Synthesis of ochnaflavone and its inhibitory activity on PGE 2 production

Abstract

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 PGE 2 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 PGE 2 production (IC 50 = 1.08 μM) 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 PGE 2 production (IC 50 = 0.52 μM), 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.