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

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

  • Eur J Med Chem. 2018 Jan 1:143:200-215. doi: 10.1016/j.ejmech.2017.11.011.
Daulat Bikram Khadka 1 Seojeong Park 2 Yifeng Jin 1 Jinhe Han 1 Youngjoo Kwon 3 Won-Jea Cho 4
Affiliations

Affiliations

  • 1 College of Pharmacy, Research Institute of Drug Development, Chonnam National University, Gwangju 61186, Republic of Korea.
  • 2 College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea.
  • 3 College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea. Electronic address: ykwon@ewha.ac.kr.
  • 4 College of Pharmacy, Research Institute of Drug Development, Chonnam National University, Gwangju 61186, Republic of Korea. Electronic address: wjcho@chonnam.ac.kr.
Abstract

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.

Keywords

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

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