Synthesis and antiproliferative evaluation of amide-containing flavone and isoflavone derivatives

Certain amide-containing flavone and isoflavone derivatives were synthesized and evaluated for their antiproliferative activities. These compounds were synthesized via alkylation of hydroxyl precursors followed by the reaction with H2SO4 and NaN3 (Schmidt reaction).The preliminary assays indicated that the inhibitory activity against the growth of NCI-H661 decreased in an order of linked chromophore flavone-6-yl 16a–d > flavone-7-yl 17a–d > flavone-3-yl 15a–d and isoflavone-7-yl 18a–d. Among these flavone-6-yl derivatives, N-(4-methoxyphenyl)-2-(4-oxo-2-phenyl-4H-chromen-6-yloxy)acetamide (16c) was the most potent with a GI50 value of 0.84 μM. The inhibitory activity against the growth of NPC-TW01 decreased in an order of linked chromophore flavone-6-yl 16a–d > isoflavone-7-yl 18a–d > flavone-7-yl 17a–d > flavone-3-yl 15a–d. Flavone-6-yl derivatives 16a–d demonstrated significant inhibitory activities against the growth of NPC-TW01 cell with an average GI50 value of 0.84 μM. The oxime derivatives 1 and 2 caused accumulation of NPC-TW01 cell in G2/M phase which were distinct from that of their amide isomers 16b and 16c, respectively, which induced cell-cycle arrest in G0/G1 phase followed by apoptosis. Therefore, the antiproliferative mechanism of flavone derivatives was affected not only by the phenyl benzopyran-4-one pharmacophore but also by the peripheral substituents.

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