Ragab F.A.Yahya T.A.A.El-Naa M.M.Arafa R.K.Pharmaceutical Chemistry DepartmentFaculty of PharmacyCairo University11562 CairoEgypt; Medicinal Chemistry DepartmentFaculty of PharmacySana'a UniversitySana'aYemen; Pharmacology and Toxicology DepartmentFaculty of PharmacyOctober University for Modern Sciences and ArtsEgypt2020-01-092020-01-0920142235234https://doi.org/10.1016/j.ejmech.2014.06.007PubMed ID 24937184https://t.ly/2d3XkScopusVarious flavonoid scaffold based derivatives viz furochalcones (3a-e, 6a-d and 9a-d), furoflavones (10a-d, 11a-d, 12a-d, 18a&b), flavones (21a-d), furoaurones (13a,b, 14a-d and 15a-d) and 7-styrylfurochromones (22a-d and 25a-e) were designed and synthesized. The novel compounds were evaluated for their antiproliferative activity against a panel of 60 cancer cell lines comprising 9 types of tumors. Ten compounds belonging to the major subgroups of flavonoids viz furochalcones (3a, 3d, 6b, 9a and 9b), furoflavones (12a and 12c), furoaurones (15d), styrylfurochromones (25b and 25e) showed very promising activity. These active compounds were also evaluated in vitro as kinase inhibitors against CDK2/cyclin E1, CDK4/cyclin D1 and GSK-3? and the best inhibition was displayed against GSK-3? with the allylfurochalcone derivative 9b exhibiting 80% decrease in GSK-3? catalytic activity. On the other hand, the styrylfurochromone 25e interestingly showed a 13% enhancement of GSK-3? catalytic power and a 12% reduction in CDK4/cyclin D1 activity. Finally, the in vivo anti-tumor activity of 25e was evaluated against breast cancer induced in mice. The results showed a profound anti-tumor effect of 25e that accompanies a significant increase and decrease in the levels of GSK-3? and cyclin D1, respectively. � 2014 Elsevier Masson SAS. All rights reserved.EnglishCytotoxicityFuroauronesFurochalconesFuroflavonesFurostyrylfurochromonesKinase inhibition1 (6 hydroxy 4 methoxy 1 benzofuran 5 yl) 3 (2 methoxyphenyl)prop 2 en 1 one1 (6 hydroxy 4 methoxy 1 benzofuran 5 yl) 3 (substituted)phenylprop 2 en 1 one1 (7 allyl 6 hydroxy 4 methoxy 1 benzofuran 5 yl) 3 (4 chlorophenyl) prop 2 en 1 one1 (7 allyl 6 hydroxy 4 methoxy 1 benzofuran 5 yl) 3 (substituted)phenyl prop 2 en 1 one1 (7 allyl 6 hydroxy 4 methoxybenzofuran 5 yl) 3 (2methoxyphenyl)prop 2 en 1 one1 (7 bromo 6 hydroxy 4 methoxy 1 benzofuran 5 yl) 3 (2 methoxy phenyl)prop 2 en 1 one1 (7 bromo 6 hydroxy 4 methoxy 1 benzofuran 5 yl) 3 (4 methoxy phenyl)prop 2 en 1 one1 (7 bromo 6 hydroxy 4 methoxy 1 benzofuran 5 yl) 3 (chlorophenyl)prop 2 en 1 one1 (7 bromo 6 hydroxy 4 methoxy 1 benzofuran-5 yl) 3 phenylprop 2 en 1 one1 (7 bromo 6 hydroxy 4 methoxy 1 benzofuran-5 yl) 3 substituted phenylprop 2 en 1 one3 (4 methoxy 5 oxo 7 (substituted)phenyl 5h furo[3,2 g]chromen 9 yl)acrylaldehyde3 (4 methoxy 5 oxo 7 phenyl 5h furo[3,2 g]chromen 9 yl) acrylaldehyde3 [4 methoxy 7 (4 methoxyphenyl) 5 oxo 5h furo[3,2 g] chromen 9 yl]acryl aldehyde3 [7 (4 chlorophenyl) 4 methoxy 5 oxo 5h furo[3,2 g] chromen 9 yl]acrylaldehyde4 methoxy 7 (2 methoxyphenyl) 5h furo[3,2 g]chromen 5 one4 methoxy 7 (substituted)phenyl furo[3,2 g]chromen 5 one4,9 dimethoxy 7 [2 (4 dimethylaminophenyl)vinyl] 6 (morpholin 4 ylmethyl) 5h furo [3,2 g]chromen 5 one9 bromo 4 methoxy 7 (2 methoxyphenyl) 5h furo[3,2 g] chromen 5 one9 bromo 4 methoxy 7 (4 methoxyphenyl) 5h furo[3,2 g] chromen 5 one9 bromo 4 methoxy 7 (substituted)phenyl furo[3,2 g]chromen 5 one9 bromo 4 methoxy 7 phenyl 5h furo[3,2 g]chromen 5 one9 bromo 7 (4 chlorophenyl) 4 methoxy 5h furo[3,2 g]chromen 5 oneantineoplastic agentcyclin D1cyclin dependent kinase 2cyclin dependent kinase 4cyclin Eflavonoidglycogen synthase kinase 3betaunclassified drugunindexed drugantineoplastic agentflavonoidanimal experimentanimal modelantineoplastic activityantiproliferative activityarticlebrain cancerbreast cancercancer cellcancer inhibitioncancer sizecolon cancercontrolled studydrug cytotoxicitydrug designdrug mechanismdrug megadosedrug screeningdrug synthesisEhrlich ascites tumorenzyme activityenzyme inhibitionhumanhuman cellkidney cancerleukemialow drug doselung non small cell cancermelanomamousenonhumanprostate cancerprotein expressionproton nuclear magnetic resonancestereospecificitystructure activity relationanimalBagg albino mouseCarcinoma, Ehrlich Tumorcell proliferationchemical structurechemistrydose responsedrug effectsfemalepathologystructure activity relationsynthesistumor cell lineAnimalsAntineoplastic AgentsCarcinoma, Ehrlich TumorCell Line, TumorCell ProliferationDose-Response Relationship, DrugDrug DesignDrug Screening Assays, AntitumorFemaleFlavonoidsHumansMiceMice, Inbred BALB CMolecular StructureStructure-Activity RelationshipArticlehttps://doi.org/10.1016/j.ejmech.2014.06.007PubMed ID 24937184