JPH07206839A - New sesquiterpene lactone a or b, and antitumor agent containing artemisia argyi levl. et vant. compositae extract or sesquiterpene lactone a, b or c as active ingredient - Google Patents
New sesquiterpene lactone a or b, and antitumor agent containing artemisia argyi levl. et vant. compositae extract or sesquiterpene lactone a, b or c as active ingredientInfo
- Publication number
- JPH07206839A JPH07206839A JP6021894A JP2189494A JPH07206839A JP H07206839 A JPH07206839 A JP H07206839A JP 6021894 A JP6021894 A JP 6021894A JP 2189494 A JP2189494 A JP 2189494A JP H07206839 A JPH07206839 A JP H07206839A
- Authority
- JP
- Japan
- Prior art keywords
- sesquiterpene lactone
- sesquiterpene
- extract
- lactone
- vant
- 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
- 229930009674 sesquiterpene lactone Natural products 0.000 title claims abstract description 37
- 150000002107 sesquiterpene lactone derivatives Chemical class 0.000 title claims abstract description 37
- 239000000284 extract Substances 0.000 title claims abstract description 24
- HATRDXDCPOXQJX-UHFFFAOYSA-N Thapsigargin Natural products CCCCCCCC(=O)OC1C(OC(O)C(=C/C)C)C(=C2C3OC(=O)C(C)(O)C3(O)C(CC(C)(OC(=O)C)C12)OC(=O)CCC)C HATRDXDCPOXQJX-UHFFFAOYSA-N 0.000 title claims abstract description 20
- 239000002246 antineoplastic agent Substances 0.000 title claims description 6
- 239000004480 active ingredient Substances 0.000 title claims description 5
- 235000010894 Artemisia argyi Nutrition 0.000 title abstract description 3
- 241001435059 Artemisia argyi Species 0.000 title abstract description 3
- 241000208838 Asteraceae Species 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 7
- 239000000126 substance Substances 0.000 claims description 17
- 235000007340 Hordeum vulgare Nutrition 0.000 claims description 7
- 240000005979 Hordeum vulgare Species 0.000 claims 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 abstract description 20
- 206010028980 Neoplasm Diseases 0.000 abstract description 12
- 230000000259 anti-tumor effect Effects 0.000 abstract description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 abstract description 4
- 239000000843 powder Substances 0.000 abstract description 4
- 239000000741 silica gel Substances 0.000 abstract description 4
- 229910002027 silica gel Inorganic materials 0.000 abstract description 4
- 238000004440 column chromatography Methods 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 3
- 238000002523 gelfiltration Methods 0.000 abstract description 2
- 150000002596 lactones Chemical class 0.000 abstract description 2
- 208000032839 leukemia Diseases 0.000 abstract description 2
- 238000004811 liquid chromatography Methods 0.000 abstract 1
- RXHIKAIVEMAPRU-JRIGQVHBSA-N sequiterpene Natural products C1=C(C)[C@@H](OC(C)=O)[C@H](O)[C@@]2(O)[C@H](C)CC[C@@H](C(C)=C)[C@H]21 RXHIKAIVEMAPRU-JRIGQVHBSA-N 0.000 abstract 1
- 230000001225 therapeutic effect Effects 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- 201000011510 cancer Diseases 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 241000209219 Hordeum Species 0.000 description 6
- 241000196324 Embryophyta Species 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 208000006268 Sarcoma 180 Diseases 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 244000061176 Nicotiana tabacum Species 0.000 description 3
- 235000002637 Nicotiana tabacum Nutrition 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 238000002054 transplantation Methods 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 206010003445 Ascites Diseases 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 238000005377 adsorption chromatography Methods 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000000419 plant extract Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 1
- 240000000073 Achillea millefolium Species 0.000 description 1
- 235000003826 Artemisia Nutrition 0.000 description 1
- 235000003261 Artemisia vulgaris Nutrition 0.000 description 1
- 244000025254 Cannabis sativa Species 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- 101100386054 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) CYS3 gene Proteins 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- 229940122803 Vinca alkaloid Drugs 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 244000030166 artemisia Species 0.000 description 1
- 235000009052 artemisia Nutrition 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000012676 herbal extract Substances 0.000 description 1
- 230000007236 host immunity Effects 0.000 description 1
- 239000003864 humus Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- XXYRTFCLQHKIDU-UHFFFAOYSA-N iso-seco-tanapartholide Natural products O1C(=O)C(=C)C(CCC(=O)C)C1C1=C(C)C(O)CC1=O XXYRTFCLQHKIDU-UHFFFAOYSA-N 0.000 description 1
- XXYRTFCLQHKIDU-MJVIPROJSA-N isosecotanapartholide Chemical compound O1C(=O)C(=C)[C@H](CCC(=O)C)[C@H]1C1=C(C)[C@@H](O)CC1=O XXYRTFCLQHKIDU-MJVIPROJSA-N 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000005445 natural material Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 101150035983 str1 gene Proteins 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Furan Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Plant Substances (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は、キク科に属する艾葉か
ら得られる抽出エキスまたは該エキス中に含まれるセス
キテルペンラクトンＡ、ＢまたはＣを有効成分として含
有する抗腫瘍剤及びそれらエキスから得られる新規化合
物であるセスキテルペンラクトンＡまたはＢに関する。TECHNICAL FIELD The present invention relates to an extract obtained from barley leaves belonging to the family Asteraceae, an antitumor agent containing sesquiterpene lactone A, B or C contained in the extract as an active ingredient, and an extract obtained from the extract. Related sesquiterpene lactones A or B which are novel compounds.
【０００２】[0002]
【従来の技術】ある種の高等植物抽出エキス及びその含
有成分が抗腫瘍作用を有することについては、これまで
多数報告されている〔「臨床医学と薬用植物」３５（１
９８５）〕。しかし、実用化されているものとしては、
ビンカアルカロイドのビンブラスチン（vinblastine）
〔The Merck Index第１０版９７８４〕、ビンクリスチ
ン（vincristine ）〔「生物活性天然物質」４３１（１
９７８）〕など極めて少ない。また、下記式（Ａ）、
（Ｂ）または（Ｃ）2. Description of the Related Art A number of reports have been reported so far that some kinds of higher plant extracts and the components contained therein have antitumor activity ["Clinical Medicine and Medicinal Plants" 35 (1
985)]. However, as one that has been put to practical use,
Vinca alkaloid vinblastine
[The Merck Index 10th Edition 9784], vincristine [[Bioactive Natural Substance] 431 (1
978)] and so on. In addition, the following formula (A),
(B) or (C)
【０００３】[0003]
【化１】[Chemical 1]
【０００４】[0004]
【化２】[Chemical 2]
【０００５】[0005]
【化３】[Chemical 3]
【０００６】で表されるセスキテルペンラクトンＡ、Ｂ
またはＣの構造類似物質のなかで、抗腫瘍作用について
報告されているのは、キク科セイヨウノコギリソウ（Ac
hilleamillefolium L.Compositae）から抽出された下記
式Sesquiterpene lactones A and B represented by
Among the structural analogues of C or C, the antitumor effect has been reported to be Asteraceae Achillea millefolium (Ac
hilleamillefolium L. Compositae)
【０００７】[0007]
【化４】 [Chemical 4]
【０００８】で示されるアキミル酸Ａラクトン（特開昭
６２−８１３７９号公報）だけである。尚、本発明の化
合物である、下記式（Ｃ）It is only an akimyl acid A lactone represented by (JP-A-62-81379). In addition, the following formula (C), which is a compound of the present invention:
【０００９】[0009]
【化３】[Chemical 3]
【００１０】で表される、セスキテルペンラクトンＣに
ついては、イソ−セコ−タナパルチオライド（iso-seco
-tanapartholide）〔Phytochemistry ２５，８８３（１
９８６）〕と称される公知の化合物であるが、その立体
異性体化合物である下記式（Ａ）及び（Ｂ）As for the sesquiterpene lactone C represented by the formula, iso-seco-tanapartiolide (iso-seco
-tanapartholide) [Phytochemistry 25,883 (1
986)], which is a known compound of the following formulas (A) and (B), which are stereoisomeric compounds thereof.
【００１１】[0011]
【化１】[Chemical 1]
【００１２】[0012]
【化２】[Chemical 2]
【００１３】で表されるセスキテルペンラクトンＡ及び
Ｂは新規物質であり、本発明の艾葉抽出エキス、及びセ
スキテルペンラクトンＡ、ＢまたはＣの抗腫瘍作用につ
いては全く報告されていない。The sesquiterpene lactones A and B represented by ## STR1 ## are novel substances, and no report has been made on the antitumor effect of the extract of bark leaf of the present invention and the sesquiterpene lactones A, B or C.
【００１４】[0014]
【発明が解決しようとする課題】従来から、種々の生薬
エキスや植物由来の天然物について抗腫瘍効果が確認さ
れており、例えば中国では種々の植物エキスが癌の治療
に用いられたり、日本においては植物アルカロイド類が
抗腫瘍剤として実用化されている。しかし、セスキテル
ペンラクトン類については、有効性、毒性の面で問題点
が多く未だ実用化されているものはない。It has been confirmed that various herbal extracts and plant-derived natural products have antitumor effects. For example, various plant extracts are used for cancer treatment in China, or in Japan. , Plant alkaloids have been put to practical use as antitumor agents. However, none of the sesquiterpene lactones has been put to practical use because it has many problems in terms of efficacy and toxicity.
【００１５】[0015]
【課題を解決するための手段】本発明者らは、従来から
抗腫瘍効果を有する種々の植物に関する研究を行ってき
た。その結果、キク科の艾葉（Artemisia argyi Levl.e
t Vant,Compositae）の抽出エキス及び抽出エキス中に
含まれるセスキテルペンラクトン類に顕著な抗腫瘍効果
があることを見いだし、本発明を完成するに至った。即
ち、本発明の目的の一つ下記式（Ａ）及び（Ｂ）Means for Solving the Problems The inventors of the present invention have conventionally conducted research on various plants having an antitumor effect. As a result, Asteraceae barley leaves (Artemisia argyi Levl.e
The present invention has been completed by discovering that an extract extracted from (T Vant, Compositae) and sesquiterpene lactones contained in the extract have a remarkable antitumor effect. That is, one of the objects of the present invention is the following formulas (A) and (B)
【００１６】[0016]
【化１】[Chemical 1]
【００１７】[0017]
【化２】[Chemical 2]
【００１８】で示される新規セスキテルペンラクトンＡ
及びＢを提供することを目的とするものであり、また本
発明の他の目的は、上記キク科の艾葉（Artemisia argy
i Levl.et Vant,Compositae） の抽出エキスを有効成分
として含有する抗腫瘍剤を提供することであり、また本
発明の他の目的は上記抽出エキス中に含まれる下記式
（Ａ）、（Ｂ）または（Ｃ）A novel sesquiterpene lactone A represented by
And B. Another object of the present invention is to provide Artemisia argy.
i Levl.et Vant, Compositae) as an active ingredient, and another object of the present invention is to provide the following formulas (A) and (B) contained in the above extract. ) Or (C)
【００１９】[0019]
【化１】[Chemical 1]
【００２０】[0020]
【化２】[Chemical 2]
【００２１】[0021]
【化３】[Chemical 3]
【００２２】で示されるセスキテルペンラクトンＡ、Ｂ
及びＣから選ばれる化合物の少なくとも一種以上を有効
成分として含有する抗腫瘍剤を提供することである。Sesquiterpene lactones A and B represented by
And an antitumor agent containing at least one compound selected from C as an active ingredient.
【００２３】本発明の抽出エキス及び、セスキテルペン
ラクトンＡ、ＢまたはＣは例えば下記の方法によって抽
出、分離することができる。まず、エキスについては艾
葉の生又は乾燥若しくは半乾燥した葉、茎葉、及び全草
のうちいずれかを水、又は水溶性有機溶媒（例えばメタ
ノール、エタノールその他のアルコール類若しくはアセ
トン、アセトニトリルなど）若しくは、これらの混合溶
媒中で室温において抽出するか、若しくは加熱して抽出
するかして得られる抽出液を濾過後、濃縮するかまたは
通常の乾燥方法（例えば凍結乾燥）で乾燥し、これを水
と混和しない有機溶媒（例えばクロロホルム、酢酸エチ
ル、ジクロロメタン、ｎ−ブタノールなど）で分配し、
更にその有機層を濃縮することによって、シロップ状の
艾葉エキスを得ることができる。また、下記式（Ａ）、
（Ｂ）及び（Ｃ）The extract of the present invention and the sesquiterpene lactone A, B or C can be extracted and separated by the following method, for example. First, for the extract, raw or dry or semi-dried leaves of humus leaves, foliage, and whole grass with water, or a water-soluble organic solvent (for example, methanol, ethanol or other alcohols or acetone, acetonitrile, etc.), or The extract obtained by extraction in these mixed solvents at room temperature or extraction by heating is filtered and then concentrated or dried by an ordinary drying method (for example, freeze-drying), and this is mixed with water. Partition with an immiscible organic solvent (eg chloroform, ethyl acetate, dichloromethane, n-butanol, etc.),
By further concentrating the organic layer, a syrupy barley leaf extract can be obtained. In addition, the following formula (A),
(B) and (C)
【００２４】[0024]
【化１】[Chemical 1]
【００２５】[0025]
【化２】[Chemical 2]
【００２６】[0026]
【化３】[Chemical 3]
【００２７】で表されるセスキテルペンラクトンＡ、Ｂ
及びＣは、上記記載の方法によって得られたエキスを各
種のカラム（例えばシリカゲルカラム、逆相カラム、ゲ
ル濾過カラムなど）を用いたオープンカラムクロマトグ
ラフィーや低圧、高圧の送液ポンプを用いた液体クロマ
トグラフィー（ＨＰＬＣ）を繰り返すことにより抗腫瘍
活性を有する単一成分として得ることができる。Sesquiterpene lactones A and B represented by
And C are liquids using the extract obtained by the above-mentioned method, open column chromatography using various columns (eg, silica gel column, reverse phase column, gel filtration column, etc.) and low-pressure and high-pressure liquid-feeding pumps It can be obtained as a single component having antitumor activity by repeating chromatography (HPLC).
【００２８】[0028]
【実施例】次に、実施例を挙げて本発明をさらに説明す
るが、本発明は、これら実施例に限られるものではない
ことは勿論である。EXAMPLES Next, the present invention will be further described with reference to examples, but it goes without saying that the present invention is not limited to these examples.
【００２９】実施例１ （艾葉エキスの抽出） 乾燥した艾葉末（日本粉末薬品株式会社製）１Ｋｇを熱
水（２０Ｌ）で２時間抽出を行った。不溶物を遠心分
離、吸引濾過で除去した後、減圧下で２Ｌまで濃縮を行
いクロロホルム（２Ｌ）で７回分配抽出を繰り返した。
得られたクロロホルム層を減圧下で溶媒を溜去すると暗
緑色油状の、Sarcoma180担癌マウスに対する活性抽出エ
キス９．６５ｇが得られた。Example 1 (Extraction of Moth Leaf Extract) 1 kg of dried moth leaf powder (manufactured by Nippon Powder Chemicals Co., Ltd.) was extracted with hot water (20 L) for 2 hours. The insoluble material was removed by centrifugation and suction filtration, concentrated under reduced pressure to 2 L, and partitioned and extracted 7 times with chloroform (2 L).
When the solvent of the obtained chloroform layer was distilled off under reduced pressure, 9.65 g of a dark green oily active extract for Sarcoma 180 tumor-bearing mice was obtained.
【００３０】実施例２ （セスキテルペンラクトンの分
離） 実施例１の抽出エキス８．８ｇを５０ｍＬのクロロホル
ムに溶解し、メルク社製シリカゲル（７０〜２３０メッ
シュ）１Ｋｇを用いた吸着クロマトグラフィーに付し
た。クロロホルム（１２Ｌ）で洗浄後、展開溶媒として
クロロホルム／メタノール（９：１ ｖ／ｖ）（４Ｌ）
で溶出してSarcoma180担癌マウスに対する活性フラクシ
ョン５．８ｇ（乾燥重量）を得た。続いて、活性フラク
ション２．７ｇを１０ｍＬのクロロホルムに溶解し、メ
ルク社製シリカゲル（２３０〜４００メッシュ）１００
ｇを用いた吸着クロマトグラフィーに付した。クロロホ
ルム（５００ｍＬ）で洗浄後、クロロホルム／メタノー
ル（９：１ ｖ／ｖ）（１．２Ｌ）で展開溶出して、Sa
rcoma180担癌マウスに対する活性フラクション７４８ｍ
ｇ（乾燥重量）を得た。さらにこの活性フラクション１
８０ｍｇを１ｍＬのメタノールに溶解し、山村化学社製
カラム担体（ＹＭＣＧＥＬ ＯＤＳ−ＡＱ １２０−Ｓ
５０）１４０ｇを用いて、逆相のオープンカラムクロマ
トグラフィーに付した。水／メタノール（７：３ ｖ／
ｖ）（１．１Ｌ）で展開溶出させると、後半（０．４
Ｌ）に溶出するフラクションから淡褐色油状の、セスキ
テルペンラクトン類含有フラクション９７ｍｇ（乾燥重
量）が得られた。セスキテルペンラクトン類含有フラク
ション１０ｍｇを０．５ｍＬのメタノールに溶解し、日
本分析工業社製リサイクル高速液体クロマトグラフィー
（カラム：Inertsil ＰＲＥＰ−ＯＤＳ φ２０×２５
０ｍｍ）を用いて、移動相として水／メタノール（７：
３ ｖ／ｖ）で４ｍＬ／分の流速で溶出させた。３２分
後にセスキテルペンラクトンＡが溶出し、４０分後にセ
スキテルペンラクトンＢ、Ｃが同時に溶出した。セスキ
テルペンラクトンＢ、Ｃは、さらに４回リサイクルクロ
マトグラフィーを繰り返すことにより、分離することが
できた。以上の操作により、実施例１に従って得られた
抽出エキス８．８ｇから白色粉末のセスキテルペンラク
トンＡを１５ｍｇ、無色油状のセスキテルペンラクトン
Ｂを１７２ｍｇ、無色油状のセスキテルペンラクトンＣ
を７０ｍｇ得ることができた。実施例２において得られ
たセスキテルペンラクトン類の性状は、以下のとおりで
あった。Example 2 (Separation of Sesquiterpene Lactone) 8.8 g of the extract of Example 1 was dissolved in 50 mL of chloroform and subjected to adsorption chromatography using 1 kg of silica gel (70-230 mesh) manufactured by Merck. . After washing with chloroform (12 L), chloroform / methanol (9: 1 v / v) (4 L) as a developing solvent
Elution was carried out to obtain 5.8 g (dry weight) of an active fraction for Sarcoma 180 tumor-bearing mice. Subsequently, 2.7 g of the active fraction was dissolved in 10 mL of chloroform, and 100 g of silica gel (230-400 mesh) manufactured by Merck Ltd. was dissolved.
It was subjected to adsorption chromatography using g. After washing with chloroform (500 mL), it was developed and eluted with chloroform / methanol (9: 1 v / v) (1.2 L), and Sa
rcoma180 Active fraction for cancer-bearing mice 748m
g (dry weight) was obtained. Furthermore, this active fraction 1
80 mg was dissolved in 1 mL of methanol, and a column carrier (YMCGEL ODS-AQ 120-S manufactured by Yamamura Chemical Co., Ltd.) was used.
50) 140 g was subjected to reverse phase open column chromatography. Water / methanol (7: 3 v /
v) (1.1 L) developed and eluted, the latter half (0.4
From the fraction eluted in L), a pale brown oily sesquiterpene lactone-containing fraction (97 mg, dry weight) was obtained. A sesquiterpene lactone-containing fraction (10 mg) was dissolved in 0.5 mL of methanol, and recycled by high performance liquid chromatography (column: Inertsil PREP-ODS φ20 × 25) manufactured by Nippon Analytical Industry Co., Ltd.
0 mm) and water / methanol (7:
3 v / v) at a flow rate of 4 mL / min. After 32 minutes, sesquiterpene lactone A was eluted, and after 40 minutes, sesquiterpene lactones B and C were simultaneously eluted. The sesquiterpene lactones B and C could be separated by repeating recycling chromatography four more times. By the above operation, 15 mg of sesquiterpene lactone A as a white powder, 172 mg of sesquiterpene lactone B as a colorless oil, and sesquiterpene lactone C as a colorless oil were obtained from 8.8 g of the extract obtained according to Example 1.
Was obtained in an amount of 70 mg. The properties of the sesquiterpene lactones obtained in Example 2 were as follows.
【００３１】セスキテルペンラクトンＡ 〔α〕D＝＋5° (MeOH) IR:νmax(KBr)3478,1756,1706,1647cm-1 HR-EIMS:m/z278.1172[M+]1 H-NMR:δppm(CDCl3)6.29,5.62,5.41,4.75,3.27,2.77,
2.42,2.32,2.18,2.12,1.5713 C-NMR:δppm(CDCl3)207.76,204.02,174.21,169.95,13
8.03,134.77,121.80,75.63,71.73,43.95,41.46,40.18,2
9.85,23.05,14.29Sesquiterpene lactone A [α] D = + 5 ° (MeOH) IR: νmax (KBr) 3478, 1756, 1706, 1647 cm -1 HR-EIMS: m / z 278.1172 [M + ] 1 H-NMR: δppm (CDCl 3 ) 6.29,5.62,5.41,4.75,3.27,2.77,
2.42,2.32,2.18,2.12,1.57 13 C-NMR: δppm (CDCl 3 ) 207.76,204.02,174.21,169.95,13
8.03,134.77,121.80,75.63,71.73,43.95,41.46,40.18,2
9.85,23.05,14.29
【００３２】セスキテルペンラクトンＢ 〔α〕D＝＋22° (DMSO) IR:νmax(KBr)3414,1765,1707,1655cm-1 HR-posFABMS:m/z279.1223[M++H]1 H-NMR:δppm(CDCl3)6.35,5.66,4.96,4.72,3.10,2.81,
2.55,2.33,2.18,2.15,1.9213 C-NMR:δppm(CDCl3)207.56,202.95,172.67,169.91,13
8.32,137.89,122.85,76.04,71.68,44.33,43.11,39.53,2
9.98,27.38,14.09Sesquiterpene lactone B [α] D = + 22 ° (DMSO) IR: νmax (KBr) 3414,1765,1707,1655cm -1 HR-posFABMS: m / z279.1223 [M + + H] 1 H- NMR: δppm (CDCl 3 ) 6.35,5.66,4.96,4.72,3.10,2.81,
2.55,2.33,2.18,2.15,1.92 13 C-NMR: δppm (CDCl 3 ) 207.56,202.95,172.67,169.91,13
8.32,137.89,122.85,76.04,71.68,44.33,43.11,39.53,2
9.98,27.38,14.09
【００３３】セスキテルペンラクトンＣ 〔α〕D＝−14° (DMSO) IR:νmax(KBr)3446,1762,1707,1654cm-1 HR-posFABMS:m/z279.1225[M++H]1 H-NMR:δppm(CDCl3)6.34,5.66,4.93,4.73,3.15,2.79,
2.55,2.32,2.18,2.15,1.9213 C-NMR:δppm(CDCl3)208.06,203.65,173.38,170.37,13
8.76,137.88,123.10,76.74,72.17,44.71,43.10,40.02,3
0.32,27.90,14.46Sesquiterpene lactone C [α] D = -14 ° (DMSO) IR: νmax (KBr) 3446,1762,1707,1654cm -1 HR-posFABMS: m / z279.1225 [M + + H] 1 H -NMR: δppm (CDCl 3 ) 6.34,5.66,4.93,4.73,3.15,2.79,
2.55,2.32,2.18,2.15,1.92 13 C-NMR: δppm (CDCl 3 ) 208.06,203.65,173.38,170.37,13
8.76,137.88,123.10,76.74,72.17,44.71,43.10,40.02,3
0.32,27.90,14.46
【００３４】[0034]
【試験例１】艾葉抽出エキス及びセスキテルペンラクト
ンＡ、Ｂ、ＣのSarcoma180腹水型腫瘍マウスに対する活
性試験を行った。被検動物として７週齢のＢＡＬＢ／ｃ
×ＤＢＡ／２Ｆ１マウス（雌）を１投与ごとに５匹用い
た。宿主免疫を抑制するために、癌細胞移植５日前に被
検動物１匹あたり１００ｍｇ／ｋｇのシクロホスファミ
ドを腹腔内投与した。試験癌種にはSarcoma180腹水型を
用い、被検動物１匹あたり１０6 個の癌細胞を腹腔内投
与した。検体は、プロピレングリコールに溶解後、エタ
ノールを添加し、生理食塩水で希釈した溶液として、癌
移植後に１日１回、５日間所定の投与量を腹腔内に連続
投与した。対照群には、検体を含まない同様に調製した
溶液を腹腔内投与した。効果の判定は、癌移植後７日後
に増殖した腫瘍細胞容積を測定し、検体投与群の腫瘍細
胞容積とコントロール群の腫瘍細胞容積より抑制率
（％）を次式[Test Example 1] An activity test was carried out on the Sarcoma 180 ascites tumor mice of the bark leaf extract and sesquiterpene lactones A, B and C. 7-week-old BALB / c as a test animal
Five DBA / 2F1 mice (female) were used for each administration. In order to suppress host immunity, cyclophosphamide (100 mg / kg / animal to be tested) was intraperitoneally administered 5 days before the transplantation of cancer cells. Sarcoma 180 ascites type was used as the test cancer type, and 10 6 cancer cells were intraperitoneally administered per test animal. The sample was dissolved in propylene glycol, ethanol was added, and the solution was diluted with physiological saline, and a predetermined dose was continuously administered intraperitoneally once a day for 5 days after cancer transplantation. A similarly prepared solution containing no sample was intraperitoneally administered to the control group. To determine the effect, the volume of tumor cells grown 7 days after cancer transplantation was measured, and the inhibition rate (%) was calculated from the tumor cell volume of the sample administration group and the tumor cell volume of the control group by the following formula.
【００３５】[0035]
【数１】 [Equation 1]
【００３６】により算出して行った。検体としては、艾
葉抽出エキス５０、１００ｍｇ／ｋｇ、セスキテルペン
ラクトンＡ、Ｂ、Ｃそれぞれ６．２５、１２．５、２５
ｍｇ／ｋｇを投与した。その結果、下表It was calculated by As the samples, 50, 100 mg / kg of barley leaf extract, sesquiterpene lactones A, B and C were 6.25, 12.5 and 25, respectively.
mg / kg was administered. As a result, the table below
【００３７】[0037]
【表１】 [Table 1]
【００３８】に示すように艾葉エキスは、５０ｍｇ／ｋ
ｇで腫瘍の増殖を完全に抑制した。又、セスキテルペン
ラクトンＡは２５ｍｇ／ｋｇ、セスキテルペンラクトン
Ｂ、Ｃについては、それぞれ１２．５ｍｇ／ｋｇで完全
に腫瘍の増殖を抑制した。As shown in (1), the barley leaf extract is 50 mg / k.
Tumor growth was completely suppressed by g. Further, sesquiterpene lactone A at 25 mg / kg and sesquiterpene lactones B and C at 12.5 mg / kg each completely suppressed tumor growth.
【００３９】[0039]
【発明の効果】本発明に係わる艾葉抽出エキス及びセス
キテルペンラクトンＡ、Ｂ、Ｃは、顕著な抗腫瘍効果を
有し、将来例えば白血病や種々の固形腫瘍に対する治療
薬として使用することが可能である。INDUSTRIAL APPLICABILITY The barley leaf extract and sesquiterpene lactones A, B and C according to the present invention have a remarkable antitumor effect and can be used as therapeutic agents for leukemia and various solid tumors in the future. is there.
───────────────────────────────────────────────────── フロントページの続き (72)発明者 真部 俊一 大阪府高槻市紫町１番１号 日本たばこ産 業株式会社医薬総合研究所内 (72)発明者 渡辺 渡 大阪府高槻市紫町１番１号 日本たばこ産 業株式会社医薬総合研究所内 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Shunichi Sanbe 1-1, Murasaki-cho, Takatsuki-shi, Osaka Inside Tobacco Research Institute, Japan Tobacco Inc. (72) Inventor, Wataru Watanabe No. 1 Murasaki-cho, Takatsuki-shi, Osaka No. 1 Japan Tobacco Inc. Pharmaceutical Research Institute
Claims (3)
る抗腫瘍剤。2. An antitumor agent containing an extract of barley leaf as an active ingredient.
選ばれる化合物を少なくとも一種以上含有してなる抗腫
瘍剤。3. The following formula (A), (B) or (C): embedded image embedded image embedded image An antitumor agent comprising at least one compound selected from sesquiterpene lactones A, B or C represented by
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP6021894A JPH07206839A (en) | 1994-01-20 | 1994-01-20 | New sesquiterpene lactone a or b, and antitumor agent containing artemisia argyi levl. et vant. compositae extract or sesquiterpene lactone a, b or c as active ingredient |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP6021894A JPH07206839A (en) | 1994-01-20 | 1994-01-20 | New sesquiterpene lactone a or b, and antitumor agent containing artemisia argyi levl. et vant. compositae extract or sesquiterpene lactone a, b or c as active ingredient |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH07206839A true JPH07206839A (en) | 1995-08-08 |
Family
ID=12067822
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP6021894A Pending JPH07206839A (en) | 1994-01-20 | 1994-01-20 | New sesquiterpene lactone a or b, and antitumor agent containing artemisia argyi levl. et vant. compositae extract or sesquiterpene lactone a, b or c as active ingredient |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH07206839A (en) |
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1994
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6350478B1 (en) * | 1996-03-28 | 2002-02-26 | Phytotech Limited | Artemisia judaica fractionation method |
| US6051565A (en) * | 1997-04-26 | 2000-04-18 | International Phytochemistry Research Labs, Ltd. | Farnesyl-protein transferase inhibitors |
| US6268394B1 (en) | 1997-04-26 | 2001-07-31 | International Phytochemistry Research Labs, Ltd. | Farnesyl-protein transferase inhibitors |
| US6262110B1 (en) | 1997-07-03 | 2001-07-17 | International Phytochemistry Research Labs, Ltd. | Farnesyl-protein transferase inhibitors |
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| CN101792375A (en) * | 2010-03-11 | 2010-08-04 | 云南烟草科学研究院 | Sesquiterpene compound in tobacco stems and preparation method and application thereof |
| CN102250106A (en) * | 2011-05-19 | 2011-11-23 | 华东理工大学 | Extraction method of sesquiterpene lactone compound from Chinese mugwort leaf and application thereof |
| WO2014175652A1 (en) * | 2013-04-26 | 2014-10-30 | 초당약품공업 주식회사 | Pharmaceutical composition containing liriodendron tulipifera l. extract for treating chronic myelogenous leukemia |
| CN105358171A (en) * | 2013-04-26 | 2016-02-24 | 草堂药品工业株式会社 | Pharmaceutical composition containing liriodendron tulipifera l. extract for treating chronic myelogenous leukemia |
| CN104042661A (en) * | 2014-06-23 | 2014-09-17 | 葛月宾 | Blumea oil transdermal patch, preparation method thereof and method for detecting active component contained in blumea oil transdermal patch |
| CN105520986A (en) * | 2016-02-11 | 2016-04-27 | 徐自升 | Folium artemisiae argyi fresh juice spray-dried decoction powder and preparation process thereof |
| CN105520987A (en) * | 2016-02-11 | 2016-04-27 | 徐自升 | Folium artemisiae argyi fresh juice vacuum-dried decoction powder and preparation process thereof |
| CN105641012A (en) * | 2016-02-11 | 2016-06-08 | 徐自升 | Argy wormwood leaf powdery decoction pieces prepared through freshly pressing and freeze-drying and preparation technology of argy wormwood leaf powdery decoction pieces |
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