JP3719689B2 - Novel substance triprostatin, process for producing the same, cell cycle inhibitor and antitumor agent - Google Patents
Novel substance triprostatin, process for producing the same, cell cycle inhibitor and antitumor agent Download PDFInfo
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Description
【0001】
【発明の属する技術分野】
本発明は、新規物質トリプロスタチン、その製造方法、それを有効成分とする細胞周期阻害剤および抗腫瘍剤に関する。
【0002】
【従来の技術】
人体を構成する細胞は恒常性を維持するためにその増殖と分化は厳しく制御されている。細胞は、M期・G1 期・S期・G2 期という一連の過程からなる細胞周期を回転することにより分裂、増殖を行う。この細胞周期の制御機構に異常が生じると癌や免疫疾患になる。最近では、細胞周期の調節機構が分子レベルで解明されつつあり、細胞周期を調節する物質には、抗腫瘍剤、免疫抑制剤の可能性が知られている。
【0003】
【発明が解決しようとする課題】
本発明は、細胞周期阻害活性、抗腫瘍活性を有する新規物質、その製造方法、それを有効成分とする細胞周期阻害剤および抗腫瘍剤の提供を目的とする。
【0004】
【課題を解決するための手段】
本発明者は上記課題の解決のために鋭意検討した結果、静岡県大井川沖の海底から採取した土壌から分離された、アスペルギルス属に属するカビBM939 株が細胞周期阻害活性および抗腫瘍活性を有する物質を生産することを見い出し、本発明を完成するに至った。
本発明は、以下の一般式(I)で表される新規物質トリプロスタチンを提供するものである。
【0005】
【化2】
式中、Rは、メトキシ基(トリプロスタチンA)または水素原子(トリプロスタチンB)である。
【0006】
本発明のトリプロスタチンは、アスペルギルス属に属する、トリプロスタチン生産菌を培地に培養し、トリプロスタチンを生成蓄積せしめ、これを採取することにより製造することができる。本発明で使用するトリプロスタチン生産菌の好ましい例としては、アスペルギルス・フミガタスBM939 株が挙げられる。
本発明はさらに、新規物質トリプロスタチンを有効成分とする細胞周期阻害剤およびトリプロスタチンを有効成分とする抗腫瘍剤を提供するものである。
【0007】
【発明の実施の形態】
以下本発明を詳細に説明する。
本発明の新規物質トリプロスタチンAおよびBは以下の式で表される。
【0008】
【化3】
【0009】
本発明の物質トリプロスタチンAおよびBを生産するアスペルギルス属に属する菌の代表例としてはアスペルギルス・フミガタスが挙げられ、その具体例としてはカビBM939 株が挙げられる。BM939 株は以下の菌学的性質を有する。
(1)各種培地上での生育形態
培養はすべて25℃で行い寒天平板培地上での生育形成を記載した。
(1-1) CYA 寒天培地
生育は良好であり、25℃、7日間の培養でコロニーの直径は65mmである。コロニーはビロード状に生育して多くの分生子を形成し分生子は青緑色である。コロニの裏面は淡黄色である。
(1-2) CY20S 寒天培地
生育は中程度であり、25℃、7日間の培養でコロニーの直径は50mmである。コロニーはビロード状に生育して分生子を形成し、分生子は青緑である。コロニーの裏面は淡黄色である。
(1-3) MEA 寒天培地
生育は中程度であり、25℃、7日間の培養でコロニーの直径は55mmである。コロニーはビロード状に生育して分生子を形成し、分生子は淡黄色である。コロニーの裏面は淡黄色である。
【0010】
(2)形態的性質
25℃、7日間、CYA 寒天培地上での形態的性質は以下のとおりであった。
分生子柄の幅は 2.5〜5μm 、長さは 100〜350 μm で、その先端に直径10〜25μm 、淡緑色の球〜半球状の頂のうを形成する。分生子柄の表面は平滑状であり、メトレは生産していない。頂のうの約2/3 より上部に淡緑色の幅 5〜10×長さ2〜3.5mm のフィアライドを一段形成する。分生子はフィアライドより連鎖して形成され、直径2〜3.5mm 、深緑色の球〜半球状である。ヒューレ細胞は観察されなかった。
以上の菌学的性状から、本菌株はアスペルギルス(Aspergillus) 属の菌であり、レイパーとフェンネル(Raper & Fennel)の「ザ・ジーナス・アスペルギルス」(1965)(“The GENUS Aspergillus") を参考に既知菌種を検索したところ、アスペルギルス・フミガタス(Aspergillus Fumigatus) の性状と一致した。なお、当該菌株Aspergillus fumigatus BM939 は生命工学工業技術研究所に1995年7月26日に寄託され、その受託番号はFERM P-15067である。
【0011】
上記菌株カビBM939 株を培養し、当該培養物から新規物質トリプロスタチンAおよびB(以下「本発明化合物」とも記載する)を採取する方法は、具体的には後述する製造例に記載するが、概ねアスペルギルス属に属する菌の培養方法に従って実施することができる。培養終了後、培養液から本発明のトリプロスタチンを精製、単離するには、一般に微生物代謝産物を採取するのに通常用いられる手段を適宜利用して行うことができる。例えば、各種イオン交換樹脂、非イオン性吸着樹脂、ゲル濾過クロマトグラフィー、又は活性炭、アルミナ、シリカゲル等の吸着剤によるクロマトグラフィー及び高速液体クロマトグラフィー、或いは結晶化、減圧濃縮、凍結乾燥等の手段をそれぞれ単独又は適宜組み合わせて、或いは反復して使用することが可能である。
【0012】
以上のようにして製造される新規なトリプロスタチンは、後述の試験例に示すように細胞周期阻害活性、抗腫瘍活性を有する。
本発明のトリプロスタチンを有効成分とする細胞周期阻害剤は、その使用目的に合わせて、使用方法、剤型、投与量(使用量)が適宜決定される。例えば、本発明のトリプロスタチンを有効成分とする抗腫瘍剤の場合、その投与形態は、経口投与でも非経口投与でもよい。剤型としては、例えば、錠剤、粉剤、カプセル剤、顆粒剤、エキス剤、シロップ剤等の経口投与剤又は注射剤もしくは座剤等の非経口投与剤を挙げることができる。これらの製剤は、賦形剤、結合剤等の製薬上許容される添加剤を用いて、既知の方法で製造される。また、上記のトリプロスタチンを有効成分として含有する抗腫瘍剤の臨床的投与量は、年齢、体重、患者の感受性、症状の程度により異なるが、通常効果的な量は、成人一日 0.1mg〜1g程度であり、一日一回又は数回にわけて投与することも可能である。また、必要により上記の範囲外の量を用いることもできる。
【0013】
また生化学試験用試薬として使用する場合、有機溶剤または含水有機溶剤に溶解して各種培養細胞系へ直接投与すると、細胞周期の進行をG2/M期で阻止する。使用可能な有機溶剤としては、例えば、メタノールやジメチルスルホキシド等を挙げることができる。剤型としては、例えば、粉末または顆粒等の固形剤もしくは有機溶剤または含水有機溶剤に溶解した液体剤等を挙げることができる。通常、上記トリプロスタチンを有効成分とする細胞周期阻害剤の効果的な使用量範囲は5〜50μm/mlであるが、適切な使用量は培養細胞系の種類や使用目的により異なる。また、必要により上記の範囲外の量を用いることもできる。
【0014】
【実施例】
以下、実施例等を記載して本発明を具体的に記載する。
【製造例】
グルコース3%、可溶性澱粉2%、大豆粉2%、リン酸第二カリウム0.5%、および硫酸マグネシウム0.05%の組成の培地(pH 6.5)に、前記菌株BM939 株を接種して28℃で48時間振盪培養を行った。この培養液70mlを同組成の培地18Lに接種し、28℃で72時間にわたって毎分7Lの通気を行いながら、毎分300回転の攪拌培養を行った。
上記培養液を高速遠心分離器(15000回転/分)で菌体と上清に分離し、菌体を80%アセトン18Lを用いて抽出した。上清を18Lの酢酸エチルで3回抽出し、含水アセトン抽出液は減圧濃縮して、得られる水溶液を5Lの酢酸エチルで3回抽出を繰り返した。抽出後、全ての酢酸エチルをあわせて減圧濃縮し、褐色のシロップ18.5gを得た。
【0015】
このシロップをメタノール200 mlにより溶解してメタノール可溶部を得、メタノール可溶部を水に混濁させ、クロロホルムと酢酸エチルで順次抽出し、クロロホルムエキスと酢酸エチルエキスを得た。クロロホルムエキスはさらにn−ヘキサン200 mlで油分を3回溶出して除去し、残るn−ヘキサン不溶部を酢酸エチルエキスと合併して本発明化合物を含有するエキス4.3gを得た。このエキスを20mlのn−ヘキサンークロロホルム(20:80) で溶解し、n−ヘキサンークロロホルム(20:80) で調製したシリカゲルカラム(ベッド容積:直径4.5 cm、長さ15cm)に浸潤させ、最初にn−ヘキサンークロロホルム溶液を配合割合20:80 、10:90 と5:95の順でそれぞれ500 mlずつ流し、引き続いてクロロホルム1Lを流した後、クロロホルムーメタノール溶液を配合割合を順次変えて(95.5:0.5 、99:1、98:2 、96:4 、92:8)それぞれ1Lずつ流し、最後にクロロホルムーメタノール割合80:20と70:30の溶液を各500 mlずつ流した。
【0016】
本発明化合物はクロロホルム溶液画分に溶出され、計880 mgの本発明化合物を含有する粗粉末を得た。
この粗粉末をメタノールで結晶化することにより、本発明化合物以外の結晶性物質を除去した。メタノール溶液部(385 mg)は、ODS カラム(直径2cm、長さ25cm; カプセルパック、資生堂社製)と60%メタノール溶出溶媒を用いて流速10ml/分と検出波長210nm の条件下で分取高速液体クロマトグラフィーにより分離し、本発明化合物トリプロスタチンAとBの粗品を得た。これら粗品は溶出溶媒のみを55%メタノールに変更した上記同条件下の分取高速液体クロマトグラフィーまたはそれに分取用シリカゲル薄層板(厚さ0.5mm 、大きさ20x20cm)および展開溶媒クロロホルムーメタノール(95:5)を用いた分取薄層クロマトグラフィーを組み合わせることにより精製した。
この結果、淡黄色結晶性固体として精製標品トリプロスタチンAとBをそれぞれ7.7 mgと6.9 mgずつ得た。表1および表2に精製標品の物性値等を示す。
【0017】
【表1】
【0018】
【表2】
【0019】
本発明化合物の活性を以下の方法に従って測定した。
【試験例1】
トリプロスタチンA、Bの細胞周期阻害活性
細胞周期の調節蛋白質である p34cdc2キナーゼが温度感受性に変異したマウス乳癌細胞tsFT210 細胞を用いた。tsFT210 細胞は通常32℃で5%仔牛血清を含むRPMI1640培地にて5%炭酸ガスと水蒸気を飽和させた培養器内で培養する。tsFT210 細胞は39℃で培養すると、細胞周期がG2期で停止し、これを32℃にシフトダウンすると再び細胞分裂を開始してG1期へ移行する。シフトダウンと同時にトリプロスタチンAまたはBを添加して、フローサイトメーターと顕微鏡観察により細胞周期 (G2→M →G1) の進行を解析した。結果を表3に示す。
【0020】
【表3】
表3の結果は本発明のトリプロスタチンが細胞周期阻害剤として有用であることを示している。
【0021】
【試験例2】
トリプロスタチンAおよびBの細胞増殖抑制効果
ヒト白血病細胞K-562 及びHL-60 をRPMI1640培地(10%の牛胎仔血清を含む)で培養した。これに一連の稀釈系列のトリプロスタチンAおよびBを加え、17時間培養したのち、MTT 試薬を加えて生育を計測した。その結果を表4に示す。
【0022】
【表4】
表4の結果は、本発明のトリプロスタチンが抗腫瘍剤として有用であることを示している。
【0023】
【製剤例1】
(注射・点滴剤)
トリプロスタチンB10mgを含有するように、粉末ぶどう糖5gを加えてバイアルに無菌的に分配し密封した上、窒素、ヘリウム等の不活性ガスを封入して冷暗所に保存した。使用前にエタノールに溶解し、0.85%生理的食塩水100mlを添加して静脈内注射剤とし、一日、10〜100mlを症状に応じて静脈内注射または点滴で投与する。
【製剤例2】
(注射・点滴剤)
トリプロスタチンB2mgを用いて、製剤例1と同様の方法により軽症用静脈内注射剤とし、一日、10〜100mlを症状に応じて静脈内注射または点滴で投与する。
【製剤例3】
(顆粒剤)
トリプロスタチンA1g、乳糖98gおよびヒドロキシプロピルセルロース1gを各々とり、よく混合した後、常法に従って粒状に成形し、これをよく乾燥して篩別してビン、ヒートシール包装などに適した顆粒剤を製造した。一日、 100〜1000mgを症状に応じて経口で投与する。
【図面の簡単な説明】
【図1】トリプロスタチンA(1)およびB(2)のメタノール中の紫外線吸収スペクトルを示す。
【図2】トリプロスタチンA(1)およびB(2)の赤外線吸収スペクトル(KBr)を示す。
【図3】トリプロスタチンA(1)およびB(2)の1H-NMR (CDCl3)スペクトルを示す。
【図4】トリプロスタチンA(1)およびB(2)の13C-NMR (CDCl3) スペクトルを示す。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a novel substance triprostatin, a method for producing the same, a cell cycle inhibitor and an antitumor agent comprising the same as an active ingredient.
[0002]
[Prior art]
Proliferation and differentiation of cells constituting the human body are strictly controlled in order to maintain homeostasis. The cells divide and proliferate by rotating the cell cycle consisting of a series of processes of M phase, G 1 phase, S phase, and G 2 phase. If an abnormality occurs in the control mechanism of this cell cycle, it becomes cancer or immune disease. Recently, the regulation mechanism of the cell cycle is being elucidated at the molecular level, and the possibility of an antitumor agent and an immunosuppressive agent is known as a substance that regulates the cell cycle.
[0003]
[Problems to be solved by the invention]
An object of the present invention is to provide a novel substance having cell cycle inhibitory activity and antitumor activity, a method for producing the same, a cell cycle inhibitor containing the same as an active ingredient, and an antitumor agent.
[0004]
[Means for Solving the Problems]
As a result of diligent investigations to solve the above problems, the present inventor has found that a mold BM939 strain belonging to the genus Aspergillus isolated from soil collected off the sea off Oigawa, Shizuoka Prefecture has a cell cycle inhibitory activity and antitumor activity It has been found that it has been produced, and the present invention has been completed.
The present invention provides a novel substance triprostatin represented by the following general formula (I).
[0005]
[Chemical formula 2]
In the formula, R is a methoxy group (triprostatin A) or a hydrogen atom (triprostatin B).
[0006]
The tryprostatin of the present invention can be produced by culturing a tryprostatin-producing bacterium belonging to the genus Aspergillus in a medium, producing and accumulating tryprostatin, and collecting it. Preferable examples of the triprostatin producing bacterium used in the present invention include Aspergillus fumigatus BM939 strain.
The present invention further provides a cell cycle inhibitor containing the novel substance triprostatin as an active ingredient and an antitumor agent containing triprostatin as an active ingredient.
[0007]
DETAILED DESCRIPTION OF THE INVENTION
The present invention will be described in detail below.
The novel substances tryprostatin A and B of the present invention are represented by the following formulae.
[0008]
[Chemical 3]
[0009]
A representative example of the bacterium belonging to the genus Aspergillus that produces the substances tryprostatin A and B of the present invention is Aspergillus fumigatus, and a specific example thereof is the mold BM939 strain. The BM939 strain has the following mycological properties.
(1) All growth forms on various media were cultured at 25 ° C., and growth formation on an agar plate medium was described.
(1-1) CYA agar medium has good growth, and the colony diameter is 65 mm when cultured at 25 ° C for 7 days. The colony grows velvety to form many conidia, which are blue-green. The back of the colony is light yellow.
(1-2) CY20S Agar medium Growth is moderate, and colony diameter is 50 mm after 7 days of culture at 25 ° C. The colony grows in a velvety form to form conidia, which are blue-green. The back of the colony is light yellow.
(1-3) MEA Agar Medium Growth is moderate, and colony diameter is 55 mm after 7 days of culture at 25 ° C. The colony grows in a velvety form to form conidia, which are pale yellow. The back of the colony is light yellow.
[0010]
(2) Morphological properties
Morphological properties on CYA agar at 25 ° C for 7 days were as follows.
The conidia handle has a width of 2.5 to 5 μm and a length of 100 to 350 μm. A diameter of 10 to 25 μm and a light green sphere to hemispherical apex are formed at the tip. The surface of conidia pattern is smooth and no metre is produced. Form a light green 5 to 10 x 2 to 3.5 mm long phialide above about 2/3 of the top. Conidia are formed by chaining from phialides and have a diameter of 2 to 3.5 mm and a deep green sphere to hemisphere. Hule cells were not observed.
Based on the above bacteriological properties, this strain belongs to the genus Aspergillus, referring to Raper &Fennel's “The Genus Aspergillus” (1965) (“The GENUS Aspergillus”). When a known bacterial species was searched, it was consistent with the properties of Aspergillus Fumigatus. The strain Aspergillus fumigatus BM939 was deposited with the Biotechnology Institute of Technology on July 26, 1995, and its deposit number is FERM P-15067.
[0011]
The method of culturing the above-mentioned strain mold BM939 strain and collecting novel substances tryprostatin A and B (hereinafter also referred to as “the compound of the present invention”) from the culture is specifically described in the production examples described below. It can be carried out according to a method for culturing bacteria belonging to the genus Aspergillus. After completion of the culture, the triprostatin of the present invention can be purified and isolated from the culture solution by appropriately utilizing means generally used for collecting microbial metabolites. For example, various ion exchange resins, nonionic adsorption resins, gel filtration chromatography, or chromatography and high performance liquid chromatography using an adsorbent such as activated carbon, alumina, silica gel, or crystallization, vacuum concentration, freeze drying, etc. Each of them can be used alone, in appropriate combination, or repeatedly.
[0012]
The novel triprostatin produced as described above has cell cycle inhibitory activity and antitumor activity as shown in Test Examples described later.
The cell cycle inhibitor containing the triprostatin of the present invention as an active ingredient is appropriately determined for the method of use, dosage form, and dose (use amount) according to the purpose of use. For example, in the case of an antitumor agent comprising the triprostatin of the present invention as an active ingredient, the administration form may be oral administration or parenteral administration. Examples of the dosage form include oral administration agents such as tablets, powders, capsules, granules, extracts and syrups, and parenteral administration agents such as injections and suppositories. These preparations are produced by a known method using pharmaceutically acceptable additives such as excipients and binders. In addition, the clinical dosage of the above-mentioned anti-tumor agent containing triprostatin as an active ingredient varies depending on age, body weight, patient sensitivity, and symptom level. It is about 1 g, and can be administered once or several times a day. Further, if necessary, an amount outside the above range can be used.
[0013]
When used as a biochemical test reagent, cell cycle progression is blocked in the G2 / M phase when dissolved in an organic solvent or water-containing organic solvent and directly administered to various cultured cell systems. Examples of the organic solvent that can be used include methanol and dimethyl sulfoxide. Examples of the dosage form include a solid agent such as powder or granule, a liquid agent dissolved in an organic solvent or a water-containing organic solvent, and the like. Usually, the effective use amount range of the cell cycle inhibitor containing triprostatin as an active ingredient is 5 to 50 μm / ml, but the appropriate use amount varies depending on the type and purpose of use of the cultured cell line. Further, if necessary, an amount outside the above range can be used.
[0014]
【Example】
Hereinafter, the present invention will be specifically described with reference to examples and the like.
[Production example]
A medium (pH 6.5) having a composition of 3% glucose, 2% soluble starch, 2% soy flour, 0.5% dibasic potassium phosphate and 0.05% magnesium sulfate was inoculated with the strain BM939 at 28 ° C. The shaking culture was performed for 48 hours. 70 L of this culture solution was inoculated into 18 L of the medium having the same composition, and agitation culture was performed at 300 revolutions per minute while aeration at 7 L per minute was performed at 28 ° C. for 72 hours.
The culture broth was separated into cells and supernatant with a high-speed centrifuge (15000 rpm), and the cells were extracted with 18 L of 80% acetone. The supernatant was extracted three times with 18 L of ethyl acetate, the aqueous acetone extract was concentrated under reduced pressure, and the resulting aqueous solution was extracted three times with 5 L of ethyl acetate. After extraction, all the ethyl acetate was combined and concentrated under reduced pressure to obtain 18.5 g of a brown syrup.
[0015]
This syrup was dissolved in 200 ml of methanol to obtain a methanol soluble part, the methanol soluble part was made turbid in water, and extracted sequentially with chloroform and ethyl acetate to obtain a chloroform extract and an ethyl acetate extract. The chloroform extract was further removed by eluting the oil three times with 200 ml of n-hexane, and the remaining n-hexane insoluble part was combined with the ethyl acetate extract to obtain 4.3 g of an extract containing the compound of the present invention. This extract was dissolved in 20 ml of n-hexane-chloroform (20:80) and infiltrated into a silica gel column (bed volume: diameter 4.5 cm, length 15 cm) prepared with n-hexane-chloroform (20:80). First, 500 ml each of n-hexane-chloroform solution is added in the order of 20:80, 10:90 and 5:95, followed by 1 L of chloroform, then the chloroform-methanol solution is changed in order. (95.5: 0.5, 99: 1, 98: 2, 96: 4, 92: 8), 1 L each, and finally 500 ml each of a solution having a chloroform-methanol ratio of 80:20 and 70:30.
[0016]
The compound of the present invention was eluted in the chloroform solution fraction to obtain a crude powder containing a total of 880 mg of the compound of the present invention.
By crystallizing this crude powder with methanol, crystalline substances other than the compound of the present invention were removed. The methanol solution part (385 mg) uses an ODS column (
As a result, 7.7 mg and 6.9 mg of purified samples of triprostatin A and B, respectively, were obtained as a pale yellow crystalline solid. Tables 1 and 2 show the physical properties of the purified samples.
[0017]
[Table 1]
[0018]
[Table 2]
[0019]
The activity of the compound of the present invention was measured according to the following method.
[Test Example 1]
Cell cycle inhibitory activity of tryprostatin A and B Mouse breast cancer cell tsFT210 cells in which p34 cdc2 kinase, a cell cycle regulatory protein, was mutated to temperature sensitivity were used. tsFT210 cells are usually cultured at 32 ° C. in an incubator saturated with 5% carbon dioxide and water vapor in RPMI1640 medium containing 5% calf serum. When tsFT210 cells are cultured at 39 ° C, the cell cycle stops at the G2 phase, and when this is shifted down to 32 ° C, cell division starts again and enters the G1 phase. Simultaneously with the shift-down, tryprostatin A or B was added, and the progression of the cell cycle (G2 → M → G1) was analyzed by flow cytometer and microscopic observation. The results are shown in Table 3.
[0020]
[Table 3]
The results in Table 3 indicate that the triprostatin of the present invention is useful as a cell cycle inhibitor.
[0021]
[Test Example 2]
Triprostatin A and B cytostatic effect Human leukemia cells K-562 and HL-60 were cultured in RPMI1640 medium (containing 10% fetal bovine serum). A series of dilution series of triprostatin A and B was added thereto and cultured for 17 hours, and then MTT reagent was added to measure growth. The results are shown in Table 4.
[0022]
[Table 4]
The results in Table 4 show that the triprostatin of the present invention is useful as an antitumor agent.
[0023]
[Formulation Example 1]
(Injection / Drip)
To contain 10 mg of triprostatin B, 5 g of powdered glucose was added and aseptically distributed and sealed in vials, and sealed with an inert gas such as nitrogen or helium and stored in a cool dark place. Before use, dissolve in ethanol, add 100 ml of 0.85% physiological saline to make an intravenous injection, and administer 10-100 ml daily by intravenous injection or infusion depending on the symptoms.
[Formulation Example 2]
(Injection / Drip)
Using
[Formulation Example 3]
(Granule)
1 g of tryprostatin A, 98 g of lactose and 1 g of hydroxypropyl cellulose were mixed together and then shaped into granules according to a conventional method. The granules were well dried and sieved to produce granules suitable for bottles, heat seal packaging and the like. . Daily doses of 100-1000 mg orally depending on symptoms.
[Brief description of the drawings]
FIG. 1 shows ultraviolet absorption spectra of triprostatin A (1) and B (2) in methanol.
FIG. 2 shows infrared absorption spectra (KBr) of tryprostatin A (1) and B (2).
FIG. 3 shows 1 H-NMR (CDCl 3 ) spectra of tryprostatin A (1) and B (2).
FIG. 4 shows 13 C-NMR (CDCl 3 ) spectra of tryprostatin A (1) and B (2).
Claims (4)
Priority Applications (1)
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JP21465995A JP3719689B2 (en) | 1995-08-23 | 1995-08-23 | Novel substance triprostatin, process for producing the same, cell cycle inhibitor and antitumor agent |
Applications Claiming Priority (1)
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JP21465995A JP3719689B2 (en) | 1995-08-23 | 1995-08-23 | Novel substance triprostatin, process for producing the same, cell cycle inhibitor and antitumor agent |
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JP3719689B2 true JP3719689B2 (en) | 2005-11-24 |
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EP1464336A1 (en) * | 2003-04-03 | 2004-10-06 | Humboldt-Universität zu Berlin | Use of tryprostatin A for the reversal of cancer drug resistance |
CN101792375B (en) * | 2010-03-11 | 2012-09-05 | 云南烟草科学研究院 | Sesquiterpene compound in tobacco stems and preparation method and application thereof |
JP2020002014A (en) * | 2018-06-25 | 2020-01-09 | 日本システム企画株式会社 | Inhibitory activity and purification method thereof |
CN115232096B (en) * | 2022-06-15 | 2023-05-05 | 福建卫生职业技术学院 | Lactone compound from aspergillus flavus, preparation method thereof and application thereof in anti-human liver cancer drugs |
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