Synthesis and antioxidant activity of 3-methoxyflavones

It is becoming increasingly apparent that the overproduction of reactive oxygen species may overwhelm the protective antioxidative defense mechanisms resulting in oxidative tissue injury. Reactive oxygen species have been implicated in several different diseases including ischemia, inflammation and cancer. Fortunately, plants contain a wide variety of free radical scavenging molecules such as flavonoids, anthocyanins, carotenoids, dietary glutathione, vitamins and endogenous metabolites. Such natural products are rich in antioxidant activities. Recently, important biological property of natural flavonoids was suggested mainly due to their antioxidant activity elicited by scavenging oxygen radicals and inhibiting peroxidation. Also, the antioxidant activity of the flavonoids varies considerably depending on the backbone structures and functional groups. In the course of searching for neuroprotective agents, we recently identified quercetin 3-O-methyl ether (1b, R1, R3, R4 = H, R2 = OH) as a potent antioxidant from Opuntia ficus-indica var. saboten. Quercetin 3-O-methyl ether also exhibited potent neuroprotective effects on the oxidative injuries to neuronal cells. For the purpose of the development of neuroprotective agents for therapeutic use, we needed to modify the structure or substitute suitable groups in the structure of 1b to improve physicochemical properties or enhance antioxidant activities. Therefore, we synthesized a series of 3-methoxyflavones (1c-g) and examined their antioxidant activities to elucidate a suitable position for modification (Figure 1). To investigate briefly the influence of substituents of 3-methoxyflavones on antioxidant activity, we methylated the C-5 or C-7 hydroxyl group at A-ring of the chromone backbone or introduced mono-, di-, and trihydroxyl groups at B-ring.