JP5555166B2 - 新規エピガロカテキンガレート3量体、およびエピガロカテキンガレート重合体を含むα−グルコシダーゼ阻害剤 - Google Patents
新規エピガロカテキンガレート3量体、およびエピガロカテキンガレート重合体を含むα−グルコシダーゼ阻害剤 Download PDFInfo
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- JP5555166B2 JP5555166B2 JP2010526793A JP2010526793A JP5555166B2 JP 5555166 B2 JP5555166 B2 JP 5555166B2 JP 2010526793 A JP2010526793 A JP 2010526793A JP 2010526793 A JP2010526793 A JP 2010526793A JP 5555166 B2 JP5555166 B2 JP 5555166B2
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- DZGQZNRJDFZFLV-UHFFFAOYSA-N theaflavin 3,3'-digallate Natural products OC1=CC(=Cc2cc(C3Oc4cc(O)cc(O)c4CC3OC(=O)c5cc(O)c(O)c(O)c5)c(O)c(O)c2C1=O)C6Oc7cc(O)cc(O)c7CC6OC(=O)c8cc(O)c(O)c(O)c8 DZGQZNRJDFZFLV-UHFFFAOYSA-N 0.000 description 1
- LYDDTLMHZWWJST-UHFFFAOYSA-N theaflavin 3-O-gallate Natural products OC1Cc2c(O)cc(O)cc2OC1c3cc(O)c(O)c4C(=O)C(=C(C=Cc34)C5Oc6cc(O)cc(O)c6CC5OC(=O)c7cc(O)c(O)c(O)c7)O LYDDTLMHZWWJST-UHFFFAOYSA-N 0.000 description 1
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- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
- C07D311/60—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with aryl radicals attached in position 2
- C07D311/62—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with aryl radicals attached in position 2 with oxygen atoms directly attached in position 3, e.g. anthocyanidins
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- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
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- A61K31/33—Heterocyclic compounds
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- A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
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- C12N9/24—Hydrolases (3) acting on glycosyl compounds (3.2)
- C12N9/2402—Hydrolases (3) acting on glycosyl compounds (3.2) hydrolysing O- and S- glycosyl compounds (3.2.1)
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- C12N9/2408—Glucanases acting on alpha -1,4-glucosidic bonds
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Description
本発明は、新規エピガロカテキンガレート3量体およびエピガロカテキンガレート重合体を含むα−グルコシダーゼ阻害剤である。これらのα-グルコシダーゼ阻害剤は、小腸上皮上に局在するα-グルコシダーゼを阻害し、糖質の分解を抑えて吸収を抑制及び/又は遅延することにより、血糖値の上昇を抑制する。よって、これらのα-グルコシダーゼ阻害剤を飲食品などに添加することで、食事由来の糖分の吸収抑制、さらには高血糖症状の慢性化に起因する糖尿病の長期的な予防及び/又は治療を目的とした飲食品を提供することができる。
新規化合物
本発明は、EGCG3量体の新規化合物に関する。
本発明は、前記新規3量体またはその塩の少なくとも一種を含有する飲食品または医薬組成物に関する。
本発明は、EGCG重合体を有効成分とするα−グルコシダーゼ阻害剤である。より具体的には、EGCG2〜4量体を有効成分とするα−グルコシダーゼ阻害剤である。
本発明のα−グルコシダーゼ阻害剤を飲食品などに添加することで、食事由来の糖分の吸収抑制、さらには高血糖症状の慢性化に起因する糖尿病の長期的な予防及び/又は治療することを目的とした飲食品を提供することができる。
ア.合成とオープンカラムによる分画:
6gのEGCG(ロッシュ社。Teavigo(登録商標))を0.02N HClを含む120mlのエタノールに溶解し、4%ホルムアルデヒドのエタノール溶液180mlを加え、室温で4時間、撹拌した。反応終了後、純水で10倍に希釈し、吸着樹脂CHP−20Pカラム(600ml、37−75μm、三菱化学株式会社)に負荷した。1200mlの水で洗浄後、900mlの25%CH3CN、1200mlの30%CH3CNで順次溶出し、25%CH3CN溶出画分は300mlずつ3フラクション(fr.1からfr.3)に分け、30%CH3CN溶出画分は300mlずつ4フラクション(fr.4からfr.7)に分画した。
イ.分取HPLC条件:
CHP−20Pカラム精製で得られた分画物をさらに逆相の分取HPLCで精製した。
<条件>
カラム: Develosil ODS−HG−5(5cmφx50cm、野村化学株式会社)
移動相:A:0.05%TFA/H2O、B:90%CH3CN,0.05%TFA/H2O、32ml/min
グラジエントプログラム:B20%アイソクラティック(30min)、B20%→B40%(100min)、B40%アイソクラティック(20min)
検出:A280nm
サンプル:CHP−20Pカラム精製で得られたfr.2からfr.7を、それぞれ20%CH3CNに溶解し、数回に分けて全量を負荷した。
ウ.化合物の構造解析:
分取HPLCで単離した化合物について、MSおよびNMR測定を行った。このうち、化合物5〜7のMSをQ−TOF Premier(Micromass社製、UK)により、ネガティブ、Vモードで測定したところ、それぞれm/z927.160、927.163、1397.248の[M−H]−のイオンピークが認められた。また、化合物5のNMRスペクトルデータは文献(Chem.Pharm.Bull 37(12),3255−3563(1989))に記載のウーロンホモビスフラバン−AのNMRスペクトルデータと一致した。化合物6のNMRスペクトルデータは文献(Chem.Pharm. Bull 37(12),3255−3563(1989))に記載のウーロンホモビスフラバン−BのNMRスペクトルデータと一致した。さらに、化合物7は特許出願(WO2005/116005)中の段落番号0029に化合物(4)として記載されているエピガロカテキン3量体(ウーロンホモビスフラバン−トリマー−1)のNMRスペクトルと一致した。これらの結果から、化合物5は式3に示すウーロンホモビスフラバン−Aと、化合物6は式4に示すウーロンホモビスフラバン−Bと、化合物7は式5に示すウーロンホモビスフラバン−トリマー−1と確認された。
化合物3:
ウーロンホモビスフラバン−トリマー−2(CD3OH中)の1HNMRは、δ 6.95, 6.92, 6.90, 6.60, 6.54, 6.44, 6.08, 6.02, 5.57, 5.55, 5.49, 5.18, 5.12, 4.91, 3.86, 3.83, 3.81, 3.76, 3.03, 3.01, 2.94, 2.89, 2.89, 2.82,のシグナル、13CNMRは、δ 167.72, 167.46, 167.37, 156.29, 155.25, 155.08, 154.79, 154.43, 153.64, 152.91, 151.64, 151.20, 147.00, 146.93, 146.38, 146.38, 146.34, 146.29, 140.03, 139.89, 139.89, 134.65, 134.48, 133.85, 130.64, 129.29, 129.10, 121.33, 121.14, 121.14, 110.31, 110.24, 110.24, 109.19, 108.07, 107.42, 107.05, 107.02, 106.79, 106.10, 101.59, 101.00, 100.45, 97.23, 96.71, 80.07, 79.94, 78.45, 70.00, 69.32, 69.28, 27.21, 27.21, 26.81, 17.91, 17.91のシグナルが認められた。
化合物4:
ウーロンホモビスフラバン−トリマー−4(DMSO−d6中)の1HNMRは、δ 10.46, 9.18, 9.16, 9.16, 9.12, 9.06, 9.05, 8.90, 8.88, 8.84,8.72, 8.69, 8.69, 8.46, 8.34, 8.05, 8.02, 8.00, 6.81, 6.78, 6.78, 6.52, 6.47, 6.35, 6.03, 5.93, 5.48, 5.46, 5.39, 5.04, 4.95, 4.89, 4.05, 3.95, 3.56, 3.56, 3.06, 3.00, 2.98, 2.76, 2.71, 2.67のシグナル、13CNMRは、δ 165.11, 165.09, 164.99, 157.66, 154.29, 153.82, 153.48, 153.07, 152.68, 152.23, 152.18, 150.88, 145.56, 145.52, 145.50, 145.26, 145.24, 145.23, 138.43, 138.43, 138.39, 132.34, 132.23, 132.19, 128.34, 128.34, 128.23, 119.17, 119.12, 119.04, 110.35, 110.31, 110.29, 109.19, 108.59, 108.56, 108.51, 106.97, 106.63, 105.26, 105.26, 105.13, 104.73, 101.28, 99.44, 99.41, 98.21, 97.34, 97.15, 96.03, 79.48, 79.07, 78.47, 69.95, 69.39, 69.28, 27.18, 26.98, 26.58, 18.16, 17.13のシグナルが認められた。
化合物1:
ウーロンホモビスフラバン−テトラマー−1は、1HNMR(DMSO−d6中)は、δ 10.34, 9.37, 9.17, 9.09, 9.01, 8.88, 8.75, 8.71, 8.68, 8.08, 8.04, 7.62, 6.81,6.77, 6.72, 6.55, 6.49, 6.39, 6.04, 5.86, 5.55, 5.47, 5.34, 5.23, 4.96, 4.79, 4.64, 4.04, 4.02, 3.92, 3.90, 3.85, 3.83, 3.73, 3.71, 3.64, 3.62, 3.54, 3.52, 3.07, 3.05, 2.96, 2.93, 2.74, 2.72, 2.70のシグナル、13CNMRは、δ165.29, 165.13, 165.02, 165.01,154.45, 154.44, 154.25, 152.33, 152.20, 151.97, 151.66, 151.62, 150.82, 150.66, 150.52, 149.66, 145.63, 145.56, 145.54, 145.50, 145.50, 145.27, 145.23, 145.18, 138.46, 138.38, 132.77, 132.26, 132.12, 128.50, 127.61, 119.20, 119.17, 118.96, 118.90, 108.73, 108.55, 107.05, 106.19, 105.19, 105.05, 104.31, 103.77, 99.01, 98.52, 77.44, 76.65, 76.51, 76.10, 67.53, 67.50, , 66.95, 66.63, 25.94, 25.63, 25.49, 25.30, 17.14, 16.74, 15.81のシグナルが認められた。
化合物2:
ウーロンホモビスフラバン−テトラマー−2は1HNMR(DMSO−d6)は、δ 9.91, 9.25, 9.16, 8.09, 7.22, 6.81, 6.76, 6.74, 6.52, 5.94, 5.50, 5.38, 4.77, 4.52, 3.95, 3.95, 3.80, 3.54, 2.80, 2.74, 2.73, 2.67のシグナル、13CNMRは、δ 165.08, 165.01, 154.06, 152.83, 152.35, 151.45, 150.78, 150.26, 145.52, 145.52, 145.24, 145.18, 138.49, 138.44, 132.21, 132.10, 128.42, 127.63, 119.05, 118.95, 108.58, 108.46, 108.46, 106.95, 105.74, 104.92, 104.06, 98.32, 97.81, 76.59, 75.94, 66.69, 66.35,26.33, 25.26, 16.72, 15.99のシグナルが認められた。
1Mリン酸ナトリウム緩衝液は、0.1M NaH2PO4・2H2Oと0.1M Na2HPO4・12H2Oを混合しpH7.0に調整し、2g/Lの牛血製アルブミン(ナカライテスク株式会社製、F−V、pH5.2、純度96%)および0.2g/LのNaN3(ナカライテスク株式会社製、試薬特級)を添加した。酵素溶液は上記、緩衝液にα−グルコシダーゼ(和光純薬工業株式会社製、酵母由来、100units/mg)を0.5units/mgタンパク/ml(100μg/20ml)となるように溶解した。基質溶液は、上記、緩衝液にp−ニトロフェニル−α−D−グルコピラノシド(ナカライテスク株式会社製、試薬特級)を5mM(7.525mg/5ml)となるように溶解した。
トリマーおよびテトラマーのLC−MS/MSの測定条件とサントリー黒烏龍茶の定量
EGCG重合物のLC−MS/MSの測定は、4000 Q TRAP(アプライド社製)で、ターボイオンスプレーを用い、以下の条件で測定した。Collision energy:46eV(nega.),Ionspray voltage:4500V,Temp:450℃。
カラム:Develosil C30−UG−3(野村化学、3mmφ×150mm)
流速:0.3ml/min、Column Temp.:40℃
移動相A:0.1%HCOOH/H2O、移動相B:0.1%HCOOH/CH3CN
グラジエントプログラム:B9%(0min)→B60%(17min)→B85%(17.1min)、B85%(17.1−19min)
これらの化合物は黒烏龍茶茶中に微量しか含まれないため、直接定量することは不可能であった。そこで、黒烏龍茶の調合液(殺菌前の溶液)をCHP−20Pカラム(三菱化学株式会社)でステップワイズに分画し、各フラクションの定量を行った後、各フラクションに検出された濃度を合算して茶溶液中の濃度とした。黒烏龍茶中の濃度は、トリマー類は検出された5成分をウーロンホモビスフラバン−トリマー−1換算で合算し、172ng/mlであった。テトラマー類は検出された4成分を合算し、ウーロンホモビスフラバン−テトラマー−2換算で55ng/mlであった。
Claims (3)
- エピガロカテキンガレート2量体、3量体および/または4量体を有効成分とするα−グルコシダーゼ阻害剤であって、
エピガロカテキンガレート2量体がウーロンホモビスフラバン−Bであり、
エピガロカテキンガレート3量体がウーロンホモビスフラバン−トリマー−1、ウーロンホモビスフラバン−トリマー−2、およびウーロンホモビスフラバン−トリマー−4から選択される一以上であり、
エピガロカテキンガレート4量体がウーロンホモビスフラバン−テトラマー−1および/またはウーロンホモビスフラバン−テトラマー−2である、
前記阻害剤。 - エピガロカテキンガレート3量体がウーロンホモビスフラバン−トリマー−4であり、エピガロカテキンガレート4量体がウーロンホモビスフラバン−テトラマー−1である、請求項1記載の阻害剤。
- 請求項1または2記載のα−グルコシダーゼ阻害剤を添加した血糖値上昇抑制用組成物。
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