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

Abstract

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 H 2SO 4 and NaN 3 (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-4 H-chromen-6-yloxy)acetamide ( 16c) was the most potent with a GI 50 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 GI 50 value of 0.84 μM. The oxime derivatives 1 and 2 caused accumulation of NPC-TW01 cell in G 2/M phase which were distinct from that of their amide isomers 16b and 16c, respectively, which induced cell-cycle arrest in G 0/G 1 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.