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 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 GI(50) value of 0.84 microM. 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 microM. 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.
Chen
I-Li
IL
Department of Pharmacy, Tajen University, Pingtung 907, Taiwan.
Chen
Jhy-Yih
JY
Shieh
Po-Chuen
PC
Chen
Jih-Jung
JJ
Lee
Choa-Hsun
CH
Juang
Shin-Hun
SH
Wang
Tai-Chi
TC
D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D006801:Humans; D007529:Isoflavones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D013329:Structure-Activity Relationship
D000577:Amides; D000970:Antineoplastic Agents; D007529:Isoflavones