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Novel 2-aryl-4-(4 '-hydroxypheny1)-5H-indeno[1,2-b]pyridines as potent DNA non-intercalative topoisomerase catalytic inhibitors

Title
Novel 2-aryl-4-(4 '-hydroxypheny1)-5H-indeno[1,2-b]pyridines as potent DNA non-intercalative topoisomerase catalytic inhibitors
Authors
Park, SeojeongKadayat, Tara ManJun, Kyu-YeonMagar, Til Bahadur ThapaBist, GaneshShrestha, AarajanaLee, Eung-SeokKwon, Youngjoo
Ewha Authors
권영주
SCOPUS Author ID
권영주scopus
Issue Date
2017
Journal Title
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
ISSN
0223-5234JCR Link1768-3254JCR Link
Citation
vol. 125, pp. 14 - 28
Keywords
Anticancer agents2-Aryl-4-(4 '-hydroxyphenyl)-5H-indeno[1,2-b]pyridineAntiproliferative activityDocking studyDual topoisomerase I and II inhibitors
Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
Indexed
SCI; SCIE; SCOPUS WOS scopus
Abstract
On the basis of previous reports on the importance of thienyl, furyl or phenol group substitution on 5H-indeno[1,2-b]pyridine skeleton, a new series of rigid 2-aryl-4-(4'-hydroxyphenyl)-5H-indeno[1,2-b]pyridine derivatives were systematically designed and synthesized. Topoisomerase inhibitory activity and antiproliferative activity of all the synthesized compounds were determined using human colorectal (HCT15), breast (T47D), prostate (DU145) and cervix (HeLa) cancer cells. Compounds 9, 10, 12, 13, 15, 16, 18 and 19 with thienyl or furyl moiety at the 2-position and hydroxyl group at the meta or para positions of 4-phenyl ring displayed strong to moderate topoisomerase II alpha (topo II alpha) inhibitory activity and significant antiproliferative activity. The evaluation of compound 16 to determine its mechanism of action was performed with topo II alpha-DNA cleavable complex, topo II alpha-mediated ATPase assay, DNA unwinding and in vitro and ex vivo topo II alpha relaxation assay. Compound 16 functioned as a DNA non-intercalative topo II alpha catalytic inhibitor with better potency than etoposide in T47D breast cancer cells. Molecular docking study revealed that compound 16 cannot intercalate into regularly stacked base-pairs of DNA duplex but can interact or intercalate to topo II alpha-bound DNA. (C) 2016 Elsevier Masson SAS. All rights reserved.
DOI
10.1016/j.ejmech.2016.09.019
Appears in Collections:
약학대학 > 약학과 > Journal papers
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