitionAntiproliferative activityNon-intercalative catalytic inhibitonAnticancer agent
Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
Indexed
SCI; SCIE; SCOPUS WOS scopus
Abstract
Novel series of conformationally constrained 2,4-chloro-and hydroxy-substituted diphenyl benzofuro 13,2-b]pyridines were rationally designed and synthesized. Their biological activities were evaluated for topoisomerase I and II inhibitory activity, and antiproliferative activity against several human cancer cell lines for the development of novel anticancer agents. Most of the compounds with phenol moiety at 4 position of central pyridine exhibited significant dual topoisomerase I and II inhibitory activities, and strong antiproliferative activity in low micromolar range. Structure activity relationship study suggested that phenol moiety at 4-position of the central pyridine regardless of chlorophenyl moiety at 2-position of the central pyridine has an important role in dual topoisomerase inhibitory activity as well as anti proliferative activity. For investigation of mode of action for compound 14 which displayed the most strong dual topoisomerase I and II inhibitory activity and antiproliferative activity against HCT15 cell, we performed cleavable complex assay, band depletion assay, comet assay, and competitive EtBr displacement assay. Compound 14 functioned as non-intercalative catalytic topo I and II dual inhibitor. In addition, compound 14 induced apoptosis in HCT15 cells through increase of Bax, decrease of Bcl-2 and increase of PARP cleavage. (C) 2017 Elsevier Masson SAS. All rights reserved.
DOI
10.1016/j.ejmech.2017.01.003
Appears in Collections:
약학대학 > 약학과 > Journal papers
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