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

Seojeong Park, Til Bahadur Thapa Magar, Tara Man Kadayat, Hwa Jong Lee, Ganesh Bist, Aarajana Shrestha, Eung Seok Lee, Youngjoo Kwon

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

Novel series of conformationally constrained 2,4-chloro- and hydroxy-substituted diphenyl benzofuro[3,2-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 antiproliferative 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.

Original languageEnglish
Pages (from-to)318-333
Number of pages16
JournalEuropean Journal of Medicinal Chemistry
Volume127
DOIs
StatePublished - 2017

Keywords

  • 2,4-chloro- and hydroxy-substituted diphenyl benzofuro[3,2-b]pyridines
  • Anticancer agent
  • Antiproliferative activity
  • Dual topoisomerase I and II inhibition
  • Non-intercalative catalytic inhibiton

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