JP4713340B2 - 硫酸基転移酵素阻害剤 - Google Patents
硫酸基転移酵素阻害剤 Download PDFInfo
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- JP4713340B2 JP4713340B2 JP2005506231A JP2005506231A JP4713340B2 JP 4713340 B2 JP4713340 B2 JP 4713340B2 JP 2005506231 A JP2005506231 A JP 2005506231A JP 2005506231 A JP2005506231 A JP 2005506231A JP 4713340 B2 JP4713340 B2 JP 4713340B2
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- Prior art keywords
- sulfate
- group
- heparin
- activity
- heparan sulfate
- Prior art date
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Description
(1)下記式1で表されることを特徴とするヘキスロン酸誘導体又はその塩の酵素阻害有効量を含むことを特徴とするヘパリン・ヘパラン硫酸硫酸基転移酵素阻害剤。
式中R1、R2、及びR3は各々独立にSO3 −又はHを示し、少なくともいずれか一つはSO3 −を示し、これらは置換基を有していても良く、XはOR4、SR4、N(R4)2又はC(R4)3を示し、R4は独立にH、アルキル基、アルケニル基、アルキニル基、アシル基、アリール基、又はアラルキル基を示し、R5及びR6は一方がCOOHであって他方はHを示し、波線はαグリコシド結合又はβグリコシド結合を示す。
(2)式1において、R1はHを示し、R2及びR3の少なくともいずれか一方はSO3 −で、他方はHを示すか、いずれもSO3 −を示し、XはOR4を示し、R4は炭素数6以下のアルキル基を示し、R5はCOOHを示し、R6はHを示すことを特徴とする(1)記載のヘパリン・ヘパラン硫酸硫酸基転移酵素阻害剤。
(3)ヘパリン骨格中のグルコサミン残基の6位ヒドロキシル基へ硫酸基を転移する活性を有するヘパリン・ヘパラン硫酸硫酸基転移酵素の前記活性を阻害することを特徴とする(1)又は(2)記載のヘパリン・ヘパラン硫酸硫酸基転移酵素阻害剤。
(4)ヘパリン骨格中のヘキスロン酸残基の2位ヒドロキシル基へ硫酸基を転移する活性を有するヘパリン・ヘパラン硫酸硫酸基転移酵素の前記活性を阻害することを特徴とする(1)又は(2)記載のヘパリン・ヘパラン硫酸硫酸基転移酵素阻害剤。
(5)下記式1で表されるヘキスロン酸グリコシド誘導体又はその塩のヘパリン・ヘパラン硫酸硫酸基転移酵素阻害剤としての使用。
式中R1、R2、及びR3は各々独立にSO3 −又はHを示し、少なくともいずれか一つはSO3 −を示し、これらは置換基を有していても良く、XはOR4、SR4、N(R4)2又はC(R4)3を示し、R4は独立にH、アルキル基、アルケニル基、アルキニル基、アシル基、アリール基、又はアラルキル基を示し、R5及びR6は一方がCOOHであって他方はHを示し、波線はαグリコシド結合又はβグリコシド結合を示す。
(6)(1)〜(4)のいずれかのヘパリン・ヘパラン硫酸硫酸基転移酵素阻害剤を有効成分として含有する医薬組成物。
(7)硫酸基受容体としてヘパリン骨格を有する糖鎖に硫酸基供与体から硫酸基を転移する活性を有する酵素の当該活性を、(1)〜(4)のいずれかのヘパリン・ヘパラン硫酸硫酸基転移酵素阻害剤によって阻害する当該酵素の硫酸基転移活性を阻害する方法。
[図2]硫酸基受容体基質としてヘパラン硫酸を用いた場合における、HS2STの活性に対するヘキスロン酸誘導体の阻害作用を示す図である。
[図3]硫酸基受容体基質としてヘパラン硫酸を用いた場合における、HS6STの活性に対するヘキスロン酸誘導体の阻害作用を示す図である。
[図4]HS2STの活性に対する誘導体2の阻害曲線を示す図である。白丸は誘導体2を添加しなかった場合のHS2STの酵素活性であり、黒丸は1mmol/l、クロスは3mmol/l、三角は10mmol/lの濃度の誘導体2を添加した場合のHS2STの酵素活性を示す。
[図5]HS6STの活性に対する誘導体2の阻害曲線を示す図である。白丸は誘導体2を添加しなかった場合のHS6STの酵素活性であり、黒丸は1mmol/l、クロスは3mmol/l、三角は10mmol/lの濃度の誘導体2を添加した場合のHS6STの酵素活性を示す。
[図6]HS2STの活性に対するヘパラン硫酸濃度及び誘導体2の濃度が与える影響を示す図である。三角はヘパラン硫酸濃度が400μmol/l、正方形は300μmol/l、菱形は200μmol/lの場合のHS2STの酵素活性を示す。
[図7]HS6STの活性に対するヘパラン硫酸濃度及び誘導体2の濃度が与える影響を示す図である。丸はヘパラン硫酸濃度が400μmol/l、三角は300μmol/l、正方形は200μmol/l、菱形は150μmol/lの場合のHS6STの酵素活性を示す。
(1)本発明阻害剤
本発明阻害剤は下記式1で表されることを特徴とするヘキスロン酸誘導体又はその塩の酵素阻害有効量を含むことを特徴とするヘパリン・ヘパラン硫酸硫酸基転移酵素阻害剤である。
従って、最も好ましいヘキスロン酸誘導体の例示としては、下記式3、及び式4で各々示される物質が挙げられる。
なお、実施例で使用したヘキスロン酸誘導体(誘導体1〜4)は、全てCarbohyd.Res.,198(1990),pp133−140の記載に従って調製したものである。また実施例で使用したHS2ST及びHS6STは特開平9−28374号及び特開平8−98684号に従って調製したものである。
硫酸基受容体基質である完全脱硫酸化N再硫酸化ヘパリン(生化学工業株式会社製:以下「CDSNSヘパリン」とも記載する)を500μmol/l、35Sで標識した3’−ホスホアデノシン−5’−ホスホ硫酸(Anal.Biocham.,148(1985),pp.303−310記載の方法により、アデノシン三リン酸(ATP)と[35S]硫酸より酵素的に合成したもの:以下3’−ホスホアデノシン−5’−ホスホ硫酸を「PAPS」とも記載する)を1μmol/l、HS6STを0.4unit、プロタミン塩酸塩(シグマ社製)を3.75μg、NaClを0.15mol/l、ヘキスロン酸誘導体(誘導体1〜4何れか一つ)を10mmol/lで含む0.05mol/lのイミダゾール緩衝液(pH6.8)を含む50μlの反応液を調製し、37℃で20分間インキュベートして反応させた。対照としてはヘキスロン酸誘導体を添加しない実験群を使用した。
硫酸基受容体基質であるヘパラン硫酸(ブタ大動脈由来:生化学工業株式会社製)を500μmol/l、35Sで標識したPAPSを1μmol/l、HS2ST又はHS6STを0.4unit、プロタミン塩酸塩(シグマ社製)を3.75μg、NaClを0.15mol/l、ヘキスロン酸誘導体(誘導体1〜4何れか一つ)を10mmol/lで含む0.05mol/lのイミダゾール緩衝液(pH6.8)を含む50μlの反応液を調製し、37℃で20分間インキュベートして反応させた。対照としてはヘキスロン酸誘導体を添加しない実験群を使用した。
実施例2の条件下で、ヘパラン硫酸の濃度を0から400μmol/l、誘導体2の濃度を0から10mmol/lで変化させて、ヘパラン硫酸への放射能の取り込みを測定して、誘導体2の阻害曲線を作成した(HS2ST:図4、HS6ST:図5)。
その結果、HS2ST及びHS6STの両者に対して誘導体2は濃度依存的に阻害作用を示すことが明かとなった。
硫酸基受容体基質であるヘパラン硫酸(ブタ大動脈由来:生化学工業株式会社製)を150〜400μmol/l、35Sで標識したPAPSを1μmol/l、HS2ST又はHS6STを0.4unit、プロタミン塩酸塩(シグマ社製)を3.75μg、NaClを0.15mol/l、誘導体2を0〜10mmol/lで調製した0.05mol/lのイミダゾール緩衝液(pH6.8)を含む50μlの反応液を調製し、37℃で20分間インキュベートして反応させた。
チャイニーズハムスターの卵巣由来の培養細胞(CHO細胞)のk1株(以下「CHOk1」とも記載する:JCRB9018)及びこの株に特開平11-69983の記載に従ってHS6STをコードするDNAを安定的にトランスフェクトした株(以下「CHO-k(t)」とも記載する)の培養液(10%牛胎児血清を含むダルベッコの調整イーグル培地(DMEM-F12:pH7.2))に誘導体2を10mmol/lとなるように添加し、48時間培養を行なった。
Claims (6)
- 下記式1で表されることを特徴とするヘキスロン酸誘導体又はその塩の酵素阻害有効量を含むことを特徴とするヘパリン・ヘパラン硫酸硫酸基転移酵素阻害剤。
- ヘパリン骨格中のグルコサミン残基の6位ヒドロキシル基へ硫酸基を転移する活性を有するヘパリン・ヘパラン硫酸硫酸基転移酵素の前記活性を阻害することを特徴とする請求項1記載のヘパリン・ヘパラン硫酸硫酸基転移酵素阻害剤。
- ヘパリン骨格中のヘキスロン酸残基の2位ヒドロキシル基へ硫酸基を転移する活性を有するヘパリン・ヘパラン硫酸硫酸基転移酵素の前記活性を阻害することを特徴とする請求項1記載のヘパリン・ヘパラン硫酸硫酸基転移酵素阻害剤。
- 下記式1で表されるヘキスロン酸グリコシド誘導体又はその塩のヘパリン・ヘパラン硫酸硫酸基転移酵素阻害剤としての使用(但し、ヒトの身体の治療による処置方法である場合を除く)。
- 請求項1〜3のいずれか一項に記載のヘパリン・ヘパラン硫酸硫酸基転移酵素阻害剤を有効成分として含有する、ヘパリン・ヘパラン硫酸硫酸基転移酵素阻害のための医薬組成物。
- 硫酸基受容体としてヘパリン骨格を有する糖鎖に硫酸基供与体から硫酸基を転移する活性を有する酵素の当該活性を、請求項1〜3のいずれか一項に記載のヘパリン・ヘパラン硫酸硫酸基転移酵素阻害剤によって阻害する当該酵素の硫酸基転移活性を阻害する方法(但し、ヒトの身体の治療による処置方法である場合を除く)。
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JP4415338B2 (ja) * | 1999-08-20 | 2010-02-17 | 生化学工業株式会社 | 硫酸基転移酵素調製物 |
US7150981B2 (en) | 2000-06-29 | 2006-12-19 | Seikagaku Corporation | Sulfate transferase and DNA encoding this enzyme |
-
2004
- 2004-05-19 US US10/557,652 patent/US7396818B2/en active Active
- 2004-05-19 DE DE602004024195T patent/DE602004024195D1/de not_active Expired - Lifetime
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US5075433A (en) * | 1988-08-05 | 1991-12-24 | Eastman Kodak Company | Substituted-3-sulfatoglucuronic acid antigens |
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CA2526022C (en) | 2011-11-29 |
EP1627640A4 (en) | 2007-05-23 |
CA2526022A1 (en) | 2004-11-25 |
DE602004024195D1 (de) | 2009-12-31 |
WO2004100961A1 (ja) | 2004-11-25 |
JPWO2004100961A1 (ja) | 2006-07-13 |
EP1627640A1 (en) | 2006-02-22 |
ATE448789T1 (de) | 2009-12-15 |
US20070066564A1 (en) | 2007-03-22 |
US7396818B2 (en) | 2008-07-08 |
EP1627640B1 (en) | 2009-11-18 |
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