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

Kyu Yeon Jun, Hanbyeol Kwon, So Eun Park, Eunyoung Lee, Radha Karki, Pritam Thapa, Jun Ho Lee, Eung Seok Lee, Youngjoo Kwon

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

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 2,4-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 R3 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.

Original languageEnglish
Pages (from-to)428-438
Number of pages11
JournalEuropean Journal of Medicinal Chemistry
Volume80
DOIs
StatePublished - 10 Jun 2014

Bibliographical note

Funding Information:
This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology ( 2011–0011007 ). K.-Y. Jun was supported by RP-Grant 2012 of Ewha Womans University .

Keywords

  • 3D-QSAR
  • Anticancer agents
  • Cytotoxicity
  • Dihydroxylated 2,4-diphenyl-6-thiophen-2-yl-pyridines
  • Topoisomerase I
  • Topoisomerase II

Fingerprint

Dive into the research topics of 'Discovery of dihydroxylated 2,4-diphenyl-6-thiophen-2-yl-pyridine as a non-intercalative DNA-binding topoisomerase II-specific catalytic inhibitor'. Together they form a unique fingerprint.

Cite this