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A variety of polyphenols have been isolated from plants, and their biological activities have been examined. Sudachitin (5,7,4′-trihydroxy-6,8,3′-trimethoxyflavone) is a polymethoxyflavone that is isolated from the peel of Citrus sudachi. Although we previously reported that sudachitin possesses an anti-inflammatory activity, its other biological activities are not yet understood. In this study, we report a novel biological activity of sudachitin, which selectively induced apoptosis in human keratinocyte HaCaT cells. Another polymethoxyflavone, nobiletin (5,6,7,8,3′,4′-hexamethoxyflavone), promoted autophagy but not apoptosis in HaCaT cells. On the other hand, 3′-demethoxysudachitin (5,7,4′-trihydroxy-6,8-dimethoxyflavone) failed to induce apoptosis and autophagy. These results show that three polymethoxyflavones have different effects on apoptosis and autophagy in HaCaT cells. Understanding the structure and biological activity of polymethoxyflavones may lead to the discovery of potential candidates for cancer drug development without significant toxic side effects. Abbreviations: ROS: reactive oxygen species; DMSO: dimethyl sulfoxide; MTT: 3-(4, 5-dimethylthiazol-2yl)-2, 5-diphenyltetrazolium bromide; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; PARP: poly(ADP-ribose) polymerase; PI: propidium iodide; MAPK: mitogen-activated protein kinase.

マイクロ波照射によるメタノール中ユコウ搾汁乾燥果皮から生理活性機能性物質タンゲレチンとノビレチンが迅速・効率よく分離され，ヘスペリジン以外にこれら2種の化合物の存在が始めて明らかにされた．マイクロ波の2.5～5分間の照射によるユコウ乾燥果皮中のポリメトキシフラボンの抽出は，通常加熱抽出法に比べて極めて短い時間で効率よく分離され優れていることが分かった．これらの結果からマイクロ波抽出法は，柑橘類搾汁残渣（果皮）からの有用成分の効率的抽出法として応用できる可能性があり，再利用に有効であることを示唆している．

2', 4'-Bis(benzyloxy)-3', 6'-dimethoxychalcones (5), which were obtained from the dibenzyl ether of 2, 4-dihydroxy-3, 6-dimethoxyacetophenone (3), were oxidatively rearranged with thallium (III) nitrate in methanol and the resultant products were converted into 7-hydroxy-5, 8-dimethoxyisoflavones (8) by hydrogenolysis, followed by cyclization. The isoflavones were quantitatively demethylated to 5, 7-dihydroxy-8-methoxyisoflavones (2) via their acetates. The isomeric 5, 7-dihydroxy-6-methoxyisoflavones (1) were also synthesized from the chalcones, obtained from 2, 3-dimethoxy- (16) or 2-isopropoxy-3-methoxy-4, 6-bis(benzyloxy)acetophenones (21), by a similar method. On the other hand, the isoflavones with two hydroxy groups at the 2'- and 4'-positions were easily synthesized by the following method. Treatment of the rearranged product from 2, 2', 4, 4'-tetrakis(bezyloxy)-3', 6'-dimethoxychalcone (5f) with hydrochloric acid (HCl) in acetic acid afforded 2', 4', 7-tris(benzyloxy)-5, 8-dimethoxyisoflavone (10f). The 5-methoxy group in the isoflavone was quantitatively cleaved to give the corresponding 5-hydroxyisoflavone (11f), which was isomerized to 2', 4', 7-tris(benzyloxy)-5-hydroxy-6-methoxyisoflavone (25f) in the presence of anhydrous potassium carbonate. Hydrogenolysis of the two 5-hydroxyisoflavones proceeded smoothly to give 2', 4', 5, 7-tetrahydroxy-8-(2f) and 6-methoxyisoflavones(1f), respectively. The 13C-NMR spectra of these isoflavones supported the proposed structures of polyhydroxyisoflavones. The proposed structures of two natural isoflavones were revised.

In the demethylation of 6-hydroxy-3, 4', 7-trimethoxy-5-tosyloxyflavone (1) with anhydrous aluminum bromide (AlBr3) or anhydrous aluminum chloride-sodium iodide (AlCl3-NaI) in acetonitrile, the elimination of the 5-tosyloxy group proceeded after demethylation to give 8-bromo-3, 6, 7-trihydroxy-4'-methoxyflavone (6) or 3, 6, 7-trihydroxy-4'-methoxyflavone (5) as a main product. The demethylation of 6-hydroxy-4', 7-dimethoxy-5-tosyloxyflavone (2) with AlCl3-NaI also afforded 6, 7-dihydroxy-4'-methoxyflavone (12), but that with AlBr3 afforded 8-bromo-5, 6, 7-trihydroxy-4'-methoxyflavone (13) as a main product. The demethylation of 1 with anhydrous aluminum chloride (AlCl3) was accompanied by migration of the tosyl group to give a mixture of 3, 6-dihydroxy-7, 4'-dimethoxy-5-tosyloxyflavone (3) and 5-hydroxy-3, 4', 7-trimethoxy-6-tosyloxyflavone (9), but that of 2 proceeded after the cleavage of the 5-tosyloxy group to give a mixture of 5, 6-dihydroxy-7, 4'-dimethoxy- (14) and 5, 6, 7-trihydroxy-4'-methoxyflavones (15) other than the corresponding 6-tosyloxyflavone (16). In the demethylation of the acetates of 1 and 2 with AlCl3, the cleavage of the 5-tosyloxy group proceeded prior to the demethylation to afford the corresponding 5, 6, 7-trihydroxyflavones (8 and 15), although the demethylation of the former acetate was accompanied by formation of 3, 5, 7-trihydroxy-4'-methoxy-6-tosyloxyflavone (10). Mechanisms are proposed for these reactions.

The demethylation of 3, 4-dioxygenated 6-methoxy-2-isopropoxyacetophenones was studied and it was found that 4-benzyloxy-6-hydroxy-3-methoxy-2-isopropoxyacetophenone was easily obtained from 4-benzyloxy-3, 6-dimethoxy-2-isopropoxyacetophenone by selective demethylation with anhydrous aluminum bromide-sodium iodide in acetonitrile. The acetophenone was converted into 7-benzyloxy-3-hydroxy-6-methoxy-5-isopropoxyflavones by cyclization followed by oxidation with dimethyldioxirane. The isopropoxy group in the flavones was selectively cleaved with anhydrous aluminum chloride via the corresponding tosylates to give 7-benzyloxy-3, 5-dihydroxy-6-methoxyflavones, which were converted into the desired 3, 5, 7-trihydroxy-6-methoxyflavones by hydrogenolysis. The process was suitable as a general method for synthesizing 3, 5, 7-trihydroxy-6-methoxyflavones and five flavones were synthesized. We also examined the 13C-NMR spectra of twelve kinds of 3, 5, 6, 7-tetraoxygenated 4'-methoxyflavones and revised the proposed structure of a natural flavone.

Although some polymethoxyflavones possess several important biological properties, including neuroprotective, anticancer, and anti-inflammatory ones, sudachitin, a polymethoxyflavone from Citrus sudachi, has been little studied. In this study, we found that sudachitin inhibited nitric oxide production by suppressing the expression of inducible nitric oxide synthase in lipopolysaccharide-stimulated macrophages, indicating that sudachitin has an anti-inflammatory effect.

The palladium-catalyzed coupling reaction of 6-iodoisoflavone, prepared from 3'-iodoacetophenone derivative, with 2-methyl-3-butyn-2-ol gave 6-alkynylisoflavone derivative, which was hydrogenated to give 6-alkylhydroxyisoflavone (luteone hydrate) (2). Dehydration of 2 gave 2',4',5,7-tetrahydroxy-6-prenylisoflavone (luteone) (1). Wighteone hydrate (3) was also synthesized from 6-iodotris(benzyloxy)isoflavone in a similar manner. 6-Alkyl-4'5,7-trihydroxy-coumaronochromone (4) was synthesized by oxidative cyclization of 2 with o-chloranil.

The condensation of 6', 7-bis(benzoyloxy)-2', 4'-dimethoxyisolfavone (18) with 2-methyl-3-buten-2-ol, followed by hydrolysis of the resultant 6', 7-bis(benzoyloxy)-2', 4'-dimethoxy-3'-(3-methyl-2-butenyl)isoflavone (19) gave 6', 7-dihydroxy-2', 4'-dimethoxy-3'-(3-methyl-2-butenyl)-isoflavone (licoricone) (1). Its isomer, 6', 7-dihydroxy-2', 4'-dimethoxy-5'-(3-methyl-2-butenyl)-isoflavone (2), was also synthesized from 7-benzoyloxy-6'-hydroxy- or 6', 7-bis(benzoyloxy)-2', 4'-dimethoxy-5'-(3-methyl-2-butenyl)isoflavone (11 or 20).

2-Hydroxy-3, 4, 6-trimethoxy-ω- (ρ-methoxybenzoyloxy) acetophenone was prepared from 2, 3, 4, 6-tetramethoxyacetophenone via the corresponding ω-bromoacetophenone. Cyclization of the acetophenone with ρ-methoxybenzoic anhydride by application of the Allan-Robinson reaction afforded 3-hydroxy-4', 5, 7, 8-tetramethoxyflavone along with 2- (α-hydroxy-4-methoxybenzylidene) -4, 6, 7-trimethoxycoumaranone. The 5-methoxy group in the tosylate or mesylate of the 3-hydroxyflavone was selectively cleaved with anhydrous aluminum bromide in acetonitrile to give the corresponding 5-hydroxyflavone, which was converted into 3, 5-dihydroxy-4', 7, 8-trimethoxyflavone with anhydrous potassium carbonate in methanol. 3, 3', 4', 5-Tetrahydroxy-7, 8-dimethoxyflavone was also synthesized by a similar method. The demethylation of the 5-methoxy group in flavones with a 3-hydroxy group is applicable to the synthesis of 3, 5-dihydroxyflavones.

Condensation of 7-hydroxy-2,2-dimethylchroman with benzoyloxyacetonitrile gave 7-hydroxy-6-benzoyl-oxyacetyl-2,2-dimethylchroman (3) which was converted into 7-hydroxy-6-acetoxyacetyl-2,2-dimethylchroman (7) in four steps. Dehydrogenation of 7 with DDQ in dried toluene afforded ripariochromene B (1). Ripariochromene B was also synthesized by oxidative cyclization of 2,4-dihydroxy-5-(3-methyl-2-butenyl)-ω-acetoxy-acetophenone (13) which was prepared from resorcinol and acetoxyacetonitrile in two steps. Ripariochromene C (2) was synthesized from resorcinol by the same method as that described above.

2′,4′,5,7-Tetrahydroxyisoflavone was partially benzoylated with benzoyl chloride to give 7-benzoyloxy-2′, 4′,5-trihydroxyisoflavone. The condensation of the 7-(benzoyloxy)isoflavone with 2-methyl-3-buten-2-ol, followed by the hydrolysis of the resultant 3′-(3-methyl-2-butenyl)isoflavone gave licoisoflavone A. Its 5′-(3-methyl-2-butenyl) isomer was also synthesized from 5-benzoyloxy-2′,4′,7-trihydroxyisoflavone in a similar manner.

The 5-methoxy group on 3, 5, 6, 7-tetramethoxyflavones and the 3-methoxy group on 3, 6, 7-trimethoxy-5-tosyloxyflavones were selectively cleaved with anhydrous aluminum bromide in acetonitrile under controlled conditions without the cleavage of benzyloxy groups on the B ring. By the application of these reactions, seven 3, 5-dihydroxy-6, 7-dimethoxyflavones were easily synthesized from the corresponding 3, 5, 6, 7-tetramethoxyflavones which were synthesized from 3, 6-dihydroxy-2, 4-ω-trimethoxyacetophenone by means of the Allan-Robinson reaction followed by methylation.

Sudachiin A was isolated from the green peels of Citrus sudachi Hort. ex Shirai. This structure was deduced to be sudachitin 4′-β-D-glucoside by means of its spectra and degradation; this was confirmed by the synthesis of the one from sudachitin 7-benzyl ether and α-acetobromoglucose via several steps. 4′,5,7-Trihydroxy-3′,6,8-trimethoxyflavone 7-glucoside (sudachitin 7-β-D-glucoside), which was isolated from Sideritis leucantha Cavanilles, was also synthesized from sudachitin and α-acetobromoglucose in a similar manner.

The 3- or 5-methoxyl group in the ditosylates of 5,7-dihydroxy-3,4′,8-trimethoxy- and 3,7-dihydroxy-4′,5,8-trimethoxyflavones was quantitatively demethylated with anhydrous aluminum bromide in acet...

3', 4'-Bis(benzyloxy)-6-hydroxy-5, 7-dimethoxyflavone (15) was obtained from 6-hydroxy-2, 4-dimethoxy-3-(methoxymethoxy)acetophenone (13) via 6'-hydroxy-2', 4'-dimethoxy-3'-methoxy-methoxy-2-[3, 4-bis(benzyloxy)benzoyl]acetophenone (14). The 5-methoxyl group of the acetate (16) of the flavone (15) was selectively split with about 5% (w/v) anhydrous aluminum chloride in acetonitrile to give 6-acetoxy-3', 4'-bix(benzyloxy)-5-hydroxy-7-methoxyflavone (17). The 5-hydroxyflavone (17) was converted into 3', 4', 5-tris(benzyloxy)-6-hydroxy-8-methoxyflavone (20) by benzylation and hydrolysis. Condensation of the 6-hydroxyflavone (20) with 2, 3, 4, 6-tetra-O-acetyl-α-D-glucosyl bromide, folowed by hydrolysis of the resultant compound afforded the corresponding 6-O-β-D-glucoside (22), which was converted into 3', 4', 5, 6-tetrahydroxy-7-methoxyflavone 6-O-β-D-glucoside (pedaliin) (1) by hydrogenolysis. The process should be useful as a general method for synthesizing 6-O-glucosides of 5, 6-dihydroxy-7-methoxyflavones.

硝酸ベンジルエステル類の不均一相 7% 硝酸酸化を検討した。この酸化反応も塩化ベンジル類の酸化と同様に, アルコールを経てアルデヒドまで酸化され, o-置換体よりも p-置換体の酸化が容易で, 多量の希硝酸を用いて酸化すれぽ, 好収率でアルデヒドが得られた。しかし, 硝酸 o-ニトロベンジルエステルの酸化については, o-置換体が p-置換体よりも酸化が容易で, アルデヒド収率も高くなっている。また, この酸化生成物から対応するベンズアルデヒドおよびベンジルアルコール以外に, 少量の 2,4-ジニトロフェノールが分離された。これらのことは, o-ニトロ基の関与を仮定することにより説明できる。

A 1,8-dioxaanthracenepropionic acid derivative (5), after being converted into methyl ester-methyl ether (6), was reduced with sodium borohydride to give methyl eriostate (7). Hydrolysis of the ester (7) with alkali afforded eriostoic acid (1). On the other hand, eriostemoic acid (2) was synthesized from methyl eriostemate (10), which was obtained from a 1,5-dioxaphenanthrenepropionic acid derivative (8) via four steps.

The condensation of 7-benzoyloxy-4′-hydroxyisoflavone with 2-methyl-3-buten-2-ol gave 7-benzoyloxy-4′-hydroxy-3′-(3-methyl-2-butenyl)isoflavone. The hydrolysis of the alkylated isoflavone with dilute alkali afforded neobavaisoflavone [7,4′-dihydroxy-3′-(3-methyl-2-butenyl)isoflavone], which was then converted into isoneobavaisoflavone on heating with formic acid. 7-Benzyloxy-4′-hydroxyisoflavone was condensed with 2-methyl-3-buten-2-ol to give a chroman derivative, which was then converted into isoneobavaisoflavone by hydrolysis. 3′-(3-Methyl-2-butenyl)-5,7,4′-trihydroxyisoflavone was also synthesized from 7-benzoyloxy-5,4′-dihydroxyisoflavone in a similar manner.

5,2′-Dihydroxy-6,8-dimethoxyflavone, which had been proposed as the structure of skullcapflavone I isolated from Scutellaria baicalensis Georgi, was synthesized from 2-hydroxy-3,5,6-trimethoxyaceto...

7,8-Dimethoxy-2,2-dimethylchroman was obtained from pyrogallol trimethyl ether and β,β-dimethylacrylyl chloride via the corresponding chroman-4-one. The Friedel-Crafts reaction of the chroman with acetyl chloride yielded 6-acetyl-7-hydroxy-8-methoxy-2,2-dimethylchroman. The dehydrogenation of the acetylchroman with DDQ in anhydrous benzene afforded ripariochromene A. Ripariochromene A was converted into methylripariochromene A

Kaempferol-3-O-rhamnoglucoside, a flavonoid glycoside, was isolated from fresh withe petals of Zephyranthes candida.

Condensation of 7-benzoyldaidzein (III) with 2-methyl-3-buten-2-ol gave 7-benzoyl-3′-(3-methyl-2-butenyl)daidzein (IV). Hydrolysis of IV with dilute alkali gave 3′-(3-methyl-2-butenyl)daidzein (neobavaisoflavone) (I), which was converted into isoneobavaisoflavone (VI) when heated with formic acid. 7-Benzyldaidzein (VII) was condensed with 2-methyl-3-buten-2-ol to give a chroman derivative (VIII), which was converted into VI by hydrogenolysis.

Background Obesity is a major risk factor for insulin resistance, type 2 diabetes, and stroke. Flavonoids are effective antioxidants that protect against these chronic diseases. In this study, we evaluated the effects of sudachitin, a polymethoxylated flavonoid found in the skin of the Citrus sudachi fruit, on glucose, lipid, and energy metabolism in mice with high-fat diet-induced obesity and db/db diabetic mice. In our current study, we show that sudachitin improves metabolism and stimulates mitochondrial biogenesis, thereby increasing energy expenditure and reducing weight gain. Methods C57BL/6 J mice fed a high-fat diet (40% fat) and db/db mice fed a normal diet were treated orally with 5 mg/kg sudachitin or vehicle for 12 weeks. Following treatment, oxygen expenditure was assessed using indirect calorimetry, while glucose tolerance, insulin sensitivity, and indices of dyslipidemia were assessed by serum biochemistry. Quantitative polymerase chain reaction was used to determine the effect of sudachitin on the transcription of key metabolism-regulating genes in the skeletal muscle, liver, and white and brown adipose tissues. Primary myocytes were also prepared to examine the signaling mechanisms targeted by sudachitin in vitro. Results Sudachitin improved dyslipidemia, as evidenced by reduction in triglyceride and free fatty acid levels, and improved glucose tolerance and insulin resistance. It also enhanced energy expenditure and fatty acid β-oxidation by increasing mitochondrial biogenesis and function. The in vitro assay results suggest that sudachitin increased Sirt1 and PGC-1α expression in the skeletal muscle. Conclusions Sudachitin may improve dyslipidemia and metabolic syndrome by improving energy metabolism. Furthermore, it also induces mitochondrial biogenesis to protect against metabolic disorders.