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 H(2)SO(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. avone-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 GI(50) value of 0.84 mu M. 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 mu M. 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. (C) 2008 Elsevier Ltd. All rights reserved.