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

Title
Design, synthesis, and biological evaluation of 1,3-diarylisoquinolines as novel topoisomerase I catalytic inhibitors
Authors
Khadka D.B.Park S.Jin Y.Han J.Kwon Y.Cho W.-J.
Ewha Authors
권영주
SCOPUS Author ID
권영주scopus
Issue Date
2018
Journal Title
European Journal of Medicinal Chemistry
ISSN
0223-5234JCR Link
Citation
vol. 143, pp. 200 - 215
Keywords
1,3-DiarylisoquinolineAntitubulin activitySuzuki couplingTopoisomeraseTopoisomerase catalytic inhibitor
Publisher
Elsevier Masson SAS
Indexed
SCI; SCIE; SCOPUS scopus
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. © 2017 Elsevier Masson SAS
DOI
10.1016/j.ejmech.2017.11.011
Appears in Collections:
약학대학 > 약학과 > Journal papers
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