JPH0436276A - Antibiotic ma-638-2-b, its production and antitumor agent comprising antibiotic ma-638-2-b as active ingredient - Google Patents
Antibiotic ma-638-2-b, its production and antitumor agent comprising antibiotic ma-638-2-b as active ingredientInfo
- Publication number
- JPH0436276A JPH0436276A JP13798190A JP13798190A JPH0436276A JP H0436276 A JPH0436276 A JP H0436276A JP 13798190 A JP13798190 A JP 13798190A JP 13798190 A JP13798190 A JP 13798190A JP H0436276 A JPH0436276 A JP H0436276A
- Authority
- JP
- Japan
- Prior art keywords
- antibiotic
- culture
- fusarium
- antitumor agent
- producing
- 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.)
- Pending
Links
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- 238000004809 thin layer chromatography Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 229910021654 trace metal Inorganic materials 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
- LEONUFNNVUYDNQ-UHFFFAOYSA-N vanadium atom Chemical compound [V] LEONUFNNVUYDNQ-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Furan Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は新規な抗生物質、その製造方法およびそれを有
効成分とする抗腫瘍剤に関する。DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a novel antibiotic, a method for producing the same, and an antitumor agent containing the same as an active ingredient.
従来から、各種の抗生物質が発見、開発されているが、
抗生物質は、使用を継続すると、被使用菌に使用抗生物
質に対する耐性が生しるという問題がある。また、癌(
がん)などの腫瘍も、抗生物質の使用を継続すると、使
用抗生物質に対して耐性が生じるようになる。Various antibiotics have been discovered and developed over the years, but
BACKGROUND OF THE INVENTION A problem with antibiotics is that continued use can cause bacteria to develop resistance to the antibiotics used. Also, cancer (
With continued use of antibiotics, tumors such as cancer can develop resistance to the antibiotics being used.
そのため、常に新しい抗生物質の出現が望まれている。 Therefore, the emergence of new antibiotics is always desired.
特に抗腫瘍活性を有し、毒性が少ない新規抗生物質の出
現が望まれている。In particular, the emergence of new antibiotics with antitumor activity and less toxicity is desired.
したがって、本発明は、抗腫瘍活性を有し、毒性が少な
い新規な抗生物質を提供することを目的とする。Therefore, the present invention aims to provide a novel antibiotic with antitumor activity and less toxicity.
本発明者らは、フザリウム(Fusarius) MA
−638−2が、抗腫瘍活性を有し、かつダラム陽性
菌およびダラム陰性菌に対して抗菌力を有し、しかも毒
性が少ない新規な抗生物質MA−6382−Bを生産す
ることを見出し、本発明を完成するにいたった。The inventors have discovered that Fusarium MA
-638-2 produces a novel antibiotic MA-6382-B, which has antitumor activity and antibacterial activity against Durum-positive bacteria and Durum-negative bacteria, and is less toxic, This led to the completion of the present invention.
上記フザリウムMA−638−2は、本発明者らが大阪
府高槻市で採取した土壌試料中より発見した微生物であ
り、通商産業省工業技術院微生物工業試験所に寄託され
ていて、その微生物寄託番号は、微工研菌寄第1148
0号である。The above Fusarium MA-638-2 is a microorganism discovered by the present inventors in a soil sample collected in Takatsuki City, Osaka Prefecture, and has been deposited with the Microbial Industrial Laboratory, Agency of Industrial Science and Technology, Ministry of International Trade and Industry. The number is 1148
It is No. 0.
本発明の抗生物質MA−638−2−Bを生産するフザ
リウムMA−638−2株は次のような菌学的性質を有
している。The Fusarium MA-638-2 strain that produces the antibiotic MA-638-2-B of the present invention has the following mycological properties.
(1)及皿学カ称量
培養は通常30°Cで行う、フザリウムMA−638−
2株の形態学的特徴は、気中菌糸を形成し、胞子を形成
することである。(1) Quantitative culture of Fusarium MA-638 is usually carried out at 30°C.
The morphological characteristics of the two strains are that they form aerial hyphae and spores.
(2) 立 上の ヒ
麦芽エキス寒天培地、あるいは、でんぷん(殿粉)酵母
エキス培地上の成育状態は良好であり、白色気菌糸がフ
ェルト状に生じ、紫色の気菌糸がフェルト状に成育する
。可溶性赤色色素を生産する。(2) The growth condition on the standing wheat germ extract agar medium or starch (starch) yeast extract medium is good, with white aerial hyphae forming in a felt shape and purple aerial hyphae growing in a felt shape. . Produces soluble red pigment.
(3)注111侃1!
フザリウムMA、−638−2株の生理学的性質を第1
表に、炭素源の資化性を第2表に示す。(3) Note 111 侃1! First, we investigated the physiological properties of Fusarium MA, -638-2 strain.
Table 2 shows the assimilability of carbon sources.
第
表
第
表
+ :利用する
+十:かなり利用する
フザリウムMA−638−2株の菌学的性質は上記のと
おりであるが、このフザリウムMA−638−2株の自
然的および遺伝子工学的方法も含む人工的変異株も抗生
物質MA−638−2−Bを生産でき、これらも抗生物
1jMA−638−2Bの生産菌として使用することが
できる。Table 1 +: Utilized + 10: Used considerably The mycological properties of Fusarium MA-638-2 strain are as described above, and natural and genetic engineering methods for this Fusarium MA-638-2 strain Artificial mutant strains including 1jMA-638-2-B can also be produced, and these can also be used as producing strains of antibiotic 1jMA-638-2B.
本発明において、抗生物質MA−638−2Bの生産に
あたり、抗生物質MA−638−2B生産菌の培養は、
−Gのかび(黴)における培養方法に準して行われる。In the present invention, in producing antibiotic MA-638-2B, the culture of antibiotic MA-638-2B producing bacteria is carried out by
- It is carried out according to the culture method for mold (mold).
これを詳しく説明すると、次のとおりである。This will be explained in detail as follows.
本発明の抗生物質MA−638−2−Bは、フザリウム
属に属する抗生物質MA−638−2B生産菌、たとえ
ばフザリウムMA−638−2株を好気的条件下に利用
しうる炭素源および窒素源を含有する栄養培地中で生育
させることにより生産される。その具体的手段としては
、液体培地中での振盪培養、深部培養あるいは通気攪拌
培養などによるのが好ましい、工業的に有利に培養すル
ニハ、前記抗生物jiMA−638−2−B生産菌の胞
子懸濁液または培養液を培地に接種し、通気攪拌培養を
行うのが好ましい。The antibiotic MA-638-2-B of the present invention is produced by using antibiotic MA-638-2B-producing bacteria belonging to the genus Fusarium, such as Fusarium MA-638-2 strain, as a carbon source and nitrogen that can be utilized under aerobic conditions. produced by growing in a nutrient medium containing sources. As a specific means, it is preferable to use shaking culture, deep culture, or aeration agitation culture in a liquid medium. It is preferable to inoculate the suspension or culture solution into a medium and perform aeration and agitation culture.
培地の栄養源としては、特に限定されることはなく、微
生物の培養に通常用いられる炭素源、窒素源、その他を
培地中に含有させ、これらを栄養源とすることができる
。培地成分としては、炭素源として、たとえばグルコー
ス、ガラクトース、シュクロース、マルトース、ラクト
ース、ラフィノース、イノシトール、マンニット、糖蜜
、グリセリン、デキストリン、でんぷん、大豆油、綿実
油などが用いられ、特にグルコース、でんぷんが好まし
い。また、窒素源としては、たとえば大豆粉、落花生粉
、綿実油、魚粉、コーンステイープリカー、ペプトン、
肉エキス、酵母、酵母エキス、麦芽、米ぬか、ふすま、
アスパラギン、硝酸ソーダ、硝酸アンモニウム、硫酸ア
ンモニウムなどが用いられ、特に大豆粉、ペプトンが好
ましい、また、無機塩として、食塩、燐酸塩、炭酸カル
シウム、塩化カルシウム、微量金属塩(たとえば、マン
ガン、亜鉛、銅、モリブデン、鉄、ホウ素、コバルト、
セレン、バナジウム、ヨウ素などのV:L酸塩、リン酸
塩、塩酸塩、硝酸塩など)などが必要に応して適宜添加
される。液体培養に際しては、シリコン油、植物油、動
物油、鉱油、液体パラフィン、界面活性側などが消泡剤
として適宜使用される。The nutrient source of the medium is not particularly limited, and carbon sources, nitrogen sources, and others commonly used for culturing microorganisms can be contained in the medium and used as nutrient sources. As a medium component, for example, glucose, galactose, sucrose, maltose, lactose, raffinose, inositol, mannitol, molasses, glycerin, dextrin, starch, soybean oil, cottonseed oil, etc. are used as a carbon source, and glucose and starch are particularly used. preferable. Examples of nitrogen sources include soybean flour, peanut flour, cottonseed oil, fishmeal, cornstarch liquor, peptone,
Meat extract, yeast, yeast extract, malt, rice bran, bran,
Asparagine, sodium nitrate, ammonium nitrate, ammonium sulfate, etc. are used, and soybean flour and peptone are particularly preferred.Inorganic salts include common salt, phosphate, calcium carbonate, calcium chloride, trace metal salts (for example, manganese, zinc, copper, molybdenum, iron, boron, cobalt,
V:L salts, phosphates, hydrochlorides, nitrates, etc. of selenium, vanadium, iodine, etc.) are added as appropriate. For liquid culture, silicone oil, vegetable oil, animal oil, mineral oil, liquid paraffin, surfactant, etc. are appropriately used as antifoaming agents.
培地のpHは、中性ないし微酸性、特にpH5,5付近
が好ましく、培養温度は25〜33°C1特に30℃前
後が好ましい。The pH of the medium is preferably neutral to slightly acidic, particularly around pH 5.5, and the culture temperature is preferably 25 to 33°C, especially around 30°C.
培養の経過に伴って生産される抗生物質MA638−2
−Bの力価の経時的変化は、枯草菌を被検菌としたペー
パーディスク[たとえば、東洋濾紙社製またはアドバン
テソク東洋社製の直径6閤の濾紙Th1nC薄)タイプ
を使用]検定法により測定することができる。通常72
〜216時間の培養で抗生物WMA−638−2−B
(以下、簡略化して、単にrMA−638−2−BJと
いう)の生産量は最高値に達する。Antibiotic MA638-2 produced during the course of culture
Changes in the titer of -B over time can be determined using a paper disk assay method using Bacillus subtilis as the test bacterium [for example, using a 6-layer filter paper Th1nC thin type manufactured by Toyo Roshi Co., Ltd. or Advantesoku Toyo Co., Ltd.]. can be measured. Usually 72
Antibiotic WMA-638-2-B with ~216 hours of culture
(hereinafter simply referred to as rMA-638-2-BJ) reaches its highest level.
MA−638−2−Bは、培養終了後、菌体その他の固
形部分を珪藻土などを濾過助剤とする濾過操作あるいは
遠心分離によって除去し、その濾液あるいは上清中から
抽出、精製することによって得られる。After culturing, MA-638-2-B is produced by removing bacterial cells and other solid parts by filtration using diatomaceous earth as a filter aid or by centrifugation, and extracting and purifying the filtrate or supernatant. can get.
また、MA−638−2−Bの物理化学的性状を利用す
ることにより、たとえば吸着剤を用いてMA−638−
2−Bを採取することができる。In addition, by utilizing the physicochemical properties of MA-638-2-B, for example, MA-638-2-B can be prepared using an adsorbent.
2-B can be collected.
咬着剤としては、たとえば活性炭、あるいは吸着用樹脂
であるアンバーライトXAD−2、XAD4、XAD−
7など(いずれもローム・アンド・ハース社製)または
ダイヤイオンHPIO1HP20、HP20AG、HP
50など(いずれも、三菱化成工業社製)が使用される
。As the occlusal agent, for example, activated carbon or adsorption resin Amberlite XAD-2, XAD4, XAD-
7 etc. (all manufactured by Rohm and Haas) or Diaion HPIO1HP20, HP20AG, HP
50 (both manufactured by Mitsubishi Chemical Industries, Ltd.) are used.
このような吸着剤を用いる場合、MA−6382−Bは
、MA−638−2−Bを含む液を上記の吸着剤の層を
通過させて該MA−638−2Bを含む液に含まれる不
純物を吸着させて取り餘くか、またはMA−638−2
−Bを吸着させた後、メタノール水、アセトン水、n−
ブタノール水などを用いて溶出することによって得られ
る。When using such an adsorbent, MA-6382-B is prepared by passing a liquid containing MA-638-2-B through a layer of the above-mentioned adsorbent to remove impurities contained in the liquid containing MA-638-2B. or MA-638-2
- After adsorbing B, methanol water, acetone water, n-
Obtained by elution using butanol water or the like.
また、MA−638−2−Bは、中性脂溶性物質を培養
液から採取する方法に準し、たとえば水と混和しないク
ロロホルム、酢酸エチル、n−フタノールなどの有機溶
媒により、MA−6382−Bを培養濾液、または水溶
液から抽出することも可能である。さらに抗生物質MA
−6382−Bを含む有機溶媒層を、希アルカリ水、希
酸性水などで洗浄することにより、混在する酸性特質あ
るいは塩基性物質を除去することも可能である。In addition, MA-638-2-B can be obtained by collecting neutral fat-soluble substances from culture fluid using an organic solvent such as chloroform, ethyl acetate, or n-phthanol, which is immiscible with water. It is also possible to extract B from the culture filtrate or aqueous solution. Furthermore, antibiotic MA
By washing the organic solvent layer containing -6382-B with dilute alkaline water, dilute acidic water, etc., it is also possible to remove mixed acidic properties or basic substances.
このようにして得られたMA−638−2−Bの精製に
あたっては、たとえばアビセル(旭化成工業社製)など
のセルロースまたはセファデックスLH−20(ファル
マソア社製)などを用いた分配カラムクロマトグラフィ
ー、シリカゲル、アルミナ、フロリジルのような担体を
用いた吸着カラムクロマトグラフィー、逆相用担体を用
いた逆相カラムクロマトグラフィー、あるいはMA−6
38−2−Bと混在する不純物との溶媒に対する分配率
の差を利用した抽出法、あるいは向流分配法などを精製
手段として採用し、これらの精製手段を単独あるいは適
宜組み合わせ、要すれば反復して用いることにより、M
A−638−2−Bを精製することができる。In purifying the MA-638-2-B obtained in this manner, for example, partition column chromatography using cellulose such as Avicel (manufactured by Asahi Kasei Corporation) or Sephadex LH-20 (manufactured by Pharmasoa), Adsorption column chromatography using a carrier such as silica gel, alumina, or florisil, reverse phase column chromatography using a reverse phase carrier, or MA-6
An extraction method that utilizes the difference in the distribution ratio of 38-2-B and mixed impurities to the solvent, or a countercurrent distribution method, etc. is adopted as a purification method, and these purification methods are used alone or in combination as appropriate, and if necessary, it is repeated. By using it as M
A-638-2-B can be purified.
また、MA−638−2−Bは、一般の脂溶性抗生物質
と同じく培養条件によっては培養液中の菌体部分に存在
する。この場合は、アルコール類、アセトンなどの親水
性有機溶媒を用いて抽出し、抽出液より溶媒を除去し、
ついで水溶液とした後、培養濾液からと同様の方法で抽
出、精製することができる。Furthermore, like general fat-soluble antibiotics, MA-638-2-B exists in the bacterial cell portion of the culture solution depending on the culture conditions. In this case, extract using a hydrophilic organic solvent such as alcohol or acetone, remove the solvent from the extract, and
After making it into an aqueous solution, it can be extracted and purified in the same manner as from the culture filtrate.
このようにして得られたMA−638−2−Bは、次の
理化学的および生物学的性状を有する。MA-638-2-B thus obtained has the following physicochemical and biological properties.
(1)物質の性状
中性の白色粉末
(2)比旋光度
〔α) ”、’−322,7゜
C= 0.022g/〆 CH,0H
(3)分子式 C1s H+ 405(4)分子量
m/z 250
(5)紫外線吸収スペクトル
メチルアルコール中(MA−638−2Bの濃度70.
02■/d)で測定した紫外線吸収スペクトルは、第1
図に示すとおり214.5n m (t =8300f
/mol cm)に極大吸収を示す。(1) Properties of the substance Neutral white powder (2) Specific rotation [α] ”,'-322,7°C= 0.022g/〆 CH,0H (3) Molecular formula C1s H+ 405 (4) Molecular weight
m/z 250 (5) Ultraviolet absorption spectrum in methyl alcohol (concentration of MA-638-2B 70.
The ultraviolet absorption spectrum measured at
As shown in the figure, 214.5 nm (t = 8300 f
/mol cm).
(6)赤外線吸収スペクトル
KBrBr法で測定した赤外線吸収スペクトルは、第2
図に示すとおりである。(6) Infrared absorption spectrum The infrared absorption spectrum measured by the KBrBr method is the second
As shown in the figure.
(7)核磁気共鳴(NMR)スペクトルCDC+、i液
中でテトラメチルシランを基準物質として測定した。
′H−核磁気共鳴スベクトルを第3図に、′3c−核磁
気共鳴スベクトルを第4図に示す、第4図における化学
シフト値は次のとおりである。(7) Nuclear magnetic resonance (NMR) spectrum CDC+, measured in liquid i using tetramethylsilane as a reference substance.
The 'H-nuclear magnetic resonance vector is shown in FIG. 3, and the '3c-nuclear magnetic resonance vector is shown in FIG. 4. The chemical shift values in FIG. 4 are as follows.
+3cm 〜北 スペクトル
δ(ppm)
18.604
29.450
29.733
30.017
30、 300
30.5B3
30、 867
31、 150
41.510
62;717
69、 975
73、 078
87.904
127、 363
12B、 226
132、 543
149、 865
159、 564
172、 542
197、 742
206、 902
207、 091
(8)元素分析
炭素
62.35%
水素 5.59%
酸素 32.06%
(9)融点 128〜130°C
Oω溶解性
酢酸エチル、アセトン、メタノールに易’R1水に難溶
tm呈色反応
ヨーソガスに陽性、KMnO,試薬に陽性02)薄層ク
ロマトグラフィー
吸着剤 シリカゲル
展開溶媒系 ベンゼン:アセトン−2:lRf =0.
63
側抗菌スペクトル
ダラム陽性菌として枯草菌Ba5illus 5ubt
ilisを選び、ダラム陰性菌として大腸菌Esche
richia coliを選び、それらに対するMA−
638−2−Bの抗菌スペクトルをアガーダイリューシ
ョン法によって測定した。その結果は第3表に示すとお
りである。+3cm ~ North Spectrum δ (ppm) 18.604 29.450 29.733 30.017 30, 300 30.5B3 30, 867 31, 150 41.510 62; 717 69, 975 73, 078 87.904 127, 363 12B, 226 132, 543 149, 865 159, 564 172, 542 197, 742 206, 902 207, 091 (8) Elemental analysis Carbon 62.35% Hydrogen 5.59% Oxygen 32.06% (9) Melting point 128~ 130°C Oω Solubility Easy to ethyl acetate, acetone, methanol 'R1 Slightly soluble in water tm Color reaction Positive for ioso gas, positive for KMnO, reagent 02) Thin layer chromatography adsorbent Silica gel developing solvent system Benzene: Acetone-2 :lRf=0.
63 Side antibacterial spectrum Bacillus subtilis Ba5illus 5ubt as a Durham-positive bacterium
ilis and Escherichia coli as a Durham-negative bacterium.
richia coli and MA- against them.
The antibacterial spectrum of 638-2-B was measured by the agardilution method. The results are shown in Table 3.
第
表
(ロ)抗腫瘍作用
MA−638−2−BのマウスにおけるP388白血病
に対する治療効果を下記方法により試験した。その試験
方法は下記に示すとおりであり、結果は第4表に示すと
おりである。Table (b) Antitumor Effect The therapeutic effect of MA-638-2-B on P388 leukemia in mice was tested by the following method. The test method is as shown below, and the results are as shown in Table 4.
なお、使用したマウスは各投与量ごとに6匹ずつであり
、第4表中の抗腫瘍活性は無処置群の平均生存日数(C
)に対する治療群の生存日数の中間値(T)の比を百分
率をもって表した。また、第4表中の生存区数は、使用
したマウス中の生存区数が理解しやすいように、使用し
たマウス数を分母に、生存したマウス数を分子に示す態
様で表した。Six mice were used for each dose, and the antitumor activity in Table 4 is based on the average survival days (C
) to the median survival days (T) of the treatment group was expressed as a percentage. In addition, the number of survivors in Table 4 is expressed in such a manner that the number of mice used is the denominator and the number of surviving mice is the numerator, so that the number of survivors in the mice used can be easily understood.
拭辰方広
B D F +マウス(♀、5週齢、日本タレア)6匹
の腹腔内に、DBA/2マウスで継代培養したP388
白血病細胞I XIO’個を接種し、24時間後より、
MA−638−2−Bを1日1回、連続5日間、計5回
腹腔内に投与した。P388 subcultured in DBA/2 mice was intraperitoneally cultured in six BDF + mice (female, 5 weeks old, Nippon Talea).
24 hours after inoculating XIO' leukemia cells,
MA-638-2-B was administered intraperitoneally once a day for 5 consecutive days, a total of 5 times.
第 4 表
抗腫瘍活性(T/C)は、一般に125〜130あれば
、抗腫瘍活性があると判断されるが、第4表に示すよう
に、MA−638−2−Bは抗腫瘍活性(T/C)が上
記数値を越えており、抗腫瘍活性があると認められる。Table 4 Antitumor activity (T/C) is generally considered to have antitumor activity if it is 125 to 130, but as shown in Table 4, MA-638-2-B has antitumor activity. (T/C) exceeds the above value, and it is recognized that it has antitumor activity.
また、被験マウス中、30日以上生存するものが認めら
れたことから、MA638−2−Bの精製方法、使用方
法などについて、さらに研究を進めることによって、よ
り以上の抗腫瘍活性を発揮させることができるものと期
待できる。In addition, as some of the test mice were observed to survive for 30 days or more, we hope to further develop MA638-2-B's antitumor activity by conducting further research on the purification method and usage method. You can expect that it will be possible.
0ω急性毒性
BDF、マウス(♀、5週齢、日本タレア)への腹腔内
投与でのLD、。は、200a/kgであり、低毒性で
あると判断できる。0ω acutely toxic BDF, LD when administered intraperitoneally to mice (♀, 5 weeks old, Nippon Talea). was 200a/kg, and it can be judged that the toxicity is low.
以上のデータの解析により(比旋光度値、分子式、分子
量、元素分析値などに加え、紫外線吸収スペクトルによ
るカルボニル基などの二重結合の存在確認、赤外線吸収
スペクトルによる官能基の類推、核磁気共鳴スペクトル
による水酸基の特定、メチル基の数、全カーボン数の特
定など)により、MA−638−2−Bの平面構造は、
と決定した。また、これを既知物質と比較した結果、M
A−638−2−Bは新規物質であると判定された。By analyzing the above data (specific optical rotation value, molecular formula, molecular weight, elemental analysis value, etc.), confirmation of the presence of double bonds such as carbonyl groups by ultraviolet absorption spectrum, analogy of functional groups by infrared absorption spectrum, nuclear magnetic resonance The planar structure of MA-638-2-B was determined to be as follows. Also, as a result of comparing this with known substances, M
A-638-2-B was determined to be a new substance.
つぎに、MA−638−2−Bを有効成分とする抗腫瘍
剤について述べる。Next, an antitumor agent containing MA-638-2-B as an active ingredient will be described.
上記MA−638−2−Bを有効成分とする抗腫瘍剤は
、経口投与、非経口投与のいずれにも適用可能である。The antitumor agent containing MA-638-2-B as an active ingredient can be administered either orally or parenterally.
経口投与する場合は、軟・硬カプセル剤または錠剤、顆
粒剤、細粒剤、散剤、腸溶剤、懸濁剤として使用するこ
とができる。非経口投与する場合は、注射剤、点滴剤、
半割、乳剤、懸濁側として使用することができ、また軟
膏剤、クリーム剤、液剤、パップ剤、テープ剤として粘
膜吸収または経皮吸収が維持できるような剤型で使用す
ることができる。When administered orally, it can be used in the form of soft or hard capsules, tablets, granules, fine granules, powders, enteric coated agents, or suspensions. For parenteral administration, injections, drips,
It can be used as a halved product, an emulsion, or a suspension, and it can also be used in a dosage form that maintains mucosal or transdermal absorption as an ointment, cream, liquid, poultice, or tape.
MA−638−2−Bを有効成分とする抗腫瘍剤の裂開
化は、医学的に許容しうる界面活性側、賦形剤、滑沢側
、佐剤、その他を用いて適宜行うことができ、固体、半
固体、液体などの裂開を得ることができる。さらに、安
定化剤、着色剤、香料などを使用してもよい。製剤中の
MA−638−2−B量は、対象腫瘍、使用方法などに
応じて適宜決定すればよい。Cleavage of the antitumor agent containing MA-638-2-B as an active ingredient can be carried out as appropriate using medically acceptable surfactants, excipients, lubricants, adjuvants, etc. It is possible to obtain cleavage of solids, semi-solids, liquids, etc. Additionally, stabilizers, colorants, fragrances, and the like may be used. The amount of MA-638-2-B in the preparation may be appropriately determined depending on the target tumor, usage method, etc.
このMA−638−2−Bを有効成分として含有する抗
腫瘍剤をヒト(人間)に使用する場合、静脈内、筋肉内
、経口または経皮投与により使用することが望ましい、
投与量は、対象腫瘍を治療するのに充分な量であればよ
く、腫瘍の症状、投与経路、剤型などによって若干異な
るが、マウスのLDs。値から考えて、一般に経口投与
の場合、MA−638−2−Bが1日あたり0.000
1〜200wg/kg体重の範囲、特に上限は約50t
g/kg体重程度にするのが好ましい、非経口投与の場
合は、MA−638−2−Bが1日あたり0.0001
〜100■/kg体重の範囲、特に上限は約5a/kg
体里程度にするのが好ましい。When using this antitumor agent containing MA-638-2-B as an active ingredient in humans, it is desirable to use it by intravenous, intramuscular, oral, or transdermal administration.
The dose may vary as long as it is sufficient to treat the target tumor, and may vary slightly depending on the tumor symptoms, route of administration, dosage form, etc. Considering the value, in general, MA-638-2-B is 0.000 per day when administered orally.
1-200wg/kg body weight range, especially the upper limit is about 50t
g/kg body weight is preferable, and in the case of parenteral administration, MA-638-2-B is 0.0001 g/kg body weight per day.
~100■/kg body weight range, especially the upper limit is about 5a/kg
It is preferable to keep it at about 1000 mph.
つぎに、MA−638−2−Bの製造例を実施例として
示す、なお、実施例は、単に本発明の例示目的に提供さ
れるものであって、本発明の範囲を限定するものではな
い。Next, a production example of MA-638-2-B will be shown as an example. It should be noted that the example is merely provided for the purpose of illustrating the present invention, and is not intended to limit the scope of the present invention. .
実施例1
フザリウムMA−638−2株を下記の培地組成−1で
示される培地101に接種し、30℃で5日間振盪培養
した。Example 1 Fusarium MA-638-2 strain was inoculated into medium 101 shown in the following medium composition-1, and cultured with shaking at 30°C for 5 days.
羞旦を戒二土
可溶性でんぷん 30 g大豆粉
5g
KHt P Oa 1 gM g
S Oa ・7HtOIg
NaCI 0.5gCa
C1t−2H,OO,5g
酵母エキス 0.5gFeCl+
・6Hz O2■
Zn5j)a ・IHz 0 3 g蒸留水
1,000 d培養終了後、培養
液を遠心分離し、得られた上清部分(液剤部分)10!
に61の酢酸エチルを加え、3回抽出した。Soluble starch 30g soybean flour
5g KHt P Oa 1 gM g
S Oa ・7HtOIg NaCI 0.5gCa
C1t-2H,OO, 5g Yeast extract 0.5gFeCl+
・6Hz O2■ Zn5j) a ・IHz 0 3 g Distilled water 1,000 d After the culture is completed, the culture solution is centrifuged and the supernatant portion (liquid portion) obtained is 10!
61 ethyl acetate was added to the solution and extracted three times.
一方、菌体部分(固形分側部分)にはメチルアルコール
6Nを加え、攪拌後、濾過した。この濾液のメチルアル
コールを減圧濃縮した後、残渣に水61を加え、これを
61!、の酢酸エチルで3回抽出した。On the other hand, 6N methyl alcohol was added to the bacterial cell portion (solid content side portion), stirred, and then filtered. After concentrating the methyl alcohol of this filtrate under reduced pressure, 61% of water was added to the residue, and 61! , and extracted three times with ethyl acetate.
得られた抽出液を前記上清部分からの抽出液と合わせ、
溶媒を減圧濃縮し、得られた油状残渣にベンゼンを加え
、不溶物を除去した後、シリカゲルカラムクロマトグラ
フィーに供した。Combine the obtained extract with the extract from the supernatant portion,
The solvent was concentrated under reduced pressure, and benzene was added to the obtained oily residue to remove insoluble materials, followed by silica gel column chromatography.
すなわち、上記ベンゼン溶液をあらかじめベンゼンを充
填したシリカゲル(和光純薬社製)3CIX 45C1
1のカラムに通導し、ベンゼン:アセトン−95:5で
溶出し、MA−638−2−Bの含まれる両分を集め、
減圧濃縮することによってMA638−2−B 2g
を得た。That is, the above benzene solution was filled with silica gel (manufactured by Wako Pure Chemical Industries, Ltd.) 3CIX 45C1.
1 column, elute with benzene:acetone-95:5, collect both fractions containing MA-638-2-B,
MA638-2-B 2g by vacuum concentration
I got it.
この実施例1で得られたMA−638−2−Bの理化学
的および生物学的性状は、前記したMA638−2−B
の理化学的および生物学的性状と一致した。The physicochemical and biological properties of MA-638-2-B obtained in Example 1 are as follows.
It was consistent with the physicochemical and biological properties of
実施例2
フザリウムMA−638−2株を培地組成−2で示され
る培地101に接種し、30″Cで5日間振盪培養した
。Example 2 Fusarium MA-638-2 strain was inoculated into medium 101 shown in medium composition-2, and cultured with shaking at 30''C for 5 days.
培m二4
グルコース 30 gペプトン
2g
KHzPOa IgM g S O
a ・IHzOIg
NaCl O,5gCaCL
−2Hz OO,5g
酵母エキス 0.5gFeCl5
・ 6Hz O2[
Zn5Oa ・ 7Hz 0 3 g
蒸留水 1,000 m培養終了後
、実施例1と同様の操作により、MA−638−2−8
1,9gを得た。Culture medium 24 glucose 30 g peptone
2g KHzPOa IgM g SO
a ・IHzOIg NaCl O, 5gCaCL
-2Hz OO, 5g Yeast extract 0.5gFeCl5
・6Hz O2 [ Zn5Oa ・7Hz 0 3 g
Distilled water 1,000 m After culturing, MA-638-2-8 was prepared in the same manner as in Example 1.
1.9 g was obtained.
この実施例2で得られたMA−638−2−Bの理化学
的および生物学的性状も、前記したMA63B−2−B
の理化学的および生物学的性状と一致した。The physicochemical and biological properties of MA-638-2-B obtained in Example 2 were also
It was consistent with the physicochemical and biological properties of
以上説明したように、本発明の抗生物質MA−638−
2−Bは、新規物質であり、抗腫瘍活性を有し、毒性が
少ない。As explained above, the antibiotic MA-638-
2-B is a new substance, has antitumor activity, and has low toxicity.
第1図は抗生物質MA−638−2−Bの紫外線吸収ス
ペクトル(メチルアルコール溶液中)である、第2図は
抗生物質MA−638−2−Bの赤外線吸収スペクトル
(KBr錠削1である。第3図は抗生物質MA−638
−2−Bの′H−核磁気共鳴スベクトルであり、第4図
は抗生物質MA−638−2
ルである。
Bの120−核磁気共鳴スペクトFigure 1 shows the ultraviolet absorption spectrum of antibiotic MA-638-2-B (in methyl alcohol solution). Figure 2 shows the infrared absorption spectrum of antibiotic MA-638-2-B (KBr tablet sharpener 1). Figure 3 shows antibiotic MA-638.
-2-B'H-Nuclear Magnetic Resonance vector, and Figure 4 shows the antibiotic MA-638-2. 120-nuclear magnetic resonance spectrum of B
Claims (5)
38−2−B。 ▲数式、化学式、表等があります▼(1) Antibiotic MA-6 represented by the following planar structural formula
38-2-B. ▲Contains mathematical formulas, chemical formulas, tables, etc.▼
−B生産菌を培養し、その培養物から抗生物質MA−6
38−2−Bを分離、採取することを特徴とする抗生物
質MA−638−2−の製造方法。(2) Antibiotic MA-638-2 belonging to the Fusarium genus
-Culture B-producing bacteria, and use the culture to produce antibiotic MA-6.
A method for producing the antibiotic MA-638-2-, which comprises separating and collecting MA-38-2-B.
ムMA−638−2株である請求項2記載の抗生物質M
A−638−2−Bの製造方法。(3) Antibiotic M according to claim 2, wherein the antibiotic MA-638-2-B producing bacteria is Fusarium MA-638-2 strain.
Method for manufacturing A-638-2-B.
ムMA−638−2株の通常手法による変異株である抗
生物質MA−638−2−Bの製造方法。(4) A method for producing antibiotic MA-638-2-B, wherein the antibiotic MA-638-2-B-producing bacterium is a mutant strain of Fusarium MA-638-2 strain obtained by a conventional method.
含有することを特徴とする抗腫瘍剤。(5) An antitumor agent characterized by containing antibiotic MA-638-2-B as an active ingredient.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP13798190A JPH0436276A (en) | 1990-05-28 | 1990-05-28 | Antibiotic ma-638-2-b, its production and antitumor agent comprising antibiotic ma-638-2-b as active ingredient |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP13798190A JPH0436276A (en) | 1990-05-28 | 1990-05-28 | Antibiotic ma-638-2-b, its production and antitumor agent comprising antibiotic ma-638-2-b as active ingredient |
Publications (1)
Publication Number | Publication Date |
---|---|
JPH0436276A true JPH0436276A (en) | 1992-02-06 |
Family
ID=15211266
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP13798190A Pending JPH0436276A (en) | 1990-05-28 | 1990-05-28 | Antibiotic ma-638-2-b, its production and antitumor agent comprising antibiotic ma-638-2-b as active ingredient |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPH0436276A (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5372940A (en) * | 1990-10-05 | 1994-12-13 | Fuji Yakuhin Kogyo Kabushiki Kaisha | D-pantolactone hydrolase and process for the preparation thereof |
CN102293767A (en) * | 2009-08-31 | 2011-12-28 | 杭州双马生物工程有限公司 | Application of active natural product B in preparing anti-vascular dementia products |
CN102293766A (en) * | 2009-08-31 | 2011-12-28 | 杭州双马生物工程有限公司 | Application of active natural product B used for preparing antifungal product |
-
1990
- 1990-05-28 JP JP13798190A patent/JPH0436276A/en active Pending
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5372940A (en) * | 1990-10-05 | 1994-12-13 | Fuji Yakuhin Kogyo Kabushiki Kaisha | D-pantolactone hydrolase and process for the preparation thereof |
CN102293767A (en) * | 2009-08-31 | 2011-12-28 | 杭州双马生物工程有限公司 | Application of active natural product B in preparing anti-vascular dementia products |
CN102293766A (en) * | 2009-08-31 | 2011-12-28 | 杭州双马生物工程有限公司 | Application of active natural product B used for preparing antifungal product |
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