JP2622700B2 - 15β-hydroxy-19-nor-testosterone - Google Patents
15β-hydroxy-19-nor-testosteroneInfo
- Publication number
- JP2622700B2 JP2622700B2 JP62318963A JP31896387A JP2622700B2 JP 2622700 B2 JP2622700 B2 JP 2622700B2 JP 62318963 A JP62318963 A JP 62318963A JP 31896387 A JP31896387 A JP 31896387A JP 2622700 B2 JP2622700 B2 JP 2622700B2
- Authority
- JP
- Japan
- Prior art keywords
- testosterone
- hydroxy
- activity
- aromatase
- substance
- 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
- 229960004719 nandrolone Drugs 0.000 title claims description 13
- NPAGDVCDWIYMMC-IZPLOLCNSA-N nandrolone Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 NPAGDVCDWIYMMC-IZPLOLCNSA-N 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 102000014654 Aromatase Human genes 0.000 description 8
- 108010078554 Aromatase Proteins 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 5
- 210000002826 placenta Anatomy 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 239000000758 substrate Substances 0.000 description 5
- 230000004071 biological effect Effects 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000006228 supernatant Substances 0.000 description 3
- 150000003515 testosterones Chemical class 0.000 description 3
- 241001019659 Acremonium <Plectosphaerellaceae> Species 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 235000010469 Glycine max Nutrition 0.000 description 2
- 244000068988 Glycine max Species 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 239000001888 Peptone Substances 0.000 description 2
- 108010080698 Peptones Proteins 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 2
- 238000000862 absorption spectrum Methods 0.000 description 2
- 210000003850 cellular structure Anatomy 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 235000019319 peptone Nutrition 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 241000228417 Sarocladium strictum Species 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- AEMFNILZOJDQLW-QAGGRKNESA-N androst-4-ene-3,17-dione Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 AEMFNILZOJDQLW-QAGGRKNESA-N 0.000 description 1
- 229960005471 androstenedione Drugs 0.000 description 1
- AEMFNILZOJDQLW-UHFFFAOYSA-N androstenedione Natural products O=C1CCC2(C)C3CCC(C)(C(CC4)=O)C4C3CCC2=C1 AEMFNILZOJDQLW-UHFFFAOYSA-N 0.000 description 1
- 150000001443 androstenes Chemical class 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000012156 elution solvent Substances 0.000 description 1
- 238000003028 enzyme activity measurement method Methods 0.000 description 1
- 235000013312 flour Nutrition 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 239000013028 medium composition Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid 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）活性阻害作用の生物学的活性を有してい
て、医療分野での利用が期待される新規なテストステロ
ン誘導体に関する。The present invention has a biological activity of inhibiting the activity of human placenta-derived estrogen synthase (aromatase), and is expected to be used in the medical field. Testosterone derivatives.
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.
本発明者は、公知のテストステロン誘導体である19−
ノル−テストステロンを基質とし、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、新規なテストステロン誘導体である15β−ヒドロキ
シ−19−ノル−テストステロンが生産されることを見出
した。The present inventor has proposed a known testosterone derivative 19-.
It has been found that a novel testosterone derivative, 15β-hydroxy-19-nor-testosterone, is produced when nor-testosterone is used as a substrate and a specific microorganism belonging to the genus Acremonium is allowed to act on the substrate.
発明が解決しようとする課題 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15β−ヒドロキシ−19−ノル−テストステロンを提供
することを課題とする。DISCLOSURE OF THE INVENTION An object of the present invention is to provide a novel 15β-hydroxy-19-nor-testosterone having a biological activity of inhibiting the activity of human placenta-derived estrodiene synthase (aromatase). .
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15β−ヒドロキシ−19−ノル−テストス
テロンは下記の理化学的性質により特定される。Constitution of the invention The 15β-hydroxy-19-nor-testosterone according to the present invention is specified by the following physicochemical properties.
外観： 白色粉末 分子量： 290 分子式： C18H26O3 融点： 231〜232 ℃ EIマススペクトル：第１図に示すとおり。（m/Z＝29
0） 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。13 C−核磁気共鳴吸収スペクトル第３図に示すとお
り。Appearance: White powder Molecular weight: 290 Molecular formula: C 18 H 26 O 3 Melting point: 231 to 232 ° C. EI mass spectrum: As shown in FIG. (M / Z = 29
0) Proton nuclear magnetic resonance absorption spectrum As shown in FIG. 13 C-nuclear magnetic resonance absorption spectrum As shown in FIG.
課題を解決するための手段 本発明に係る15β−ヒドロキシ−19−ノル−テストス
テロンは下記方法により製造し得る。Means for Solving the Problems 15β-Hydroxy-19-nor-testosterone according to the present invention can be produced by the following method.
15β−ヒドロキシ−19−ノル−テストステロンの製造 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
工研条寄第2716号（FERM BP−2716）微工研菌寄第9143
号より移管））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、19−ノ
ル−テストステロンを基質とし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 15β-hydroxy-19-nor-testosterone Acremonium strictutam
m) NN 106 strain (available from the Hungarian National Institutes of Health, microfabrication lab. No. 2716 (FERM BP-2716)
) In a medium containing a carbon source such as malt extract, and a nitrogen source such as peptone and soybean powder to which inorganic salts have been added. -Using testosterone as a substrate, a solution prepared by dissolving it in dimethylformamide at a concentration of 0.1 g / ml in advance is added to carry out the reaction.
反応終了後、培養液中より濾過又は遠心分離にて固形
分及び菌体成分を除去し、得られた上澄を酢酸エチルで
抽出を行い、溶媒を除去して粗製製画分を得る。次い
で、この画分を少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、生成した15β−ヒドロキシ
−19−ノル−テストステロンを分取する。After completion of the reaction, the solid content and the cell components are removed from the culture solution by filtration or centrifugation, and the obtained supernatant is extracted with ethyl acetate, and the solvent is removed to obtain a crude fraction. Next, this fraction was dissolved in a small amount of chloroform or methanol, and the silica gel column and an elution solvent (chloroform:
The produced 15β-hydroxy-19-nor-testosterone is collected using methanol = 98: 2).
発明の利用性 上述のようにして得られる15β−ヒドロキシ−19−ノ
ル−テストステロ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、時に制癌剤としての開発
が期待される。Since the 15β-hydroxy-19-nor-testosterone obtained as described above has a biological activity of inhibiting the activity of estrogen synthase (aromatase) derived from human placenta, it is sometimes used in the medical field. It is expected to be developed as an anticancer drug.
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〔ジャーナル オブ バイオロジ
カル ケミストリイ（J.Biol.Chem.、249,p5364〜537
2、1974）〕に準じ、ヒト胎盤よりアロマテースを抽
出、精製し〔１β、２β−3H〕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。Measurement method: EAThompson method [Journal of Biological Chemistry (J. Biol. Chem., 249 , p5364-537)
2, 1974)], aromatase was extracted and purified from human placenta, and the inhibitory effect of this substance in the enzyme activity measurement using [1β, 2β-3H] 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 濃度 阻害率（％） 本物質 100μＭ 67.6 無添加 − ０ 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. Additive steroid concentration inhibition rate (%) This substance 100 μM 67.6 No addition-0 The production method of this substance will be specifically described with reference to Examples.
実施例 15β−ヒドロキシ−19−ノル−テストステロンの製造 アクレモニウム・ストリクタム NN 106（FERM BP−27
16）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 15 Preparation of β-hydroxy-19-nor-testosterone Acremonium strictum NN 106 (FERM BP-27
16) was inoculated into a 500 ml Erlenmeyer flask containing 100 ml of a medium having the following composition.
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 1000ml 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19−ノル−テストステロンを予め
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2
4〜48時間、上記条件下に反応を行つた。Medium composition: Malt extract 30g Peptone 20g Soybean flour 10g Potassium dihydrogen phosphate 5g Magnesium sulfate 5g Purified water 1000ml Using a rotary shaking incubator, incubate for 48 hours at a temperature of 24 ° C and 200rpm at 200 ℃. I went. After completion of the culture, 19-nor-testosterone as a substrate is previously added.
2 ml of a solution dissolved in dimethylformamide to a concentration of 0.1 g / ml was added to the flask after the above culture, and further 2
The reaction was carried out under the above conditions for 4-48 hours.
反応終了後、培養液中より濾過又は遠心分離にて固形
分及び菌体成分を除去し、得られた上澄を、その1/3容
量の酢酸エチルにて３回抽出を行い、得られた抽出液よ
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, the solid content and the bacterial cell components were removed from the culture solution by filtration or centrifugation, and the obtained supernatant was extracted three times with 1/3 volume of ethyl acetate to obtain the obtained supernatant. The solvent component was removed from the extract using 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15β−ヒ
ドロキシ−19−ノル−テストステロンを分取した。収量
3mg。Next, this fraction was dissolved in a small amount of chloroform, and 15β-hydroxy-19-nor-testosterone was fractionated using a silica gel (20 φ × 300 mm) column using chloroform: methanol (98: 2) as an eluent. . yield
3 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.
Claims (1)
19−ノル−テストステロン 1. A compound having the formula (I):
19-nor-testosterone
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62318963A JP2622700B2 (en) | 1987-12-18 | 1987-12-18 | 15β-hydroxy-19-nor-testosterone |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62318963A JP2622700B2 (en) | 1987-12-18 | 1987-12-18 | 15β-hydroxy-19-nor-testosterone |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH01160995A JPH01160995A (en) | 1989-06-23 |
| JP2622700B2 true JP2622700B2 (en) | 1997-06-18 |
Family
ID=18104947
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP62318963A Expired - Lifetime JP2622700B2 (en) | 1987-12-18 | 1987-12-18 | 15β-hydroxy-19-nor-testosterone |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2622700B2 (en) |
-
1987
- 1987-12-18 JP JP62318963A patent/JP2622700B2/en not_active Expired - Lifetime
Non-Patent Citations (1)
| Title |
|---|
| ACTA.MICROBIOL.ACAD.SCI.HUNG=1975 * |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH01160995A (en) | 1989-06-23 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| SU1442077A3 (en) | Method of producing substituted androsta-1,4-dien-3,17-diones | |
| KR100432054B1 (en) | Microorganism having ability to convert sterol into Androst-4-ene-3,17-dione/Androsta-1,4-diene-3,17-dione and preparation method thereof | |
| US7419972B2 (en) | 2-substituted estra-1,3,5(10)-trien-17-ones as inhibitors of 17β-hydroxy steroid dehydrogenase type 1 | |
| JP3064416B2 (en) | BE-13793C derivative antitumor substance | |
| JPH04117394A (en) | New steroid compounds having substituted ethyl group in position 10, their manufacture, their use as medicines and pharmaceutical compositions containing them | |
| DE2558088C2 (en) | Process for the preparation of 4-androstene-3,17-dione derivatives | |
| JP2622700B2 (en) | 15β-hydroxy-19-nor-testosterone | |
| US5079377A (en) | Novel androst-4-ene-3,17-dione derivatives and method for preparing same | |
| JP2622712B2 (en) | 7α, 14α-dihydroxy-androst-1,4-diene-3,17-dione | |
| JP2689144B2 (en) | 7〆, 11〆-dihydroxy-androsto-1,4-diene-3,17-dione | |
| JP2623285B2 (en) | Method for producing 2 (3-hydroxy-1,3,5 (10) -estrien-17-yl) propionic acid | |
| CA1252085A (en) | Steroidic aromatase inhibitors | |
| CS231188B2 (en) | Processing method of derivative of 6 alpha-methyl hydrocortisene | |
| Gould et al. | Some new active corticosteroids | |
| EP0665238B1 (en) | Corticoid derivatives and pharmaceutical and cosmetic compositions | |
| HU181505B (en) | Process for preparing 21-hydroxy-20-methyl-pregnane derivates | |
| JPH0150716B2 (en) | ||
| JPH0150717B2 (en) | ||
| DE2558090C2 (en) | Process for the preparation of 4-androstene-3,17-dione derivatives | |
| JPH0369357B2 (en) | ||
| JPH0256423A (en) | Naphthopyran derivative and use thereof | |
| JPS63192794A (en) | 14alpha-hydroxy-4-androsterone-3,6,17-trione | |
| JPH0567157B2 (en) | ||
| JPS5840476B2 (en) | New physiologically active substance ML-236C and its manufacturing method | |
| CA2120726A1 (en) | Androst-4-eno¬4,5-b|pyrrole derivatives and process for their preparation |