JP2008540682A - プロテアソーム阻害剤及びその使用法 - Google Patents
プロテアソーム阻害剤及びその使用法 Download PDFInfo
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- JP2008540682A JP2008540682A JP2008512563A JP2008512563A JP2008540682A JP 2008540682 A JP2008540682 A JP 2008540682A JP 2008512563 A JP2008512563 A JP 2008512563A JP 2008512563 A JP2008512563 A JP 2008512563A JP 2008540682 A JP2008540682 A JP 2008540682A
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Abstract
【解決手段】マテ茶から単離されるケイ皮酸エステル化合物。この化合物は、局所的又は全身的にプロテアソーム活性と関連した障害の治療に使用できる。単離されたケイ皮酸エステル化合物は様々な皮膚疾患に対して局所的に使用できる。当該ケイ皮酸エステル化合物はまた、異常なプロテアソーム機能に関連する障害(例えば皮膚疾患(乾癬、ざ瘡など))、特定の前ガン症状(例えば骨髄異形成症状)、並びに癌(例えば白血病、リンパ腫、肉腫、上皮癌又はHIV)に対して全身的に使用できる。
【選択図】なし
Description
Greavesら(1995),Drug Therapy,332:581−588
式中、Wはメチル基、アルキル基、メチレン基、アミン基、アシル基、カルボニル基、酸素原子、硫黄原子からなる群から選択され、X1からX5は水素原子、ハロゲン、水酸基、エーテル基、アルキル基、アリール基、ニトロ基、シアノ基、チオール基、チオエーテル基、アミノ基、アミド基及びOR基からなる群から独立に選択され、Rはケイ皮酸エステル、ジヒドロケイ皮酸エステル及び水酸基である。
式中、Wはメチレン基、アルキル基、メチレン基、アミン基、アシル基、カルボニル基、酸素原子、硫黄原子からなる群から選択され、X1からX4は水素原子、ハロゲン、水酸基、エーテル基、アルキル基、アリール基、ニトロ基、シアノ基、チオール基、チオエーテル基、アミノ基、アミド基及びOR基からなる群から独立に選択され、Rはケイ皮酸エステル、ジヒドロケイ皮酸エステル及び水酸基である。
式中、Wはメチレン基、アルキル基、メチレン基、アミン基、アシル基、カルボニル基、酸素原子、硫黄原子からなる群から選択され、X1からX5は水素原子、ハロゲン、水酸基、エーテル基、アルキル基、アリール基、ニトロ基、シアノ基、チオール基、チオエーテル基、アミノ基、アミド基及びOR基からなる群から独立に選択され、Rはケイ皮酸エステル、ジヒドロケイ皮酸エステル及び水酸基である。
式中、Wはメチレン基、アルキル基、メチレン基、アミン基、アシル基、カルボニル基、酸素原子、硫黄原子からなる群から選択され、X1からX4は水素原子、ハロゲン、水酸基、エーテル基、アルキル基、アリール基、ニトロ基、シアノ基、チオール基、チオエーテル基、アミノ基、アミド基及びOR基からなる群から独立に選択され、Rはケイ皮酸エステル、ジヒドロケイ皮酸エステル及び水酸基である。
本実施例では、マテ茶からプロテアソーム抑制活性を有する化合物を単離するのに必要な方法及び材料を示し、単離された化合物の効果を測定するための方法及びアッセイの説明を行う。
粉末化マテ茶(Chimarrao Laranjeiras Puraerva Cascavel、ブラジル)(100g)を500mlの水で30分間沸騰させて抽出した。ペンタエリトリトールテトラキス(3,5−ジ−tert−ブチル−4−ヒドロキシヒドロケイ皮酸)(PTTC)は、Aldrich Chemical Co(セントルイス、MO)から得られた。冷却後、粗水抽出物を最初に0.45μフィルタで濾過し、更に濾過して3000MWを超える材料を除去した。濾過した水抽出物を凍結乾燥して乾燥粉を調製し、蒸留水に溶解し、HPLC分析し、5本のフラクションを回収した。HPLCフラクションを凍結乾燥した。各フラクションを10mg/mlの溶液として再調整し、SVR細胞の増殖を阻害する能力を試験した。
SVR細胞(1×104個)を24ウエルプレートで24時間培養された。更に培地を10mg/mlの濃度の精製抽出物を含有するDMEM培地に交換した。細胞を72時間薬剤に曝露し、Lamontagneらの方法に従って、コールターカウンター(Coulter、Hialeah、FL)で計測した(LaMontagneら,(2000)Am.J.Pathol.157,1937−1945)。濾過したマテ茶の水抽出物は、SVR内皮に対する強い抑制効果を示した。マテ茶の有効成分を解析するため、抽出液をHPLCで分析し、フラクションのSVR細胞増殖阻害能を評価した。最も強い抑制効果を示したフラクションは、フラクションT−2、T−5及びT−6であった。T−2、T−5及びT−6の構造を、陽子NMR及び質量分析により解析した(図1)。フラクションT−2が5−カフェオイルキナ酸(ネオクロロゲン酸)であり、フラクションT−5が3,5−ジカフェオイルキナ酸であり、フラクションT−6が3,4−ジカフェオイルキナ酸であることが明らかとなった。化合物のNMRスペクトルを以下に示す。
NMRスペクトルは、Bruker DRX 400分光計を用いて、400MHzで1H、13Cで100MHzで操作し、濃度勾配を設け、内部参照として残留する溶媒のピークを使用し、CD3ODで記録した。HRESIMSデータは、Bruker BioAPEX 30es(NCNPR、ミシシッピ大学)により得た。
1H NMR(CD3OD,400MHz):d7.58(1H,d,J=15.9Hz,H−7’),7.05(1H,d,J=1.2Hz,H−2’),6.94(1H,dd,J=8.2,1.5Hz,H−6’),6.78(1H,d,J=8.2Hz,H−5’),6.31(1H,d,J=15.9Hz,H−8’),5.37(1H,brd,J=4.8Hz,H−5),4.18(1H,m,H−3),3.66(1H,dd,J=8.6,3.2Hz,H−4),2.17(3H,m,H−6ax,H−6eq,H−2eq),1.97(1H,dd,J=13.2,10.4Hz,H−2ax)。
13C NMR(CD3OD,100MHz):d178.4(C,C−7),169.2(C,C−9’),149.5(C,C−4’),147.0(CH,C−7’),146.8(C,C−3’),128.1(C,C−1’),123.0(CH,C−6’),116.6(CH,C−5’),115.9(CH,C−2’),115.2(CH,C−8’),75.5(C,C−1),75.0(CH,C−4),73.2(CH,C−5),68.3(CH,C−3),41.7(CH2,C−2),36.8(CH2,C−6)。
HRESIMS m/z377.0807[M+Na]+(計算値:C16H18O9Na,377.0843)。
1H NMR(CD3OD,400MHz):d7.62(1H,d,J=16.0Hz,H−7’又はH−7’’),,7.58(1H,d,J=16.0Hz,H−7’又はH−7’’),7.07(2H,brs,H−2’,−2’’),6.97(2H,m,H−6’,H−6’’),6.79(1H,d,J=8.0Hz,H−5’,H−5’’),6.35(1H,d,J=16.0Hz,H−8’又はH−8’’),6.27(1H,d,J=16.0Hz,H−8’又はH−8’’),5.44(1H,m,H−3),5.40(1H,brd,J=5.9Hz,H−5),3.99(1H,dd,J=7.4,3.1Hz,H−4),2.34−2.15(4H,m,H−2,H−6)。
13C NMR(CD3OD,100MHz):d177.5(C,C−7),168.5(C,C−9’又はC−9’’),168.3(C,C−9’又はC−9’’),149.7(2C,C−4’,C−4’’),147.4(CH,C−7’又はC−7’’),147.2(CH,C−7’又はC7’’),146.9(2C,C−3’,C−3’’),128.0(2C,C−1’,C−1’’),123.2(CH,C−6’又はC−6’’),123.1(CH,C−6’又はC−6’’),116.6(2CH,C−5’,C−5’’),115.7(1C each,d,C−2’’),115.5(1C each,d,C−2’),115.4(1C each,d,C−8’’),115.2(1C each,d,C−8’),74.8(C,C−1),72.6(CH,C−5),72.2(CH,C−3),70.7(CH,C−4),37.7(CH2,C−2),36.1(CH2,C−6)。
HRESIMS m/z539.1160[M+Na]+(計算値:C25H24O12Na,539.1116)。
1H NMR(CD3OD,400MHz):d7.60(1H,d,J=15.9Hz,H−7’又はH−7’’),7.52(1H,d,J=15.9Hz,H−7’又はH−7’’),7.03(1H,brs,H−2’又はH−2’’),7.01(1H,brs,H−2’又はH−2’’),6.91(2H,m,H−6’,H−6’’),6.75(1H,d,J=8.0Hz,H−5’,−5’’),6.29(1H,d,J=15.9Hz,H−8’又はH−8’’),6.20(1H,d,J=15.9Hz,H−8’又はH−8’’),5.64(1H,m,H−3),5.14(1H,dd,J=9.0,2.6Hz,H−4),4.39(1H,m,H−5),2.32−2.11(4H,m,H−2,H−6)。
13C NMR(CD3OD,100MHz):d176.8(C,C−7),168.7(C,C−9’又はC−9’’),168.4(C,C−9’又はC−9’’),149.7(2C,C−4’,C−4’’),147.7(2CH,C−7’,7’’),146.8(2C,C−3’,C−3’’),127.7(2C,C−1’,C−1’’),123.3(2CH,C−6’,C−6’’),116.6(2CH,C−5’,C−5’’),115.3(2CH,C−2’,C−2’’),114.8(2CH,C−8’,C−8’’),76.3(C,C−1),75.8(CH,C−4),69.4(CH,C−5),69.1(CH,C−3),39.4(CH2,C−2),38.4(CH2,C−6)。
この実施例は、単離されたマテ茶のフラクション、及び精製20Sプロテアソームを使用した、インヴィトロでの抑制効果を分析する方法を記載する。精製20Sプロテアソームのキモトリプシン様活性を、Namら,(2001)J.Biol.Chem.276,13322−13330)の方法に従い測定した。簡潔には、精製した原核20Sプロテアソーム(0.5μg)を、所定濃度のマテ茶フラクションの有無において、20μMの蛍光ペプチド基質Suc−Leu−Leu−Val−Tyr−AMCと共に、アッセイ緩衝液(50mMのトリスHCl、pH7.5)100μL中、37℃で30分間インキュベートした。インキュベーション後、加水分解された7−アミド−4−メチル−クマリン(AMC)基の生成を、380nmの励起フィルタ及び460nm(バイオラド)の発光フィルタを有するマルチウエルプレートVersaFluorTM Fluorometerを使用して測定した。
この実施例では、Jurkat癌細胞系からの細胞抽出物を使用した、単離されたマテ茶のフラクションのインビボでの抑制効果を分析する方法を記載する。Jurkat T細胞の全体細胞抽出物(20μg)を、所定濃度のマテ茶フラクションの有無において、20μMの蛍光ペプチド基質Suc−Leu−Leu−Val−Tyr−AMCと共に、アッセイ緩衝液100mL中、37℃で60分間インキュベートした。加水分解AMCsを上記の通りに定量した。
Claims (26)
- プロテアソーム活性の阻害にとり有効量のケイ皮酸エステル化合物を含有する組成物。
- 前記ケイ皮酸エステル化合物がプロテアソームのキモトリプシン様活性を阻害する、請求項1記載の組成物。
- 前記ケイ皮酸エステル化合物がカフェオイルエステルである、請求項1記載の組成物。
- 前記カフェオイルエステル中のエステルの数が約1〜6である、請求項5記載の組成物。
- 前記カフェオイルエステルが5−カフェオイルキナ酸、3,5−ジカフェオイルキナ酸、3,4−ジカフェオイルキナ酸、及びそれらの類似体又は誘導体からからなる群から選択される、請求項5記載の組成物。
- 局所輸送に適する担体を更に含んでなる、請求項1記載の組成物。
- 全身輸送に適する担体を更に含んでなる、請求項1記載の組成物。
- 薬学的に許容できる局所投与用の担体との組合せでカフェオイルエステルを含有する組成物であって、前記カフェオイルエステルが、乾癬、ざ瘡、ニキビ及び湿疹からなる群から選択される皮膚疾患の治療に効果的な投与量で存在する組成物。
- 前記カフェオイルエステルが3,5−ジカフェオイルキナ酸、及びその類似体若しくは誘導体である、請求項10記載の組成物。
- 約0.01%〜10%の濃度でカフェオイルエステルを含有する、請求項10記載の組成物。
- プロテアソーム活性と関連する障害の治療方法であって、有効量のケイ皮酸エステル化合物を含む組成物を投与することを含んでなり、前記ケイ皮酸エステル化合物がプロテアソームと相互作用してプロテアソーム活性を阻害し、前記プロテアソーム活性の阻害により障害が治療される方法。
- 前記ケイ皮酸エステル化合物がプロテアソームのキモトリプシン様活性を阻害する、請求項13記載の方法。
- 前記ケイ皮酸エステル化合物がカフェオイルエステルである、請求項13記載の方法。
- 前記カフェオイルエステル中のエステルの数が約1〜6である、請求項17記載の方法。
- 前記カフェオイルエステルが、5−カフェオイルキナ酸、3,5−ジカフェオイルキナ酸、3、4、ジカフェオイルキナ酸、並びにその類似体若しくは誘導体からなる群から選択される、請求項18記載の方法。
- 前記プロテアソーム活性と関連する障害が、乾癬、リンパ管起源、幼年期の血管腫、ストウジ−ウェーバー症候群、尋常性疣贅、神経線維腫症、結節状硬化症、化膿性肉芽腫、劣性ジストロフィ表皮水泡症、静脈潰瘍、ざ瘡、ニキビ、湿疹、接触感染性の軟属腫、脂漏性角化症、光線性角化症、血管肉腫、血管内皮腫、基底細胞癌、扁平上皮癌、悪性黒色腫及びカポージ肉腫からなる群から選択される皮膚の障害である、請求項13記載の方法。
- 前記障害が乾癬である、請求項13記載の方法。
- 前記障害がざ瘡である、請求項13記載の方法。
- 前記プロテアソーム活性と関連する障害が自己免疫不全、前ガン症状、癌及びヒト免疫不全ウイルス(HIV)からなる群から選択される全身性障害である、請求項13記載の方法。
- プロテアソーム活性と関連する障害の治療方法であって、有効量の酸化防止化合物を含有する組成物を投与することを含んでなり、前記酸化防止化合物がプロテアソームと相互作用してプロテアソーム活性を阻害し、前記プロテアソーム活性の阻害により障害が治療される方法。
- 前記酸化防止化合物がフェノール系の酸化防止剤を含んでなる、請求項24に記載の方法。
- 前記酸化防止剤が、Ciba(登録商標)IRGANOX(登録商標)1010、Ciba(登録商標)IRGANOX(登録商標)245 DW、Ciba(登録商標)IRGANOX(登録商標)1035、Ciba(登録商標)IRGANOX(登録商標)565、Ciba(登録商標)IRGANOX(登録商標)1076、Ciba(登録商標)IRGANOX(登録商標)1425、Ciba(登録商標)IRGANOX(登録商標)1098、Ciba(登録商標)IRGANOX(登録商標)1520、Ciba(登録商標)IRGANOX(登録商標)1135、Ciba(登録商標)IRGANOX(登録商標)1726、Ciba(登録商標)IRGANOX(登録商標)1330、Ciba(登録商標)IRGANOX(登録商標)5057、Ciba(登録商標)IRGANOX(登録商標)245、Ciba(登録商標)IRGANOX(登録商標)HP 2225、Ciba(登録商標)IRGANOX(登録商標)B 215、Ciba(登録商標)IRGANOX(登録商標)B 612、Ciba(登録商標)IRGANOX(登録商標)B 225及びCiba(登録商標)IRGANOX(登録商標)1171からなる群から選択される、請求項24記載の方法。
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AU (1) | AU2006251655B2 (ja) |
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ES (1) | ES2891179T3 (ja) |
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JP2018533629A (ja) * | 2015-11-06 | 2018-11-15 | アキュイティス ファーマシューティカルズ、インコーポレイテッド | 眼障害を治療するためのプロテアソーム阻害剤の使用 |
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US20110118274A1 (en) * | 2007-08-23 | 2011-05-19 | Cornell Research Foundation, Inc. | Proteasome inhibitors and their use in treating pathogen infection and cancer |
FR2926955B1 (fr) | 2008-02-01 | 2012-07-20 | Agronomique Inst Nat Rech | Procede de preparation d'acides dicafeoylquiniques et leur utilisation dans la lutte contre les pucerons |
CN103889396B (zh) | 2011-08-17 | 2017-08-01 | 巴斯夫公司 | 基于海洋的化妆品活性成分及其用途 |
PL2841075T3 (pl) | 2012-04-26 | 2020-09-21 | The General Hospital Corporation | Środki i sposoby leczenia i zapobiegania rogowaceniu łojotokowemu |
CN109096370B (zh) * | 2012-07-26 | 2022-03-18 | 圣特莱国际公司 | 多肽环氧酮化合物 |
KR101483990B1 (ko) | 2013-04-23 | 2015-01-20 | 한국식품연구원 | 시료의 통증 완화, 예방 또는 치료 효능에 대한 평가방법 |
WO2014175518A1 (ko) * | 2013-04-23 | 2014-10-30 | 한국식품연구원 | 마테 추출물을 유효성분으로 포함하는 통증의 완화, 예방 또는 치료용 조성물 및 시료의 통증 완화, 예방 또는 치료 효능에 대한 평가방법 |
US10508309B2 (en) | 2013-05-17 | 2019-12-17 | The General Hospital Corporation | Methods for detecting and treating variants of seborrheic keratoses |
GB201317286D0 (en) * | 2013-09-30 | 2013-11-13 | Calscience Internat Ltd | Composition and Use |
CN104546819A (zh) * | 2013-10-09 | 2015-04-29 | 中国医学科学院药物研究所 | 二咖啡酰奎宁酸在治疗系统性自身免疫性疾病中的用途 |
WO2015103012A1 (en) * | 2013-12-31 | 2015-07-09 | Applied Biology, Inc. | Methods and compositions for administering a specific wavelength phototherapy |
GB201502268D0 (en) | 2015-02-11 | 2015-04-01 | Calscience Internat Ltd | Dental composition and use |
WO2018140858A1 (en) | 2017-01-30 | 2018-08-02 | Western New England University | Thiol isomerases inhibitors and use thereof |
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FR3080032B1 (fr) * | 2018-04-13 | 2020-04-17 | Societe D'exploitation De Produits Pour Les Industries Chimiques Seppic | Utilisation d'une nouvelle composition pour empecher ou ralentir l'apparition de signes d'inflammation |
FR3080030B1 (fr) * | 2018-04-13 | 2020-04-24 | Societe D'exploitation De Produits Pour Les Industries Chimiques Seppic | Utilisation d’une nouvelle composition pour empecher ou ralentir l’apparition des signes inesthetiques lies a la presence de sebum en exces |
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CN101222900B (zh) | 2013-02-13 |
US20070004647A1 (en) | 2007-01-04 |
AU2006251655B2 (en) | 2012-10-11 |
EP1895971A4 (en) | 2012-08-08 |
EP1895971A2 (en) | 2008-03-12 |
JP2013177463A (ja) | 2013-09-09 |
CA2609213C (en) | 2016-08-23 |
JP5745743B2 (ja) | 2015-07-08 |
HK1122988A1 (en) | 2009-06-05 |
US8809283B2 (en) | 2014-08-19 |
IL187463A (en) | 2015-08-31 |
WO2006127525A2 (en) | 2006-11-30 |
CN101222900A (zh) | 2008-07-16 |
IL187463A0 (en) | 2008-03-20 |
WO2006127525A3 (en) | 2007-03-15 |
AU2006251655A1 (en) | 2006-11-30 |
CA2609213A1 (en) | 2006-11-30 |
ES2891179T3 (es) | 2022-01-26 |
EP3087969B1 (en) | 2021-06-30 |
EP3087969A1 (en) | 2016-11-02 |
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