Synthesis of Ochnaflavone and Its Inhibitory Activity on PGE₂Production

This is the authors' abstract. We don't add key points for this paper.

Ochnaflavone, a naturally occurring biflavonoid composed of two units of apigenin (5,7,4'-trihydroxyflavone) joined via a C-O-C linkage, was first synthesized and evaluated its inhibitory activity on <TEX>PGE₂</TEX> production. Total synthesis was accomplished through modified Ullmann diaryl ether formation as a key step. Coupling reactions of 4'-halogenoflavones and 3'-hydroxy-5,7,4'-trimethoxyflavone were explored in diverse reaction conditions. The reaction of 4'-fluoro-5,7-dimethoxyflavone (2c) and 3'-hydroxy-5,7,4'-trimethoxyflavone (2d) in N,N-dimethylacetamide gave the coupled compound 3 in 58% yield. Synthetic ochnaflavone strongly inhibited PGE2 production (<TEX>IC₅₀=1.08μM</TEX>) from LPS-activated RAW 264.7 cells, which was due to reduced expression of COX-2. On the contrary, the inhibition mechanism of wogonin was somewhat different from that of ochnaflavone although wogonin, a natural occurring anti-inflammatory flavonoid, showed strong inhibitory activity of <TEX>PGE₂</TEX> production (<TEX>IC₅₀=0.52μM</TEX>), and seems to be COX-2 enzyme inhibition. Our concise total synthesis of ochnaflavone enable us to provide sufficient quantities of material for advanced biological studies as well as to efficiently prepare derivatives for structure-activity relationship study.