JP2689144B2 - 7〆, 11〆-dihydroxy-androsto-1,4-diene-3,17-dione - Google Patents
7〆, 11〆-dihydroxy-androsto-1,4-diene-3,17-dioneInfo
- Publication number
- JP2689144B2 JP2689144B2 JP25234588A JP25234588A JP2689144B2 JP 2689144 B2 JP2689144 B2 JP 2689144B2 JP 25234588 A JP25234588 A JP 25234588A JP 25234588 A JP25234588 A JP 25234588A JP 2689144 B2 JP2689144 B2 JP 2689144B2
- Authority
- JP
- Japan
- Prior art keywords
- dione
- dihydroxy
- diene
- androst
- androsto
- 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.)
- Expired - Lifetime
Links
Landscapes
- Steroid Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【発明の詳細な説明】 産業上の利用分野 本発明は、ヒト胎盤由来エストロジエン合成酵素（ア
ロマテース）活性阻害作用を有することから、医療分野
での利用が期待される新規なアンドロステン誘導体に関
する。Description: TECHNICAL FIELD The present invention relates to a novel androstene derivative which has a human placenta-derived estrogen synthase (aromatase) activity inhibitory activity and is expected to be used in the medical field.
技術的背景 従来、種々のアンドロステン誘導体が合成されてお
り、その多くは種々の生物学的活性を有することが知ら
れている。TECHNICAL BACKGROUND Conventionally, various androstene derivatives have been synthesized, and many of them are known to have various biological activities.
本発明は、公知のアンドロジエンである４−アンドロ
ステン−3,17−ジオン基質とし、これにアクレモニウム
属（Acremonium）に属する特定な微生物を作用させる
と、新規なアンドロステン誘導体である７α,11α−ジ
ヒドロキシ−アンドロスト−1,4−ジエン−3,17−ジオ
ンが生産されることを見出した。The present invention is a known androdiene 4-androstene-3,17-dione substrate, when a specific microorganism belonging to the genus Acremonium is allowed to act on it, a novel androstene derivative 7α, It was found that 11α-dihydroxy-androst-1,4-diene-3,17-dione was produced.
発明が解決しようとする課題 したがつて、本発明は、ヒト胎盤由来エストロジエン
合成酵素（アロマテース）活性阻害作用の生物学的活性
を有する新規な７α,11α−ジヒドロキシ−アンドロス
ト−1,4−ジエン−3,17−ジオンを提供することを課題
とする。DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention Accordingly, the present invention provides a novel 7α, 11α-dihydroxy-androst-1,4-, which has a biological activity of inhibiting human placenta-derived estrodiene synthase (aromatase) activity. An object is to provide diene-3,17-dione.
以下本発明を詳しく説明する。 Hereinafter, the present invention will be described in detail.
発明の構成 本発明に係る７α,11α−ジヒドロキシ−アンドロス
ト−1,4−ジエン−3,17−ジオンは下記の理化学的性質
を有することにより特定される。Structure of the Invention The 7α, 11α-dihydroxy-androst-1,4-diene-3,17-dione according to the present invention is specified by having the following physicochemical properties.
外観：白色粉末 分子量:318 分子式:C19H26O4 融点:278℃ 〔α〕D:204 溶解性：エタノール、メタノール、酢酸エチル、クロ
ロホルムに可溶、水、ヘキサンに不溶。Appearance: White powder Molecular weight: 318 Molecular formula: C 19 H 26 O 4 Melting point: 278 ° C [α] D : 204 Solubility: Soluble in ethanol, methanol, ethyl acetate and chloroform, insoluble in water and hexane.
UVスペクトラム:242nm（ε＝257806） EIマススペクトル：第１図に示すとおり（m/Z 318） NMRスペクトル： プロトン核磁気共鳴吸収スペクトル 第２図に示すとおり 13C−核磁気共鳴吸収スペクトル 第３図に示すとおり 課題を解決するための手段 本発明に係る７α,11α−ジヒドロキシ−アンドロス
ト−1,4−ジエン−3,17−ジオンは下記方法により製造
し得る。UV spectrum: 242 nm (ε = 257806) EI mass spectrum: As shown in Fig. 1 (m / Z 318) NMR spectrum: Proton nuclear magnetic resonance absorption spectrum As shown in Fig. 13 C-nuclear magnetic resonance absorption spectrum No. 3 As shown in the figure, means for solving the problem 7α, 11α-dihydroxy-androst-1,4-diene-3,17-dione according to the present invention can be produced by the following method.
７α,11α−ジヒドロキシ−アンドロスト−1,4−ジエン
−3,17−ジオンの製造： アクレモニウム・ストリクタム（Acremonium strictu
m）NN 106株（ハンガリー国立衛生研究所より分譲、微
工研菌寄第9142号）を、麦芽エキスなどの炭素源、ペプ
トン、大豆粉のような窒素源を含有する培地に無機塩類
を添加した培地中で培養して増殖後、この培養液に、４
−アンドロステン−3,17−ジオンを基質としてこれを予
めジメチルホルムアミドに0.1g/mlの濃度に溶解した溶
液を加え、反応を行う。Preparation of 7α, 11α-dihydroxy-androst-1,4-diene-3,17-dione: Acremonium strictu
m) NN 106 strain (sold by the National Institute of Health, Hungarian Institute of Microbiology No. 9142) was added to a medium containing carbon sources such as malt extract, nitrogen sources such as peptone and soybean powder, and inorganic salts added. After culturing and proliferating in the culture medium,
-Using androstene-3,17-dione as a substrate, a solution prepared by dissolving this in dimethylformamide at a concentration of 0.1 g / ml is added and the reaction is carried out.
反応終了後、培養液中より濾過又は遠心分離にて固形
分及び固体成分を除去し、得られた上澄を酢酸エチルで
抽出を行い、溶媒を除去して粗精製画分を得る。次い
で、この画分を小量のクロロホルム又はメタノールに溶
解し、シリカゲルカラム及び溶出溶媒（クロロホルム：
メタノール＝98:2）を用い、高速液体クロマトグラフィ
ーにより、上記反応により生産された７α,11α−ジヒ
ドロキシ−アンドロスト−1,4−ジエン−3,17−ジオン
を溶出して、分取する。After completion of the reaction, the solid content and solid components are removed from the culture broth by filtration or centrifugation, the obtained supernatant is extracted with ethyl acetate, and the solvent is removed to obtain a crudely purified fraction. Then, this fraction was dissolved in a small amount of chloroform or methanol, and a silica gel column and an elution solvent (chloroform:
The 7α, 11α-dihydroxy-androst-1,4-diene-3,17-dione produced by the above reaction is eluted and fractionated by high performance liquid chromatography using methanol = 98: 2).
発明の利用性 上述のようにして得られる７α,11α−ジヒドロキシ
−アンドロスト−1,4−ジエン−3,17−ジオンはヒト胎
盤由来エストロジエン合成酵素（アロマテース）活性阻
害作用の生物学的活性を有するので、医療分野での利
用、特に制癌剤としての開発が期待される。Utility of the Invention The 7α, 11α-dihydroxy-androst-1,4-diene-3,17-dione obtained as described above is a biological activity of human placenta-derived estrodiene synthase (aromatase) activity inhibitory activity. Therefore, it is expected to be used in the medical field, especially as a carcinostatic agent.
次に、本物質のヒト胎盤由来エストロジエン合成酵素
（アロマテース）活性阻害作用を試験した結果を示す。Next, the results of tests on the inhibitory effect of this substance on human placenta-derived estrogen synthase (aromatase) activity are shown.
測定方法： E.A.Thompsonの方法〔ジヤーナル オブ バイオロジ
カル ケミストリイ（J.Biol.Chem.、249,p 5364〜537
2、1974）〕に準じ、ヒト胎盤よりアロマテースを抽
出、精製し、〔１β、２β3H〕アンドロステンジオンを
基質とした酵素活性測定における本物質の阻害作用を測
定した。Measuring method: EAThompson method [Journal of Biological Chemistry (J. Biol. Chem., 249 , p 5364-537
2, 1974)], aromatase was extracted and purified from human placenta, and the inhibitory action of this substance in the enzyme activity measurement using [1β, 2β3H] androstenedione as a substrate was measured.
上記測定結果は下記のとおりである。添加ステロイド 疎外率（％） 本物質（100μＭ） 45.3 以下に実施例を示して本物質の製造法を具体的に説明
する。The above measurement results are as follows. Added steroid alienation ratio (%) This substance (100 μM) 45.3 The production method of this substance will be specifically described with reference to the following examples.
実施例 ７α,11α−ジヒドロキシ−アンドロスト−1,4−ジエン
−3,17−ジオンの製造： アクレモニウム・ストリクタム NN 106（FERMP−914
3）を下記に示す組成の培地100mlを収容した500ml容の
三角フラスコ中に接種した。Example 7 Preparation of 7α, 11α-dihydroxy-androst-1,4-diene-3,17-dione: Acremonium strictum NN 106 (FERMP-914
3) was inoculated into a 500 ml Erlenmeyer flask containing 100 ml of a medium having the composition shown below.
培地組成： 麦芽エキス 30g ペプトン 20g 大豆粉 10g リン酸二水素カリウム 5g 硫酸マグネシウム 5g 精製水 100ml 上記接種したものを、ロータリー式振とう培養機を用
い、24℃の温度で200rpmにて48時間培養を行つた。培養
終了後、基質としての４−アンドロステン−3,17−ジオ
ンを予め0.1g/mlの濃度になるようにジメチルホルムア
ミドに溶解した液2mlを、上記培養後のフラスコに添加
し、更に24〜48時間、上記条件下に反応を行つた。Medium composition: Malt extract 30 g Peptone 20 g Soybean powder 10 g Potassium dihydrogen phosphate 5 g Magnesium sulfate 5 g Purified water 100 ml The above inoculum was cultivated at 200 rpm for 48 hours at 200 rpm using a rotary shaker. I went. After completion of the culturing, 2 ml of a solution of 4-androstene-3,17-dione as a substrate dissolved in dimethylformamide in advance to a concentration of 0.1 g / ml was added to the flask after the culturing, and 24 to The reaction was carried out under the above conditions for 48 hours.
反応終了後、培養液中より濾過又は遠心分離にて固体
分及び菌体成分を除去し、得られた上澄を、その13容量
の酢酸エチルにて３回抽出を行い、得られた抽出よりロ
ータリーエバポレーターにて溶媒成分を除去して粗精製
画分を得た。After completion of the reaction, solids and bacterial components were removed from the culture solution by filtration or centrifugation, and the obtained supernatant was extracted 3 times with 13 volumes of ethyl acetate. The solvent component was removed by a rotary evaporator to obtain a crudely purified fraction.
次いで、この画分を少量のクロロホルムに溶解し、シ
リカゲル（20φ×300mm）カラムを用い、クロロホル
ム：メタノール（98:2）を溶出液として用いて高速液体
クロマトグラフィー（センシュー科学社製）にて７α,1
1α−ジヒドロキシ−アンドロスト−1,4−ジエン−3,17
−ジオン溶出、分取した。収量0.8mg。Then, this fraction was dissolved in a small amount of chloroform and subjected to high performance liquid chromatography (manufactured by Senshu Scientific Co.) using a silica gel (20φ × 300 mm) column and chloroform: methanol (98: 2) as an eluent to obtain 7α. , 1
1α-dihydroxy-androst-1,4-diene-3,17
-Dione was eluted and collected. Yield 0.8 mg.
添付の第１図は、本発明の物質のEIマススペクトル、第
２図は、プロトン核磁気共鳴スペクトルを、及び第３図
は13C−核磁気共鳴スペクトルをそれぞれ示す。FIG. 1 shows the EI mass spectrum of the substance of the present invention, FIG. 2 shows the proton nuclear magnetic resonance spectrum, and FIG. 3 shows the 13 C-nuclear magnetic resonance spectrum.
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.6 識別記号 庁内整理番号 ＦＩ 技術表示箇所 Ｃ１２Ｒ 1:645） ──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. 6 Identification code Agency reference number FI Technical display location C12R 1: 645)
Claims (1)
ロキシ−アンドロスト−1,4−ジエン−3,17−ジオン 1. A 7α, 11α-dihydroxy-androst-1,4-diene-3,17-dione having the following (I):
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP25234588A JP2689144B2 (en) | 1988-10-06 | 1988-10-06 | 7〆, 11〆-dihydroxy-androsto-1,4-diene-3,17-dione |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP25234588A JP2689144B2 (en) | 1988-10-06 | 1988-10-06 | 7〆, 11〆-dihydroxy-androsto-1,4-diene-3,17-dione |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH02101096A JPH02101096A (en) | 1990-04-12 |
| JP2689144B2 true JP2689144B2 (en) | 1997-12-10 |
Family
ID=17235987
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP25234588A Expired - Lifetime JP2689144B2 (en) | 1988-10-06 | 1988-10-06 | 7〆, 11〆-dihydroxy-androsto-1,4-diene-3,17-dione |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2689144B2 (en) |
-
1988
- 1988-10-06 JP JP25234588A patent/JP2689144B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPH02101096A (en) | 1990-04-12 |
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