Selected 4-phenyl hydroxycoumarins: in vitro cytotoxicity, teratogenic effect on zebrafish (Danio rerio) embryos and molecular docking study.
A study of structure cytotoxic-activity relationship of three hydroxy 4-phenyl-coumarins and basic coumarin molecule against two human cell lines (MRC5 fibroblasts and A375 melanoma cells) is presented. Of all investigated compounds the highest cytotoxic activity in both cell lines was determined for 7,8-dihydroxy-4-phenyl coumarin. SAR studies revealed the influence of phenyl group and hydroxyl group's number and position on cytotoxic activity. In addition, to get an insight about their binding preferences at the active site of the receptor (catalytic subunit of cAMP-dependent protein kinase) molecular docking studies were performed. Docking studies suggest that 4-phenyl hydroxycoumarins are potent cAMP-dependent protein kinase inhibitors, better than their analogs without phenyl group. The teratogenic potential was assessed in zebrafish embryo toxicity test and results showed that 4-phenyl dihydroxycoumarins were more while 7-hydroxy-4-phenyl coumarin was less embryo toxic in comparison to coumarin. In order to examine selected 4-phenyl hydroxycoumarins as a new lead compounds the druglikeness of selected 4-phenyl hydroxycoumarins was estimated by using Lipinski's "rule of five". All selected 4-phenyl hydroxycoumarins proved to have satisfying pharmacokinetic profile.
Faculty of Medicine, Department of Chemistry, University of Niš, Niš, Serbia.
Jovana B
JB
Veselinović
Faculty of Medicine, Department of Biochemistry, University of Niš, Niš, Serbia.
Gordana M
GM
Kocić
Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, 11000 Belgrade, Serbia.
Aleksandar
A
Pavic
Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, 11000 Belgrade, Serbia.
Jasmina
J
Nikodinovic-Runic
Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, 11000 Belgrade, Serbia.
Lidija
L
Senerovic
Faculty of Medicine, Department of Chemistry, University of Niš, Niš, Serbia.
Goran M
GM
Nikolić
Faculty of Medicine, Department of Chemistry, University of Niš, Niš, Serbia. Electronic address: aveselinovic@medfak.ni.ac.rs.
Aleksandar M
AM
Veselinović
D015110:4-Hydroxycoumarins / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity*; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D004625:Embryo, Nonmammalian / Q000002:abnormalities / Q000187:drug effects* / Q000648:ultrastructure; D006801:Humans; D062105:Molecular Docking Simulation; D013329:Structure-Activity Relationship; D013723:Teratogens / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity*; D015027:Zebrafish / Q000196:embryology*
D015110:4-Hydroxycoumarins; D013723:Teratogens; D017868:Cyclic AMP-Dependent Protein Kinases
4-Phenyl hydroxycoumarins; Cytotoxicity; Molecular docking; Protein kinase inhibitors; Teratogenic potential