Design, synthesis, and biological evaluation of 1,3-diarylisoquinolines as novel topoisomerase I catalytic inhibitors
- 주제(키워드) 1 , 3-Diarylisoquinoline , Antitubulin activity , Suzuki coupling , Topoisomerase , Topoisomerase catalytic inhibitor
- 등재 SCIE, SCOPUS
- 발행기관 Elsevier Masson SAS
- 발행년도 2018
- URI http://www.dcollection.net/handler/ewha/000000150101
- 본문언어 영어
- Published As http://dx.doi.org/10.1016/j.ejmech.2017.11.011
- 저작권 이화여자대학교 논문은 저작권에 의해 보호받습니다.
초록/요약
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. © 2017 Elsevier Masson SAS
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