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

• Novel semisynthetic flavonoid derivatives were prepared as antiproliferative agents.
• 9a, 9b, 25c and 25e showed the lowest results for GI50, TGI and LC50.
• Kinase inhibitory ability against CDK2/cyclin E1, CDK4/cyclin D1 and GSK-3β.
• Mice-bearing EAC solid tumor were used to test the in vivo antitumor activity of 25e.
• 25e caused decrease in tumor size, increase in GSK-3β and decrease in cyclin D1.

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-3β and the best inhibition was displayed against GSK-3β with the allylfurochalcone derivative 9b exhibiting 80% decrease in GSK-3β catalytic activity. On the other hand, the styrylfurochromone 25e interestingly showed a 13% enhancement of GSK-3β 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-3β and cyclin D1, respectively.

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