JP5339848B2 - Nfatシグナル阻害剤、並びにnfatシグナル阻害活性を有する新規化合物 - Google Patents
Nfatシグナル阻害剤、並びにnfatシグナル阻害活性を有する新規化合物 Download PDFInfo
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- JP5339848B2 JP5339848B2 JP2008271078A JP2008271078A JP5339848B2 JP 5339848 B2 JP5339848 B2 JP 5339848B2 JP 2008271078 A JP2008271078 A JP 2008271078A JP 2008271078 A JP2008271078 A JP 2008271078A JP 5339848 B2 JP5339848 B2 JP 5339848B2
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Images
Description
本発明に係るNFATシグナル阻害剤は、アメリカンアンジェリカ植物又は当該植物の抽出物などから得ることが出来る。ここで、アメリカンアンジェリカとは、学名をAngelica atropurpureaと称し、セリ科に分類される植物である。
〔実施例1〕アメリカンアンジェリカからの活性成分類の単離
(1)図1に示す工程に従って、アメリカンアンジェリカ(Angelica atropurpurea(セリ科)の根茎から本発明の化合物「成分A」、「成分B」及び「成分C」を単離した。
fr. A: 0.23 g
fr. B: 0.01 g
fr. C: 0.03 g
fr. D: 0.07 g
fr. E: 0.05 g
fr. F: 0.02 g
fr. G: 0.02 g
fr. H: 0.15 g
fr. I: 0.24 g
fr. J: 0.10 g
fr. K: 0.03 g
fr. I - 1: 46.5 mg
fr. I - 2: 27.6 mg
fr. I - 3: 3.4 mg
fr. I - 4: 6.3 mg
fr. I - 5: 18.8 mg
fr. I - 6: 84.6 mg
fr. I - 7: 5.4 mg
fr. I - 8: 46.9 mg
本発明の化合物は、分析の結果、fr. I-6(成分A)、fr. I-8(成分B)、fr. I-5(成分C)にほぼ単一化合物として得られた。
(1)実施例1で得られた化合物について、1H NMR解析及び13C NMR解析を行った。
1H NMR(500 MHz, CDCl3)及び13C NMR(125 MHz, CDCl3)解析の結果として得られたデータを表1に示す。
本例では、実施例1及び2で成分Aとして単離したアルカンジェリシンの脱アシル化を行った。まず、成分A(70mg)を7mLのアセトンに溶解後、濃アンモニア水7mLを添加し、室温で一昼夜攪拌した。反応液を濃縮後(75mg)、分取高速液体クロマトグラフィ(内径10×250mm)に付し、0.1%ギ酸-アセトニトリル系で溶出し、主生成物を分取した(17mg)。
(1)実施例3で得られた化合物について、1H NMR解析及び13C NMR解析を行った。1H NMR(500 MHz, CDCl3)及び13C NMR(125 MHz, CDCl3)解析の結果として得られたデータを表2に示す。
本例では、実施例1で得られた成分A、成分B及び成分C並びに実施例3で調製した成分Aの脱アシル体についてのNFATシグナル阻害効果を検証した。
細胞培養
上記評価システムには、ヒト腎(HEK293)細胞をATCC(American Type Culture Collection)より購入し、使用した。HEK293細胞は、DMEM(High glucose、10% heat-inactivated FBS)中37℃、5% CO2条件下で培養した。
上記評価システムには、NFAT結合配列の下流にホタルルシフェラーゼが導入されたプラスミドpNFAT-Luc(Stratagene)をHEK293細胞にトランスフェクションしたものを使用した。詳細には、NFAT転写活性の評価用に4連のNFAT結合配列の下流にホタルルシフェラーゼ遺伝子が導入されたpNFAT-luc(STRATAGENE)をHEK293細胞にトランスフェクションした。また、トランスフェクション効率によるばらつきをなくすことを目的として、ホタルルシフェラーゼに由来するシグナルを補正するためにCMV promoterの下流にウミシイタケルシフェラーゼが導入されたpRL-CMV(Promega)を同時にトランスフェクションした。
ルシフェラーゼレポーターアッセイは、Dual-Glo Luciferase Assay System(Promega)を用い、使用説明書に従って行った。すなわち、培地を除去後、PBSにより2倍希釈したDual-Glo luciferase reagentを加え、攪拌した後、20分後にホタルルシフェラーゼ活性を測定した。その後、等量のDual-Glo Stop&Glo reagentを加え、攪拌した後にウミシイタケルシフェラーゼ活性を測定した。ルシフェラーゼ活性測定はMiniLumat LB 9506(EG&G BERTHOLD)を用いて行い、ルシフェラーゼによる発光量を定量的に検出した。双方ともルシフェラーゼ活性の測定時間は2秒とした。
全てのNFAT転写活性(ホタルルシフェラーゼ活性)はトランスフェクション効率補正のために導入されたウミシイタケルシフェラーゼ活性にて除することで補正した。その後、NFATシグナル阻害率を以下の式にて算出した。
NFATシグナル阻害率(%)=100−(試験サンプル及びIonomycin添加群−無刺激群)/(Ionomycinのみ添加群−無刺激群)×100
上記計算により、Ionomycin刺激によるNFATシグナル活性化をテストサンプルが何%阻害したかについて算出することができる。
NFATシグナル阻害率を算出した結果を図2に示す。図2から判るように、実施例1で得られた成分A、成分B及び成分C並びに実施例3で調製した成分Aの脱アシル体は、いずれもNFATシグナルを阻害した。すなわち、成分A、成分B及び成分Aの脱アシル体は、NFATにより正に制御される転写を抑制することができる。したがって、成分A、成分B及び成分Aの脱アシル体は、優れたNFATシグナル阻害剤であり、例えば免疫抑制剤、乾癬治療剤、アトピー性皮膚炎治療剤、(心)筋肥大抑制剤及び抗リウマチ薬等の候補物質として同定されたこととなる。
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