Design, synthesis and structure-activity relationship of novel semi-synthetic flavonoids as antiproliferative agents

Ragab F.A.; Yahya T.A.A.; El-Naa M.M.; Arafa R.K.

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Design, synthesis and structure-activity relationship of novel semi-synthetic flavonoids as antiproliferative agents

Ragab F.A.; Yahya T.A.A.; El-Naa M.M.; Arafa R.K.

Full Text link: https://t.ly/2d3Xk

Date issued: 2014

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Doi: https://doi.org/10.1016/j.ejmech.2014.06.007 PubMed ID 24937184

Publisher: Elsevier Masson SAS

Series Info: European Journal of Medicinal Chemistry
82

Type: Article

Keywords: Cytotoxicity , Furoaurones , Furochalcones , Furoflavones , Furostyrylfurochromones , Kinase inhibition , 1 (6 hydroxy 4 methoxy 1 benzofuran 5 yl) 3 (2 methoxyphenyl)prop 2 en 1 one , 1 (6 hydroxy 4 methoxy 1 benzofuran 5 yl) 3 (substituted)phenylprop 2 en 1 one , 1 (7 allyl 6 hydroxy 4 methoxy 1 benzofuran 5 yl) 3 (4 chlorophenyl) prop 2 en 1 one , 1 (7 allyl 6 hydroxy 4 methoxy 1 benzofuran 5 yl) 3 (substituted)phenyl prop 2 en 1 one , 1 (7 allyl 6 hydroxy 4 methoxybenzofuran 5 yl) 3 (2methoxyphenyl)prop 2 en 1 one , 1 (7 bromo 6 hydroxy 4 methoxy 1 benzofuran 5 yl) 3 (2 methoxy phenyl)prop 2 en 1 one , 1 (7 bromo 6 hydroxy 4 methoxy 1 benzofuran 5 yl) 3 (4 methoxy phenyl)prop 2 en 1 one , 1 (7 bromo 6 hydroxy 4 methoxy 1 benzofuran 5 yl) 3 (chlorophenyl)prop 2 en 1 one , 1 (7 bromo 6 hydroxy 4 methoxy 1 benzofuran-5 yl) 3 phenylprop 2 en 1 one , 1 (7 bromo 6 hydroxy 4 methoxy 1 benzofuran-5 yl) 3 substituted phenylprop 2 en 1 one , 3 (4 methoxy 5 oxo 7 (substituted)phenyl 5h furo[3,2 g]chromen 9 yl)acrylaldehyde , 3 (4 methoxy 5 oxo 7 phenyl 5h furo[3,2 g]chromen 9 yl) acrylaldehyde , 3 [4 methoxy 7 (4 methoxyphenyl) 5 oxo 5h furo[3,2 g] chromen 9 yl]acryl aldehyde , 3 [7 (4 chlorophenyl) 4 methoxy 5 oxo 5h furo[3,2 g] chromen 9 yl]acrylaldehyde , 4 methoxy 7 (2 methoxyphenyl) 5h furo[3,2 g]chromen 5 one , 4 methoxy 7 (substituted)phenyl furo[3,2 g]chromen 5 one , 4,9 dimethoxy 7 [2 (4 dimethylaminophenyl)vinyl] 6 (morpholin 4 ylmethyl) 5h furo [3,2 g]chromen 5 one , 9 bromo 4 methoxy 7 (2 methoxyphenyl) 5h furo[3,2 g] chromen 5 one , 9 bromo 4 methoxy 7 (4 methoxyphenyl) 5h furo[3,2 g] chromen 5 one , 9 bromo 4 methoxy 7 (substituted)phenyl furo[3,2 g]chromen 5 one , 9 bromo 4 methoxy 7 phenyl 5h furo[3,2 g]chromen 5 one , 9 bromo 7 (4 chlorophenyl) 4 methoxy 5h furo[3,2 g]chromen 5 one , antineoplastic agent , cyclin D1 , cyclin dependent kinase 2 , cyclin dependent kinase 4 , cyclin E , flavonoid , glycogen synthase kinase 3beta , unclassified drug , unindexed drug , antineoplastic agent , flavonoid , animal experiment , animal model , antineoplastic activity , antiproliferative activity , article , brain cancer , breast cancer , cancer cell , cancer inhibition , cancer size , colon cancer , controlled study , drug cytotoxicity , drug design , drug mechanism , drug megadose , drug screening , drug synthesis , Ehrlich ascites tumor , enzyme activity , enzyme inhibition , human , human cell , kidney cancer , leukemia , low drug dose , lung non small cell cancer , melanoma , mouse , nonhuman , prostate cancer , protein expression , proton nuclear magnetic resonance , stereospecificity , structure activity relation , animal , Bagg albino mouse , Carcinoma, Ehrlich Tumor , cell proliferation , chemical structure , chemistry , dose response , drug effects , female , pathology , structure activity relation , synthesis , tumor cell line , Animals , Antineoplastic Agents , Carcinoma, Ehrlich Tumor , Cell Line, Tumor , Cell Proliferation , Dose-Response Relationship, Drug , Drug Design , Drug Screening Assays, Antitumor , Female , Flavonoids , Humans , Mice , Mice, Inbred BALB C , Molecular Structure , Structure-Activity Relationship

Abstract:

Various 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.