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.
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 μm) and human breast cancer T-47D cells (GI50 = 1.9 μm). 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 μm 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.
authors.affiliation: Blokhin Cancer Center, Kashirskoe sh 24, Moscow, 115478, Russia.|Pirogov Russian National Research Medical University (RNRMU), Ostrovitianov str. 1, Moscow, 117997, Russia.
authors.forename: Gennady B
authors.initials: GB
authors.lastname: Lapa
authors.affiliation: Department of Cell Biology, Faculty of Medicine, Fukuoka University, Fukuoka 814-0180, Japan.|Central Research Institute for Advanced Molecular Medicine, Fukuoka University, Fukuoka 814-0180, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Tsunoda
authors.affiliation: Department of Cell Biology, Faculty of Medicine, Fukuoka University, Fukuoka 814-0180, Japan.|Central Research Institute for Advanced Molecular Medicine, Fukuoka University, Fukuoka 814-0180, Japan.
authors.forename: Senji
authors.initials: S
authors.lastname: Shirasawa
authors.affiliation: Blokhin Cancer Center, Kashirskoe sh 24, Moscow, 115478, Russia.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Baryshnikova
authors.affiliation: Blokhin Cancer Center, Kashirskoe sh 24, Moscow, 115478, Russia.
authors.forename: Gregory G
authors.initials: GG
authors.lastname: Evseev
authors.affiliation: Blokhin Cancer Center, Kashirskoe sh 24, Moscow, 115478, Russia.
authors.forename: Daria A
authors.initials: DA
authors.lastname: Afanasyeva
authors.affiliation: Federal State Unitary Enterprise IREA, Bogorodsky shaft, 3, Moscow, 107076, Russia.
authors.forename: Elena A
authors.initials: EA
authors.lastname: Chigorina
mesh_terms: D045744:Cell Line, Tumor; D002853:Chromatography, Liquid; D003198:Computer Simulation; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013058:Mass Spectrometry; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology*; D066244:Proton Magnetic Resonance Spectroscopy
chemical_list: D007546:Isoquinolines; D058988:Phosphodiesterase 4 Inhibitors; C039109:isoquinoline
keywords: 3-amino-isoquinoline; 3D floating culture; HCT116; HKe3; K562; KRAS; PDE; T-47D; breast cancer; colorectal cancer; cytotoxic activity; leukemia; phenotypic screening; phosphodiesterase; reversal docking; virtual screening