JPH06256308A - New tripyrrole derivative - Google Patents
New tripyrrole derivativeInfo
- Publication number
- JPH06256308A JPH06256308A JP31258392A JP31258392A JPH06256308A JP H06256308 A JPH06256308 A JP H06256308A JP 31258392 A JP31258392 A JP 31258392A JP 31258392 A JP31258392 A JP 31258392A JP H06256308 A JPH06256308 A JP H06256308A
- Authority
- JP
- Japan
- Prior art keywords
- bilirubin
- derivative
- tripyrrole
- vinyl
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Landscapes
- Pyrrole Compounds (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は、新規なトリピロール誘
導体に関するものである。FIELD OF THE INVENTION The present invention relates to a novel tripyrrole derivative.
【０００２】[0002]
【従来技術】テトロピロール誘導体の１つであるビリル
ビンは、生体にとって有害無益な物質と考えられてき
た。事実、ヘムからのビリルビンへの中間代謝産物であ
るビリベルジンは、水溶性であって細胞毒性もなく、鳥
類などではそのまま排泄されている。しかし、ヒトをは
じめとする哺乳動物類では、無害なビルルビンをＮＡＤ
ＰＨのような貴重な補酵素を消費する酵素反応によって
ビリルビンにわざわざ代謝しなければならないのかは長
い間疑問とされてきた。しかしながら、最近、本発明者
により、ビリルビンを始めとするビリルビン誘導体に対
するモノクローナル抗体が発明され、それらのモノクロ
ーナル抗体を用いての種々の実験による知見から、この
ビリルビンが生体内で活性酸素種のスカベンジャーとし
て作用しているとの可能性が示唆されてきた。2. Description of the Related Art Bilirubin, which is one of the tetropyrrole derivatives, has been considered to be a harmful and harmful substance to the living body. In fact, biliverdin, which is an intermediate metabolite of heme to bilirubin, is water-soluble, has no cytotoxicity, and is excreted as it is in birds and the like. However, in humans and other mammals, harmless birurubin
It has long been questioned whether or not bilirubin must be purposefully metabolized by an enzymatic reaction that consumes a valuable coenzyme such as PH. However, recently, the present inventor has invented monoclonal antibodies against bilirubin derivatives including bilirubin, and based on the findings of various experiments using these monoclonal antibodies, this bilirubin was used as a scavenger of reactive oxygen species in vivo. The possibility that it is working has been suggested.
【０００３】更に、ビリルビンを始めとする種々のビリ
ルビン誘導体が、種々の疾病を患っている患者や、手術
後の患者ばかりでなく、健常人からも代謝されているこ
とが分かっている。しかしながら、従来ビリルビンの臨
床検査法として汎用されているジアゾ法では、ビリルビ
ンを始めとするビリルビン誘導体の総量を測定するする
ものであり、その総量の内、ビリルビン誘導体のどの物
質がいかなる割合で含まれているかは不明である。そこ
で、ビリルビン誘導体に対するモノクローナル抗体を作
製して、これらのモノクローナル抗体を用いて、患者ば
かりでなく、健常人から代謝されるビリルビン誘導体を
測定した結果、ある特定の疾病を患っている患者や、手
術後の患者からは、ジアゾ法では検出することができな
い、ある種のビリルビン誘導体が異常に高濃度で代謝さ
れることも分かってきた。Further, it is known that various bilirubin derivatives including bilirubin are metabolized not only by patients suffering from various diseases and after surgery but also by healthy persons. However, the diazo method, which is generally used as a clinical test method for bilirubin, conventionally measures the total amount of bilirubin derivatives including bilirubin, and among the total amount, which substance of the bilirubin derivative is contained in any proportion. It is unknown if it is. Therefore, we prepared monoclonal antibodies against bilirubin derivatives, and using these monoclonal antibodies, not only patients, but the results of measuring the bilirubin derivatives metabolized from healthy people, patients suffering from a certain disease, surgery Later patients have also found that certain bilirubin derivatives, which cannot be detected by the diazo method, are metabolized at abnormally high concentrations.
【０００４】[0004]
【発明が解決しようとする課題】したがって、かかるビ
リルビン誘導体の化学構造式を同定することができれ
ば、そのビリルビン誘導体を抗原として、モノクローナ
ル抗体を作製することができ、このモノクローナル抗体
を用いて疾病を診断する診断用キットを作製することが
できることになる。このモノクローナル抗体を用いた診
断用キットは当然のことながら、そのモノクローナル抗
体に対するビリルビン誘導体のみを認識することができ
るので、疾病等の病因などを正確に診断することができ
るようになり、疾病の診断にあたって極めて有用であ
る。Therefore, if the chemical structural formula of such a bilirubin derivative can be identified, a monoclonal antibody can be prepared using the bilirubin derivative as an antigen, and a disease can be diagnosed using this monoclonal antibody. It will be possible to produce a diagnostic kit for As a matter of course, the diagnostic kit using this monoclonal antibody can recognize only the bilirubin derivative against the monoclonal antibody, which makes it possible to accurately diagnose the etiology of diseases and the like, and to diagnose diseases. It is extremely useful in this regard.
【０００５】そこで、本発明は、抗原として利用するこ
とができ、かつ、疾病等の診断に際して重要な作用を有
するビリルビン誘導体を提供することを目的とする。Therefore, an object of the present invention is to provide a bilirubin derivative which can be used as an antigen and has an important action in the diagnosis of diseases and the like.
【０００６】[0006]
【課題を解決するための手段】本発明に係るビリルビン
誘導体は、The bilirubin derivative according to the present invention is
【化１】 （式中、Ｒ１はメチル基またはビニル基を意味し、Ｒ２
はメチル基またはビニル基を意味し、そしてＲ３は水素
原子またはメチル基を意味する）で表されるトリピロー
ル誘導体であって、新規な化合物である。[Chemical 1] (In the formula, R1 means a methyl group or a vinyl group, and R2
Represents a methyl group or a vinyl group, and R3 represents a hydrogen atom or a methyl group), and is a novel compound.
【０００７】ビリルビンとたんぱくとを結合させたハプ
テンとして抗原を調製した。つまり、ロス（Ｒｏｓｓ）
の方法に準じた酸無水物法によって非抱合型ビリルビン
ＩＸα（ＵＣＢ）を作成し、そのプロピル基を介してア
ルブミン（ＢＳＡ）と共有結合させて抗原を得た。The antigen was prepared as a hapten in which bilirubin and protein were bound. In other words, Ross
An unconjugated bilirubin IXα (UCB) was prepared by an acid anhydride method according to the method described in 1. above and covalently bound to albumin (BSA) via its propyl group to obtain an antigen.
【０００８】生後４−５週齢のＢａｌｂ／ｃマウス雌
に、上記２つの抗原と等量のフロインド完全アジュバン
トとを混合したエムルジョンを腹腔内に注射した。追加
免疫を行った後、免疫された脾臓細胞とマウス骨髄細胞
とをポリエチレングリコールを用いて細胞融合させ、常
法によりハイブリドーマの培養を行った。この培養上清
を用いてスクリーニングアッセイを行ってモノクローナ
ル抗体を調製した。Female Balb / c mice aged 4-5 weeks were intraperitoneally injected with emulsion, which was a mixture of the above two antigens and an equal amount of Freund's complete adjuvant. After the booster immunization, the immunized spleen cells and mouse bone marrow cells were cell-fused with polyethylene glycol, and the hybridomas were cultured by a conventional method. A screening assay was performed using this culture supernatant to prepare a monoclonal antibody.
【０００９】上記のようにして得られたモノクローナル
抗体のうち、ＵＣＢ、ビリルビンモノグルクロナイドお
よびビリルビンジグルクロナイドのいずれに対しても高
い反応性を示したクローンを選んでＩｇＧの精製を行っ
た。その結果、このクローンのＩｇＧサブクラスはＩｇ
Ｇ，であった。また、このクローンは、同じテトラピロ
ール構造を有するヘミン、ビリベルジン、ＵＣＢのアゾ
化合物ならびにコール酸に対しては全く反応性を示さな
かった。Among the monoclonal antibodies obtained as described above, a clone showing high reactivity with UCB, bilirubin monoglucuronide and bilirubin diglucuronide was selected and purified of IgG. . As a result, the IgG subclass of this clone was Ig
It was G. In addition, this clone did not show any reactivity to hemin, biliverdin, UCB azo compounds having the same tetrapyrrole structure, and cholic acid.
【００１０】手術症例患者の血清および尿中のビリルビ
ン値を酵素抗体法（ＥＬＩＳＡ）にて測定し、ジアゾ法
による値との比較をしたところ、直腸ガンの手術施行例
で両測定値を術前、術後１−６日目および１３日目の各
時期におけてみたところ、術前と術後１３日目において
はＥＬＩＳＡとジアゾ法との測定値は近似の値を示し相
関関係が得られた。ところが、術後１−６日目の測定値
には前述のクローンを用いたＥＬＩＳＡでの測定値が、
ジアゾ法による測定値の約５−１０倍も高い値を示し
た。また、前述したクローンを用いたＥＬＩＳＡ法によ
れば、尿中のビリルビン値も術後に著しく増加している
ことが判明した。Serum and urinary bilirubin levels of patients undergoing surgery were measured by enzyme-linked immunosorbent assay (ELISA) and compared with those by the diazo method. The results of ELISA and the diazo method showed similar values and correlations were obtained before and 13 days after surgery. It was However, the measured values on the 1st to 6th day after the operation were measured by ELISA using the above-mentioned clone,
The value was about 5 to 10 times higher than the value measured by the diazo method. In addition, according to the ELISA method using the above-mentioned clone, it was found that the bilirubin level in urine was significantly increased after the operation.
【００１１】さらに、健常人の２才から７０才に至る各
年代の尿中に排泄されるビリルビン量をＥＬＩＳＡ法で
測定した結果、加齢とともにその排泄量が一定の傾向を
持って消長することが確認された。Furthermore, as a result of measuring the amount of bilirubin excreted in urine of healthy persons from 2 years old to 70 years old by the ELISA method, it was found that the excretion amount had a constant tendency with age. Was confirmed.
【００１２】つまり、これらの事実から、長時間を要し
た開腹手術症例の術後早期の血清中には、ジアゾ反応陰
性であって、上記クローンに反応するビリルビン誘導体
が増加していることが分かった。また、これらのビルル
ビン誘導体は、開腹手術中に腹腔内が大気中の酸素に暴
露されることによって体内に生成した活性酸素をビリル
ビン自らが抗酸化剤となり解毒し、ビリルビン自体は酸
化分解産物に変化して、術後の血中に増加し、上記クロ
ーンを用いたＥＬＩＳＡによって検出されたものと考え
られる。[0012] In other words, from these facts, it is clear that the amount of bilirubin derivative that is negative for diazo reaction and that reacts with the above-mentioned clones is increased in the serum in the early stage after the operation of the laparotomy, which took a long time. It was In addition, these birurubin derivatives detoxify the active oxygen generated in the body by exposing the abdominal cavity to atmospheric oxygen during laparotomy, and the bilirubin itself becomes an antioxidant and detoxifies, and the bilirubin itself changes into an oxidative degradation product. It is considered that the amount increased in the blood after the operation and was detected by ELISA using the above clone.
【００１３】さらに、健常人の尿中にも、上記クローン
にのみに反応するビリルビン誘導体が常時排泄されてい
ることが判明した。この物質の排泄量は、生理的代謝活
性がが高い若年者ほど大きく、逆に高年者ほどその排泄
量は小さくなっている。この現象は、加齢に伴って酸素
消費を含む基礎代謝率の変化が、抗酸化剤としてのビリ
ルビンの量と密接な相関関係を示しているものと思われ
る。Further, it was found that the bilirubin derivative which reacts only with the above-mentioned clones is constantly excreted also in the urine of a healthy person. The excretion amount of this substance is larger in the younger people who have higher physiological metabolic activity, and conversely, the excretion amount is smaller in the older people. This phenomenon seems to indicate that changes in basal metabolic rate including oxygen consumption with aging show a close correlation with the amount of bilirubin as an antioxidant.
【００１４】[0014]
【実施例】本発明に係るトリピロール誘導体を実施例に
より説明する。EXAMPLES The tripyrrole derivative according to the present invention will be described by way of examples.
【実施例１】ヒト尿のサンプルをＨＰＬＣによって、上
記クローンに対してのみ反応する物質ＡおよびＢを回収
した。物質ＡおよびＢは、ＨＰＬＣの挙動とＵＶスペク
トルのパターンとからして、お互いに構造が類似してい
ることが示唆されている。Example 1 A sample of human urine was collected by HPLC to collect substances A and B that react only with the above clones. From the behavior of HPLC and the pattern of UV spectrum, it is suggested that the substances A and B have similar structures to each other.
【００１５】物質ＡのＵＶスペクトルは、２７８．２、
３４４．５，５１３．８ｎｍに主な吸収ピークを有して
いる。また、物質Ａの分子式は、ＨＲ−ＦＡＢ−ＭＳに
よって測定した結果、下記の通りであることを確認し
た。 Ｃ２５Ｈ２７Ｎ３Ｏ６ 計算値： ４６６．１９７８；４６５．１９００ 測定値： ４６６．１９６６（ＭＨ＋），４６５．１９
２９（ＭＨ＋） 更に、物質Ａの１Ｈ−ＮＭＲスペクトル（５００ＭＨ
ｚ；ＤＭＳＯ−ｄ６溶液）は次の通りであった。 １．８０（３Ｈ，ｓ）；１．９６（３Ｈ，ｓ）；２．０
２（３Ｈ，ｓ）；２．１４（２Ｈ，ｔ，Ｊ＝７．３Ｈ
ｚ）； ２．１７（２Ｈ，ｔ，Ｊ＝７．３Ｈｚ）；２．
７４（２Ｈ，ｔ，Ｊ＝７．３Ｈｚ）；２．７７（２Ｈ，
ｔ，Ｊ＝７．３Ｈｚ）；５．６７（２Ｈ，ｍ）；６．１
０（１Ｈ，ｓ）；６．５３（１Ｈ，ｂｒ ｓ）；６．８
４（１Ｈ，ｄｄ，Ｊ＝１７．１，１２．２Ｈｚ）；１
０．１２（１Ｈ，ｓ）；１０．２１（１Ｈ，ｓ）；１
０．４１（１Ｈ，ｓ） 以上の結果から、物質Ａは、１、１４、１５、１７−テ
トラヒドロ−２、７、１３−トリメチル−１、１４−ジ
オキソ−３−ビニル−１６Ｈ−トリピリン−８、１２−
ジプロピオン酸であることが確認された。The UV spectrum of substance A is 278.2,
It has main absorption peaks at 344.5 and 513.8 nm. In addition, the molecular formula of substance A was confirmed to be as follows as a result of measurement by HR-FAB-MS. C 25 H 27 N 3 O 6 Calculated: 466.1978; 465.1900 measured value: 466.1966 (MH +), 465.19
29 (MH + ) Furthermore, 1 H-NMR spectrum (500 MH) of substance A
z; DMSO-d 6 solution) was as follows. 1.80 (3H, s); 1.96 (3H, s); 2.0
2 (3H, s); 2.14 (2H, t, J = 7.3H
z); 2.17 (2H, t, J = 7.3 Hz);
74 (2H, t, J = 7.3 Hz); 2.77 (2H,
t, J = 7.3 Hz); 5.67 (2H, m); 6.1
0 (1H, s); 6.53 (1H, br s); 6.8
4 (1H, dd, J = 17.1, 12.2Hz); 1
0.12 (1H, s); 10.21 (1H, s); 1
0.41 (1H, s) From the above results, the substance A was 1,14,15,17-tetrahydro-2,7,13-trimethyl-1,14-dioxo-3-vinyl-16H-tripyrine-8. , 12-
It was confirmed to be dipropionic acid.
【００１６】[0016]
【実施例２】物質ＢのＵＶスペクトルは、２８２．０、
３４４．０，５２０．０ｎｍに主な吸収ピークを有して
いる。また、物質Ｂの分子式は、ＨＲ−ＦＡＢ−ＭＳに
よって測定した結果、下記の通りであることを確認し
た。 Ｃ２５Ｈ２７Ｎ３Ｏ６ 計算値： ４６６．１９７８；４６５．１９００ 測定値： ４６６．１９８７（ＭＨ＋），４６５．１８
７３（ＭＨ＋） 更に、物質Ｂの１Ｈ−ＮＭＲスペクトル（５００ＭＨ
ｚ；ＤＭＳＯ−ｄ６溶液）は次の通りであった。 １．８２（３Ｈ，ｓ）；２．０６（３Ｈ，ｓ）；２．１
８（３Ｈ，ｓ）；２．２７（２Ｈ，ｔ，Ｊ＝７．３Ｈ
ｚ）； ２．３５（２Ｈ，ｔ，Ｊ＝７．３Ｈｚ）；２．
７４（２Ｈ，ｔ，Ｊ＝７．３Ｈｚ）；２．７８（２Ｈ，
ｔ，Ｊ＝７．３Ｈｚ）；５．３５（１Ｈ，ｄｄ，Ｊ＝１
１．６，２．５Ｈｚ）；６．０９（１Ｈ，ｓ）； ６．
２５（１Ｈ，ｄｄ，Ｊ＝１７．７，２．５Ｈｚ）；６．
２７（１Ｈ，ｂｒ ｓ）；６．６１（１Ｈ，ｄｄ，Ｊ＝
１７．７，１１．６Ｈｚ）；１０．１７（１Ｈ，ｓ）；
１０．２７（１Ｈ，ｓ）；１０．２９（１Ｈ，ｓ） 以上の結果から、物質Ｂは、１、１４、１５、１７−テ
トラヒドロ−３、７、１３−トリメチル−１、１４−ジ
オキソ−２−ビニル−１６Ｈ−トリピリン−８、１２−
ジプロピオン酸であることが確認された。Example 2 The UV spectrum of substance B is 282.0,
It has main absorption peaks at 344.0 and 520.0 nm. Moreover, the molecular formula of the substance B was confirmed to be as follows as a result of measurement by HR-FAB-MS. C 25 H 27 N 3 O 6 Calculated: 466.1978; 465.1900 measured value: 466.1987 (MH +), 465.18
73 (MH + ) Further, the 1 H-NMR spectrum of the substance B (500 MH
z; DMSO-d 6 solution) was as follows. 1.82 (3H, s); 2.06 (3H, s); 2.1
8 (3H, s); 2.27 (2H, t, J = 7.3H)
2.35 (2H, t, J = 7.3 Hz);
74 (2H, t, J = 7.3 Hz); 2.78 (2H,
t, J = 7.3 Hz); 5.35 (1H, dd, J = 1)
1.6, 2.5 Hz); 6.09 (1H, s);
25 (1H, dd, J = 17.7, 2.5Hz); 6.
27 (1H, br s); 6.61 (1H, dd, J =
17.7, 11.6 Hz); 10.17 (1H, s);
10.27 (1H, s); 10.29 (1H, s) From the above results, the substance B is 1,14,15,17-tetrahydro-3,7,13-trimethyl-1,14-dioxo-. 2-Vinyl-16H-tripyrin-8,12-
It was confirmed to be dipropionic acid.
【００１７】[0017]
【発明の効果】前述したように、本発明に係るトリピロ
ール誘導体は、新規な化合物であり、ビリルビンの酸化
分解産物といえるところから、このトリピロール誘導体
を、モノクローナル抗体によって測定することにより、
術後の経過ばかりでなく、病因等を診断するのに極めて
有用である。As described above, the tripyrrole derivative according to the present invention is a novel compound and can be said to be an oxidative degradation product of bilirubin. Therefore, by measuring the tripyrrole derivative with a monoclonal antibody,
It is extremely useful for diagnosing the etiology as well as the postoperative course.
Claims (3)
ことを特徴とする新規なトリピロール誘導体。Claims: (In the formula, R1 means a methyl group or a vinyl group, R2 means a methyl group or a vinyl group, and R3 means a hydrogen atom or a methyl group). .
し、Ｒ２がビニル基を意味し、そしてＲ３が水素原子を
意味することを特徴とすること。2. The method according to claim 1, wherein R1 means a methyl group, R2 means a vinyl group, and R3 means a hydrogen atom.
し、Ｒ２がメチル基を意味し、そしてＲ３が水素原子を
意味することを特徴とすること。3. The method according to claim 1, wherein R1 means a vinyl group, R2 means a methyl group, and R3 means a hydrogen atom.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP31258392A JP3230062B2 (en) | 1992-10-10 | 1992-10-10 | New tripyrrole derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP31258392A JP3230062B2 (en) | 1992-10-10 | 1992-10-10 | New tripyrrole derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH06256308A true JPH06256308A (en) | 1994-09-13 |
| JP3230062B2 JP3230062B2 (en) | 2001-11-19 |
Family
ID=18030956
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP31258392A Expired - Fee Related JP3230062B2 (en) | 1992-10-10 | 1992-10-10 | New tripyrrole derivatives |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP3230062B2 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001062245A3 (en) * | 2000-02-25 | 2001-12-20 | Isis Innovation | Bilirubin or biliverdin degradation fragments |
| WO2007103427A2 (en) * | 2006-03-06 | 2007-09-13 | Wang Xiang H | Medical use of bilirubin and its structural analogues |
-
1992
- 1992-10-10 JP JP31258392A patent/JP3230062B2/en not_active Expired - Fee Related
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001062245A3 (en) * | 2000-02-25 | 2001-12-20 | Isis Innovation | Bilirubin or biliverdin degradation fragments |
| JP2003525881A (en) * | 2000-02-25 | 2003-09-02 | メディカル リサーチ カウンシル | Fragment |
| US7098238B2 (en) | 2000-02-25 | 2006-08-29 | Medical Research Council | Degradation fragments |
| US7498421B2 (en) | 2000-02-25 | 2009-03-03 | Medical Research Council | Degradation fragments |
| WO2007103427A2 (en) * | 2006-03-06 | 2007-09-13 | Wang Xiang H | Medical use of bilirubin and its structural analogues |
| WO2007103427A3 (en) * | 2006-03-06 | 2007-11-08 | Xiang H Wang | Medical use of bilirubin and its structural analogues |
Also Published As
| Publication number | Publication date |
|---|---|
| JP3230062B2 (en) | 2001-11-19 |
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