Design, synthesis, and biological evaluation of 1,3-diarylisoquinolines as novel topoisomerase I catalytic inhibitors

Daulat Bikram Khadka, Seojeong Park, Yifeng Jin, Jinhe Han, Youngjoo Kwon, Won Jea Cho

Research output: Contribution to journalArticlepeer-review

12 Scopus citations


With a goal of identifying potent topoisomerase (topo) inhibitor, the C4-aromatic ring of the anticancer agent, 3,4-diarylisoquinolone, was strategically shifted to design 1,3-diarylisoquinoline. Twenty-two target compounds were synthesized in three simple and efficient steps. The 1,3-diarylisoquinolines exhibited potent anti-proliferative effects on cancer cells but few compounds spared non-cancerous cells. Inhibition of topo I/IIα-mediated DNA relaxation by several derivatives was greater than that by camptothecin (CPT)/etoposide even at low concentration (20 μM). In addition, these compounds had little or no effect on polymerization of tubulin. A series of biological evaluations performed with the most potent derivative 4cc revealed that the compound is a non-intercalative topo I catalytic inhibitor interacting with free topo I. Collectively, the potent cytotoxic effect on cancer cells including the drug resistance ones, absence of lethal effect on normal cells, and different mechanism of action than topo I poisons suggest that the 1,3-diarylisoquinolines might be a promising class of anticancer agents worthy of further pursuit.

Original languageEnglish
Pages (from-to)200-215
Number of pages16
JournalEuropean Journal of Medicinal Chemistry
StatePublished - 1 Jan 2018

Bibliographical note

Funding Information:
This work was financially supported by Chonnam National University – South Korea , 2016 and by the National Research Foundation of Korea (Grant: 2016R1A2B4009512 ).

Publisher Copyright:
© 2017 Elsevier Masson SAS


  • 1,3-Diarylisoquinoline
  • Antitubulin activity
  • Suzuki coupling
  • Topoisomerase
  • Topoisomerase catalytic inhibitor


Dive into the research topics of 'Design, synthesis, and biological evaluation of 1,3-diarylisoquinolines as novel topoisomerase I catalytic inhibitors'. Together they form a unique fingerprint.

Cite this