Design, synthesis, and biological evaluation of heterotetracyclic quinolinone derivatives as anticancer agents targeting topoisomerases

Jiann Fong Lee, Ting Yu Chang, Zheng Fang Liu, Nian Zhe Lee, Yen Hsiu Yeh, Yi Song Chen, Tsung Chih Chen, Hao Syun Chou, Tsai Kun Li, Sung Bau Lee, Mei Hsiang Lin

Research output: Contribution to journalArticle


A series of thiochromeno[2,3-c]quinolin-12-one derivatives with various substitutions were synthesized and evaluated as topoisomerase (Topo) inhibitors. Six (8, 10, 12, 14, 19, and 26) of 23 compounds showed strong inhibitory activities against Topo-mediated DNA relaxation and proliferation of five human cell lines including breast (MDA-MB-231, MDA-MB-468 and MCF7), colorectal (HCT116) and non-small cell lung (H1299) cancers. Among these, compounds 14 and 26 exhibited full inhibitory activities against Topo I at 3 μM and Topo IIα at 1 μM. Cancer cells treated with 26 accumulated DNA damage and were arrested at the G2/M phase. With time, cells proceeded to apoptosis, as revealed by increased amounts of cells with fragmented DNA and cleavage of caspase-8 and -9. In contrast, normal breast epithelial cells showed low sensitivity to 26. Taken together, our study identifies 26 as a potent Topo dual-inhibitor with low toxicity to normal cells, and elucidates that the terminal amino group of N-2-aminoethylamino or N-3-aminopropylamino at the 6th position and 8,10-di-halogen substituents on thiochromeno[2,3-c]quinolin-12-one are critical for the Topo-inhibiting and cancer-killing activities.

Original languageEnglish
Article number112074
JournalEuropean Journal of Medicinal Chemistry
Publication statusPublished - Mar 15 2020



  • Dual inhibitor
  • Thiochromeno[2,3-c]quinolin-12-one
  • Topoisomerase

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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