TY - JOUR
T1 - Design, synthesis, and biological evaluation of 1,3-diarylisoquinolines as novel topoisomerase I catalytic inhibitors
AU - Khadka, Daulat Bikram
AU - Park, Seojeong
AU - Jin, Yifeng
AU - Han, Jinhe
AU - Kwon, Youngjoo
AU - Cho, Won Jea
N1 - Funding Information:
This work was financially supported by Chonnam National University – South Korea , 2016 and by the National Research Foundation of Korea (Grant: 2016R1A2B4009512 ).
Publisher Copyright:
© 2017 Elsevier Masson SAS
PY - 2018/1/1
Y1 - 2018/1/1
N2 - 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.
AB - 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.
KW - 1,3-Diarylisoquinoline
KW - Antitubulin activity
KW - Suzuki coupling
KW - Topoisomerase
KW - Topoisomerase catalytic inhibitor
UR - http://www.scopus.com/inward/record.url?scp=85034655194&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2017.11.011
DO - 10.1016/j.ejmech.2017.11.011
M3 - Article
C2 - 29174815
AN - SCOPUS:85034655194
SN - 0223-5234
VL - 143
SP - 200
EP - 215
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
ER -