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- Title
Synthesis of New Congeners of 1-methyl-3-aminoisoquinolines, Evaluation of Their Cytotoxic Activity, In Silico and In Vitro Study of Their Molecular Targets as PDE4B.
- Authors
Lapa, Gennady B.; Tsunoda, Toshiyuki; Shirasawa, Senji; Baryshnikova, Maria A.; Evseev, Gregory G.; Afanasyeva, Daria A.; Chigorina, Elena A.
- Abstract
To examine the cytotoxic activity of congeners of 3-amino-isoquinoline, we performed the phenotypic screening using panel of 60 cell lines and found that (N-(6,7-dimethoxy-1-methyl-isoquinolin-3-yl)-4-{[(1-ethyl-4-methyl-1H-pyrazol-3-yl)methyl]amino}benzamide ( 4d)) exhibited the significant effect against different tumor cell lines while showing the high activity toward human colorectal cancer HCT-116 cells (IC50 = 18 μ m) and human breast cancer T-47D cells (GI50 = 1.9 μ m). Virtual screening indicated that these compounds target protein kinases and phosphodiesterases (PDE). However, wet screening among panel of protein kinases did not show any significant activity. By contrast, 50 μ m of 4c and 4d inhibited the growth of HKe3-mtKRAS spheroids in the 3D floating (3DF) culture suggesting that 4c and 4d target PDE4B which is selectively upregulated by mtKRAS in 3DF culture.
- Subjects
ISOQUINOLINE; QUINOLINE derivatives; CELL-mediated cytotoxicity; COLON cancer treatment; CANCER cells; CELL lines; CHEMICAL synthesis
- Publication
Chemical Biology & Drug Design, 2016, Vol 87, Issue 4, p575
- ISSN
1747-0277
- Publication type
Article
- DOI
10.1111/cbdd.12691