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

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.

• Authors: Daulat Bikram Khadka, Seojeong Park, Yifeng Jin, Jinhe Han, Youngjoo Kwon, Won-Jea Cho
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 143 Pg. 200-215 (Jan 01 2018) ISSN: 1768-3254 [Electronic] France
• PMID: 29174815 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Chemical References

• Antineoplastic Agents
• Isoquinolines
• Topoisomerase I Inhibitors
• Tubulin
• DNA Topoisomerases, Type I

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Biocatalysis
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• DNA Topoisomerases, Type I (metabolism)
• Dose-Response Relationship, Drug
• Drug Design
• Drug Screening Assays, Antitumor
• Humans
• Isoquinolines (chemical synthesis, chemistry, pharmacology)
• Molecular Structure
• Polymerization (drug effects)
• Structure-Activity Relationship
• Topoisomerase I Inhibitors (chemical synthesis, chemistry, pharmacology)
• Tubulin (metabolism)