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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
Author(s) -
Lapa Gennady B.,
Tsunoda Toshiyuki,
Shirasawa Senji,
Baryshnikova Maria A.,
Evseev Gregory G.,
Afanasyeva Daria A.,
Chigorina Elena A.
Publication year - 2016
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12691
Subject(s) - cytotoxic t cell , benzamide , in vitro , kinase , chemistry , ic50 , cell culture , phenotypic screening , growth inhibition , in silico , microbiology and biotechnology , phenotype , cancer research , biochemistry , stereochemistry , biology , genetics , gene
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 (IC 50 = 18 μ m ) and human breast cancer T‐47D cells (GI 50 = 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.