JP4215514B2 - J300冬虫夏草から抽出したhiv活性抑制剤組成物 - Google Patents
J300冬虫夏草から抽出したhiv活性抑制剤組成物 Download PDFInfo
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- JP4215514B2 JP4215514B2 JP2002578960A JP2002578960A JP4215514B2 JP 4215514 B2 JP4215514 B2 JP 4215514B2 JP 2002578960 A JP2002578960 A JP 2002578960A JP 2002578960 A JP2002578960 A JP 2002578960A JP 4215514 B2 JP4215514 B2 JP 4215514B2
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- Medicines Containing Plant Substances (AREA)
Description
従って、AIDSを退治することは、世界的な関心事であって、副作用がなく且つ治療効果が高い新しい薬剤の開発が至急な実情である。
その結果、本発明者らは、J300冬虫夏草の抽出物が抗HIV活性があることを知見し、その活性分画を決定してその活性物質を分析し、またこの抗HIV活性物質を有機合成することによって、毒性が弱くて副作用症が軽微な新規のAIDS治療剤を開発した。
また、本発明は、J300冬虫夏草から分離及び精製した抗HIV活性物質である、下記化学式(1)で表される3-[5-(メトキシ-エチル)-3,6-ジオキソ-ピペラジン-2-イル]-プロピオン酸、下記化学式(2)で表される4-メチル-2-[(ピロリジン-2-カルボニル)-2-アミノ]-ペンタノン酸、及びこれらの誘導体を提供する。
1)Amination(アミノ化)of L-Boc-Glu and L-Threonine(GT−2)
2-(2-tert-butoxycarbonylamino-4-methoxycarbonyl-butyrylamino)-3-hydroxy-butyric acid methyl esterの製造
このようにして得られた2-(2-tert-butoxycarbonylamino-4-methoxycarbonyl-butyrylamino)-3-hydroxy-butyric acid methyl esterをGT−2という。
2-(2-Amino-4-methoxycarbonyl-butyrylamino)-3-hydroxy-butyric acid methyl esterの製造
このようにして製造された2-(2-Amino-4-methoxycarbonyl-butyrylamino)-3-hydroxy-butyric acid methyl esterをGT−3という。
3-[5-(1-Hydroxy-ethyl)-3,6-dioxo-piperazin-2-yl]-propionic acid methyl esterの製造
得られた化合物3-[5-(1-hydroxy-ethyl)-3,6-dioxo-piperazin-2-yl]-propionic acid methyl esterをGT−4という。
3-[5-(1-Hydroxy-ehtyl)-3,6-dioxo-piperazin-2-yl]-propionic acidの製造
前記得られた3-[5-(1-Hydroxy-ehtyl)-3,6-dioxo-piperazin-2-yl]-propionic acidをGT−5という。
前記得られたGT−5をデプロテクション及びメチル化して、所望の最終結果物である3-[5-(メトキシ-エチル)-3,6-ジオキソ-ピペラジン-2-イル]-プロピオン酸を得る。
1)Amination(アミノ化)of L-Boc-Proline and L-Leucine(LP−3)
2-(1-Methoxycarbonyl-3-methyl-butylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl esterの製造
前記得られた2-(1-Methoxycarbonyl-3-methyl-butylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl esterをLP−3という。
4-Methyl-2-[(pyrrolidine-2-carbonyl)-amino]-pentanoic acid methyl esterの製造
4-Methyl-2-[(pyrrolidine-2-carbonyl)-2-amino]pentanoic acidの製造
一方、当業者なら前記方法によって3-[5-(メトキシ-エチル)-3,6-ジオキソ-ピペラジン-2-イル]-プロピオン酸の誘導体又は4-メチル-2-[(ピロリジン-2-カルボニル)-2-アミノ]-ペンタノン酸の誘導体をも製造できる。
先ず、J300冬虫夏草抽出物の抗HIV活性を確認するために、J300冬虫夏草の水抽出物及びメタノール抽出物の抗HIV活性を比較した。
水抽出物は、J300冬虫夏草粉末を70℃で30分間水中で加熱して得られた水溶液分画を使用し、メタノールに対しても同じ方法で抽出した。
その結果は図面を参考にして説明する。
図5は、J300冬虫夏草の水抽出物の中で、1,000D以下部分に対する活性を検索した結果で、その抗HIV活性が優れていることが分かる。
J300冬虫夏草から抗HIV活性物質を精製及び分離する方法は、図1を参考にして説明する。
1)J300冬虫夏草粉末を70℃で30分間水中で加熱し、その水溶液分画を凍結乾燥して得られた粉末であるJ300冬虫夏草粗抽出物2.63gに対してHP20吸着クロマトグラフィ(adsorption chromatography)を実施した。
1. 活性物質の安定性確認
活性物質を捜し出すために活性が安定に維持されることができる最適の条件を捜し出し、分離精製過程でこの条件を維持することは、極めて重要である。温度と保存期間を体系的に変化させ、活性の程度を測定した;−20℃、4℃、22℃及び37℃などで1週間保管してから活性検査を実施した。前記それぞれの場合において、変質が発見されないところ、前記抽出物は、安定した物質であることを確認することができた。
本実施例で使用した抗HIV活性検査は、米国の癌研究所(National Cancer Institute)で開発されて使用しているもので、処理した試料により宿主細胞がHIVの殺傷効果から保護される細胞生存程度を測定することによって、試料の抗HIV効果有無及びその程度を決定する。
(2)細胞+HIV処理区:陰性対照群であって、大部分の細胞がHIVにより殺傷され、これを細胞生存率0%にした。
(4)各濃度の試料だけを処理:試料により生ずる背景色を測定するための処理区である。
(5)細胞+HIV+AZT:AZTは、既に知られた抗HIV活性物質であるから、グラフ上に一定のパターンが予想される。このパターンを調べることによって、実験のための全条件の適合性を確認することができる処理区である。
J300冬虫夏草の分画物を上記で説明した方法で検索した時、活性成分の有無によって次のように区別される。
宿主細胞であるT細胞にHIVを感染させれば、大部分の細胞は死滅するようになる。しかし、試料に抗HIV効果があれば、濃度を高めて添加するに応じて、試料の活性物質がウイルスの増殖を抑制することによって、細胞の殺傷が保護される。
活性物質が細胞内で作用するかについて調べるために、細胞と試料を30分間インキュベーションしウイルスを感染させた。細胞に冬虫夏草分画(Dong 1-2-4)を共に入れ、30分後ウイルスを感染させた場合、活性を現した。冬虫夏草分画(Dong 1-2-5)を共に入れ、30分後、ウイルスを感染させた場合にも、活性を現した。この場合、試料が細胞膜を透過して細胞内側でウイルスの増殖を抑制する時ばかりでなく、細胞膜外部に付着してウイルスの侵入を遮断する時にも、このような現象が発生することができる(図7)。
HIVが特異的に脳だけで発現されるように遺伝工学的処理をしたトランスジェニックマウスを用いてin vivo実験をした。
本発明の物質を含んだ冬虫夏草の水抽出物を経口又は静脈投与する方法で亜急性検査を実施した。
その結果を表1に示す。
結果を表2に示す。
1)Amination(アミノ化)of L-Boc-Glu and L-Threonine
2-(2-tert-butoxycarbonylamino-4-methoxycarbonyl-butyrylamino)-3-hydroxy-butyric acid methyl esterの製造
収量(Yield) 340mg(94%)
Rf値 0.55(EA)
1H-NMR (CDCl3、300MHz);δ7.31(d、1H、J=8.4Hz)、5.54(d、1H、J=7.8Hz)、4.54(dd、1H、J=2.5、9.0Hz)、4.29(m、2H)、3.72(s、3H)、3.70(s、3H)、2.43(t、2H、J=7.3Hz)、2.09(m、1H)、1.93(m、1H)、1。38(s、9H)、1.16(d、3H、J=5.0Hz)
2-(2-Amino-4-methoxycarbonyl-butyrylamino)-3-hydroxy-butyric acid methyl esterの製造
前記製造されたGT−2の100mg(0.266mmol)を5mlのジクロロメタンに溶かした後、72μL(0.932mmol)のTFAで処理し、常温で12時間攪拌した。次いで、溶媒を蒸発させて乾燥する。
Rf値 0.40(EA:MeOH=3:1)
1H-NMR(D2O、300MHz)δ5.00(m、1H)、4.84(m、1H)、4.64(m、1H)、4.21(s、3H)、4.19(s、3H)、3.05(t、2H、J=7.4Hz)、2.66(m、2H)、1.63(d、3H、J=6.6Hz)
3-[5-(1-hydroxy-ethyl)-3,6-dioxo-piperazin-2-yl]-propionic acid methyl esterの製造
前記得られたGT−3の50mg(0.181mmol)を3mlのTHFに溶かし、151μL(1.09mmol)のTEAで処理した後、常温で12時間攪拌した。前記混合物をMCと水で抽出する。水層をさらにMCで2回抽出する。これを硫酸マグネシウム(Mg2SO4)で乾燥した。前記結果物をヘキサン:酢酸エチル=4:1であるシリカゲルコラムを使用して精製した。
Rf値 0.67(EA)
1H-NMR(CDCl3、300MHz)δ7.67(d、1H、J=4. 1Hz)、7.30(d、1H、J=8.9Hz)、4.64(dd、1H、J=7.8、12.8Hz)、4.53(d、1H、J=8.9Hz)、4.40(m、1H)、3.80(s、3H)、3.68(s、3H)、2.51(m、2H)、2.21(m、1H)、2.04(m、1H)、1.20(d、3H、J=6.5Hz)
3-[5-(1-Hydroxy-ehtyl)-3,6-dioxo-piperazin-2-yl]-propionic acid及び3-[5-(メトキシ-エチル)-3,6-ジオキソ-ピペラジン-2-イル]-プロピオン酸の製造
前記得られたGT−4の35mg(0.146mmol)を水に溶かした後、20%-NaOHで処理した後、常温で30分間攪拌する。溶媒を蒸発させ乾燥した後、これを精製してGT−5を得た。次いで、これをメチル化(methylation)して、最終結果物である3-[5-(メトキシ-エチル)-3,6-ジオキソ-ピペラジン-2-イル]-プロピオン酸を得た。
Rf値 0.12(酢酸エチル:メタノール=1:3)
1H-NMR (D2O、300MHz)δ4.19(m、2H)、3.90(t、1H、J=6.5Hz)、2.36(m、2H)、2.05(m、2H)、1.20(d、3H、J=6.2Hz)
1)Amination(アミノ化)of L-Boc-Proline and L-Leucine(LP-3)
2-(1-Methoxycarbonyl-3-methyl-butylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl esterの製造
Rf値 0.67(EA)
1H-NMR(CDCl3、300MHz)δ7.36(m、1H)、4.52(m、1H)、4.27(m、1H)、3.72(s、3H)、3.31(m、2H)、2.17-1.59(m、7H)、1.46(s、9H)、0.91(d、6H、J=5.8Hz)
4-Methyl-2-[(pyrrolidine-2-carbonyl)-amino]-pentanoic acid methyl
esterの製造
前記LP−3の50mg(0.146mmol)をジクロロメタンに溶かした後、39μL(0.511mmol)のTFAで処理し、常温で12時間攪拌した。次いで、溶媒を蒸発させ乾燥した。前記結果物を酢酸エチル:メタノール=20:1であるシリカゲルコラムを使用して精製した。
Rf値 0.27(EA:MeOH=3:1)
1H-NMR(CDCl3、300MHz)δ8.30(d、1H、J=7.5Hz)、4.69(t、1H、J=7.3Hz)、4.45(dd、1H、J=3.0、7.3Hz)、3.70(s、3H)、3.39(m、2H)、2.43(m、1H)、2.10(m、2H)、2.01(m、1H)、1.62(m、3H)、0.90(d、3H、J=5.9Hz)、0.88(d、3H、J=5.7Hz)
4-Methyl-2-[(pyrrolidine-2-carbonyl)-2-amino]pentanoic acidの製造
前記得られたLP−4の35mg(0.146mmol)を水に溶かした後、20%-NaOHで処理し、常温で30分間攪拌した。次いで、溶媒を蒸発させ乾燥した。得られた結果物を酢酸エチル:メタノール=2:1であるシリカゲルコラムを使用して精製した。
Rf値 0.24(酢酸エチル:メタノール=1:3)
1H-NMR(D2O、300MHz)δ4.20(m、2H)、3.76(m、1H)、3.24(m、1H)、2.36-1. 58(m、7H)、0.88(d、3HJ=5. 7Hz)、0.87(d、3H、J=6.5Hz)
Claims (6)
- 請求項1に記載の化合物を有効成分として含有するHIV活性抑制剤組成物。
- 請求項1に記載の化合物を有効成分として含有するAIDS治療剤。
- 請求項1に記載の化合物を有効成分として含有するAIDS用補助食品。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR10-2001-0018664A KR100416912B1 (ko) | 2001-04-09 | 2001-04-09 | J300동충하초로부터 분리 및 정제한3-[5-(메톡시-에틸)-3,6-디옥소-피페라진-2-일]-프로피온산, 이를 포함하는 항 hiv 활성을 갖는 약제학적 조성물,aids 치료제 및 aids 치료보조식품 |
KR10-2001-0018665A KR100434843B1 (ko) | 2001-04-09 | 2001-04-09 | J300동충하초로부터 분리 및 정제한4-메틸-2-[(피롤리딘-2-카보닐)-2-아미노]-펜타논산, 및이를 포함하는 항 hiv활성을 갖는 약제학적 조성물,aids 치료제 및 aids 치료보조식품 |
PCT/KR2002/000625 WO2002080921A1 (en) | 2001-04-09 | 2002-04-09 | Composition for inhibiting hiv activity extracted from paecilomyces sp. (tochu-kaso) j300 |
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JP2004533426A JP2004533426A (ja) | 2004-11-04 |
JP4215514B2 true JP4215514B2 (ja) | 2009-01-28 |
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US (1) | US7704957B2 (ja) |
EP (1) | EP1389111A1 (ja) |
JP (1) | JP4215514B2 (ja) |
WO (1) | WO2002080921A1 (ja) |
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CN106086058B (zh) * | 2016-06-24 | 2021-04-09 | 上海市农业科学院 | 一种减少蛹虫草出菇时间及提高出菇产量的方法 |
CN110698548B (zh) * | 2019-11-01 | 2021-07-23 | 武汉轻工大学 | 一种蛹虫草活性蛋白CMPr及其制备方法与应用 |
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US4416871A (en) * | 1978-07-10 | 1983-11-22 | The United States Of America As Represented By The Department Of Health And Human Services | Inhibition by peptides of tolerance to and physical dependence on morphine |
EP0472077A3 (en) * | 1990-08-24 | 1993-03-31 | Bayer Ag | Phosphonate containing hydroxyethylamin- and norstatin-type pseudopeptides |
HUT60282A (en) | 1991-02-08 | 1992-08-28 | Sankyo Co | Process for producing new beta-amino-alpha-hydroxycarboxylic acid derivatives and pharmaceutical compositions comprising such compounds |
IT1245700B (it) * | 1991-05-29 | 1994-10-14 | Arrigo Claudio D | Chemioterapico antineoplastico di origine vegetale, ad elevata selettivita' e tossicita' fortemente ridotta e procedimento per la sua preparazione |
WO1996000580A1 (fr) * | 1994-06-30 | 1996-01-11 | Meiji Milk Products Company Limited | Composition favorisant la sante |
JPH0925237A (ja) | 1995-07-11 | 1997-01-28 | Genkou Yakuhin Kk | 冬虫夏草を含有するウイルス性疾病治療剤 |
JP3252110B2 (ja) | 1996-12-05 | 2002-01-28 | 大韓民国 | 家蚕を用いた冬虫夏草の人工栽培方法 |
AU9733698A (en) * | 1997-10-24 | 1999-05-17 | Institute Of Materia Medica Chinese Academy Of Medical Sciences | Process for making and uses of cordyceps fermentation products |
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2002
- 2002-04-09 WO PCT/KR2002/000625 patent/WO2002080921A1/en active Application Filing
- 2002-04-09 US US10/474,292 patent/US7704957B2/en not_active Expired - Fee Related
- 2002-04-09 EP EP02718653A patent/EP1389111A1/en not_active Withdrawn
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WO2002080921A1 (en) | 2002-10-17 |
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JP2004533426A (ja) | 2004-11-04 |
US7704957B2 (en) | 2010-04-27 |
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