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Design, synthesis, and biological evaluation of heterotetracyclic quinolinone derivatives as anticancer agents targeting topoisomerases.
- Source :
-
European Journal of Medicinal Chemistry . Mar2020, Vol. 190, pN.PAG-N.PAG. 1p. - Publication Year :
- 2020
-
Abstract
- A series of thiochromeno[2,3- c ]quinolin-12-one derivatives with various substitutions were synthesized and evaluated as topoisomerase (Topo) inhibitors. Six (8 , 10 , 12 , 14 , 19 , and 26) of 23 compounds showed strong inhibitory activities against Topo-mediated DNA relaxation and proliferation of five human cell lines including breast (MDA-MB-231, MDA-MB-468 and MCF7), colorectal (HCT116) and non-small cell lung (H1299) cancers. Among these, compounds 14 and 26 exhibited full inhibitory activities against Topo I at 3 μM and Topo IIα at 1 μM. Cancer cells treated with 26 accumulated DNA damage and were arrested at the G 2 /M phase. With time, cells proceeded to apoptosis, as revealed by increased amounts of cells with fragmented DNA and cleavage of caspase-8 and -9. In contrast, normal breast epithelial cells showed low sensitivity to 26. Taken together, our study identifies 26 as a potent Topo dual-inhibitor with low toxicity to normal cells, and elucidates that the terminal amino group of N -2-aminoethylamino or N -3-aminopropylamino at the 6th position and 8,10-di-halogen substituents on thiochromeno[2,3- c ]quinolin-12-one are critical for the Topo-inhibiting and cancer-killing activities. Image 1 • Six compounds identified as dual Topo inhibitors. • 26 exhibits the highest toxicity in five cancer cell lines but is less toxic in normal breast epithelial cells. • 26 traps Topo I and IIα on chromatin and suppresses their activities. • 26 triggers DNA damage, cell-cycle arrest at the G 2 /M phase, followed by apoptosis. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 02235234
- Volume :
- 190
- Database :
- Academic Search Index
- Journal :
- European Journal of Medicinal Chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 141918623
- Full Text :
- https://doi.org/10.1016/j.ejmech.2020.112074