Study on the Synthesis and Structure-activity Relationship of 3-Styrylflavones Possessing Variously Hydroxylated...

Flavones are known as a prominent subclass within the flavonoid family and occupy an important part of the human diet. Their distinctive structure has been considered to show the activities and thus they represent a privileged scaffold in medicinal chemistry. Although we recently reported the systematic synthesis of polymethoxylated 3-styrylflavones, they did not show significant antiproliferative activity. Therefore, we designed and synthesized a series of 3-styrylflavones possessing a variously hydroxylated D-ring moiety due to investigating contribution of the hydroxyl groups to the antiproliferative activity.

3-Styrylflavones with a hydroxylated D-ring were systematically synthesized by the Wittig reaction between the various hydroxylated benzaldehyde derivatives and the 3-(bromomethyl)flavone derivatives prepared from 3-methylflavones, and their antiproliferative activity against HL60 was evaluated.

Among the synthesized compounds, 2‴,5‴-dihydroxy-2',3',4'-trimethoxy-3-styrylflavone and 2‴,5‴-dihydroxy-3',4',5'-trimethoxy-3-styrylflavone (IC₅₀=16 μM) demonstrated the most significant antiproliferative activity.

The introduction of a hydroxyl group in 3-styryl substituent of 3-styrylflavone greatly increased the antiproliferative activity. Structure-activity relationship studies clearly indicated the importance of the hydroquinone structure as the D-ring moiety and suggested the possibility that the 3-styrylflavones possessing hydroquinone-type D-ring moiety act as "mitocan".