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

• Published in: Bioorganic & medicinal chemistry 2008-08, Vol.16 (16), p.7639-7645
• Main Authors: Chen, I-Li, Chen, Jhy-Yih, Shieh, Po-Chuen, Chen, Jih-Jung, Lee, Choa-Hsun, Juang, Shin-Hun, Wang, Tai-Chi
• Format: Article
• Language: English
• Subjects: Amides - chemical synthesis; Amides - chemistry; Amides - pharmacology; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antiproliferative activity; Apoptosis; Biological and medical sciences; Cell Cycle - drug effects; Cell Growth Processes - drug effects; Cell Line, Tumor; Cytotoxicity; Flavone; General aspects; Humans; Isoflavone; Isoflavones - chemical synthesis; Isoflavones - chemistry; Isoflavones - pharmacology; Magnetic Resonance Spectroscopy; Medical sciences; Pharmacology. Drug treatments; Structure-Activity Relationship
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2008.07.013

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.