JPH07247291A - Okadaic acid lactone derivative - Google Patents

Okadaic acid lactone derivative

Info

Publication number
JPH07247291A
JPH07247291A JP6064410A JP6441094A JPH07247291A JP H07247291 A JPH07247291 A JP H07247291A JP 6064410 A JP6064410 A JP 6064410A JP 6441094 A JP6441094 A JP 6441094A JP H07247291 A JPH07247291 A JP H07247291A
Authority
JP
Japan
Prior art keywords
okadaic acid
added
groups
group
mixture
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
Application number
JP6064410A
Other languages
Japanese (ja)
Inventor
Daisuke Kamimura
大輔 上村
Kaoru Yamada
薫 山田
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sagami Chemical Research Institute
Original Assignee
Sagami Chemical Research Institute
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Sagami Chemical Research Institute filed Critical Sagami Chemical Research Institute
Priority to JP6064410A priority Critical patent/JPH07247291A/en
Publication of JPH07247291A publication Critical patent/JPH07247291A/en
Pending legal-status Critical Current

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Classifications

    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

PURPOSE:To provide a new okadaic acid derivative derived from okadaic acid, exhibiting an activity to inhibit the multiplication of a cancer cell P388 in vitro, expected as a masking substance for the highly poisonous okadaic acid, and useful as an antitumor agent, etc. CONSTITUTION:The new okadaic acid lactone derivative of formula I (R<1>-R<3> are H, a hydroxyl group-protecting group), having a multiplication-inhibiting activity against a murine lymphocytic leukemia cell P388 in vitro, useful as an antitumor agent, and having an use as a masking substance against highly poisonous okadaic acid. The compound is obtained by esterifying the carboxyl group of the okadaic acid of formula II (Me is methyl), treating the all secondary hydroxyl groups of the produced ester with a largely excessive silylating agent, treating the protected product with tetrabutylammonium chloride at a low temperature to remove the protecting group only on the 24-hydroxyl group, hydrolyzing the treated ester, subjecting the hydrolyzed groups to a Yamaguchi method to produce lactone groups, and subsequently removing the protecting groups.

Description

【発明の詳細な説明】Detailed Description of the Invention

【０００１】[0001]

【産業上の利用分野】本発明は新規なオカダ酸ラクトン
誘導体に関する。この化合物は癌細胞であるマウスリン
パ性白血病細胞（Ｐ３８８）に対してインビトロ増殖阻
害活性を持ち、抗腫瘍剤として利用しうる。The present invention relates to a novel okadaic acid lactone derivative. This compound has in vitro growth inhibitory activity against mouse lymphocytic leukemia cells (P388) which are cancer cells, and can be used as an antitumor agent.

【０００２】[0002]

【従来の技術】近年、海綿動物の成分検索が広く行わ
れ、種々の生物活性を有する化合物が単離された［例え
ば、ブリオスタチン（G. R. Pettit et al., Tetrahedr
on, 41,985 (1985)）、ハリコンドリン（Y. Hirata et
al., Pure Appl. Chem., 58, 701 (1986)）］。その中
でも、クロイソカイメンから単離された下記式2. Description of the Related Art In recent years, the composition of sponges has been widely searched, and compounds having various biological activities have been isolated [eg, bryostatin (GR Pettit et al., Tetrahedr
on, 41,985 (1985)), Halichondrin (Y. Hirata et
al., Pure Appl. Chem., 58, 701 (1986)]]. Among them, the following formula isolated from croisokaimen

【０００３】[0003]

【化２】 [Chemical 2]

【０００４】で表されるオカダ酸は強い腫瘍細胞増殖阻
害活性及びプロティンフォスファターゼ阻害活性を有し
ている。しかしながら、その急性毒性も強く薬剤として
の用途が絶たれている。一方、医療の場では常に、より
有効で、より副作用の少ない薬剤が求められているのが
現状である。The okadaic acid represented by the formula (1) has a strong tumor cell growth inhibitory activity and protein phosphatase inhibitory activity. However, its acute toxicity is strong and its use as a drug is cut off. On the other hand, in the medical field, there is always a demand for drugs that are more effective and have fewer side effects.

【０００５】[0005]

【発明が解決しようとする課題】オカダ酸の活性発現に
はＣ１位のカルボキシル基とＣ２４位の水酸基との間の
水素結合によって形成されるフレキシブル・キャビティ
構造が重要な役割を担っていると考えられる。従って、
このキャビティ構造を固定した物質が得られれば、マス
ク化による特異性発現等の新たな効果が期待される。そ
こで、本発明はオカダ酸のキャビティ構造が固定され、
抗腫瘍活性を示すマスクされたオカダ酸誘導体を提供す
ることを目的とする。It is considered that the flexible cavity structure formed by the hydrogen bond between the carboxyl group at the C1 position and the hydroxyl group at the C24 position plays an important role in the expression of the activity of okadaic acid. To be Therefore,
If a substance with this cavity structure fixed is obtained, new effects such as specificity expression by masking are expected. Therefore, in the present invention, the cavity structure of okadaic acid is fixed,
It is an object to provide a masked okadaic acid derivative which exhibits antitumor activity.

【０００６】[0006]

【課題を解決するための手段】本発明者等はオカダ酸よ
り誘導した前記一般式（１）で表される新規オカダ酸ラ
クトン誘導体が癌細胞Ｐ３８８に対して穏和なインビト
ロ増殖阻害活性を示すことを見出し、本発明を完成し
た。Means for Solving the Problems The present inventors have found that the novel okadaic acid lactone derivative represented by the general formula (1) derived from okadaic acid exhibits mild in vitro growth inhibitory activity against cancer cells P388. And completed the present invention.

【０００７】すなわち本発明は、一般式That is, the present invention has the general formula

【０００８】[0008]

【化３】 [Chemical 3]

【０００９】（式中、Ｒ1 、Ｒ2 、Ｒ3 は水素原子また
は水酸基の保護基を表す。）で表されるオカダ酸ラクト
ン誘導体を提供するものである。The present invention provides an okadaic acid lactone derivative represented by the formula: wherein R 1 , R 2 and R 3 represent a hydrogen atom or a hydroxyl-protecting group.

【００１０】前記一般式（１）中、Ｒ1 、Ｒ2 、Ｒ3 で
示される水酸基の保護基は、水酸基の保護基として通常
用いられるいずれの保護基であってもよい［例えば、T.
W.Greene et al., "Protective Groups in Organic Sy
nthesis" John Wiley & Sons, Inc., New York, 1991
に記載のもの］が、好ましくは、アセチル基、プロパノ
イル基、ベンゾイル基、トリメチルシリル基、t-ブチル
ジメチルシリル基、メトキシメチル基、メチルチオメチ
ル基等が例示できる。In the general formula (1), the protective group for the hydroxyl group represented by R 1 , R 2 and R 3 may be any protective group usually used as a protective group for the hydroxyl group [eg T.
W. Greene et al., "Protective Groups in Organic Sy
nthesis "John Wiley & Sons, Inc., New York, 1991
Those described in [1] above are preferably acetyl group, propanoyl group, benzoyl group, trimethylsilyl group, t-butyldimethylsilyl group, methoxymethyl group, methylthiomethyl group and the like.

【００１１】本発明の前記一般式（１）で表される新規
オカダ酸誘導体は次の手順で合成できる。即ち、オカダ
酸のカルボキシル基をエステル化し、大過剰のシリル化
剤と反応させて全ての２級水酸基がシリル基によって保
護されたトリシリル体を得る。次いで例えばＤＭＳＯ中
無水酢酸を作用させることにより３級水酸基も保護され
たトリシリルメチルチオメチルエーテル体とした後、低
温でテトラブチルアンモニウムフロリドを作用させＣ２
４位水酸基のみを脱保護し、続いてエステルを加水分解
してモノヒドロキシカルボン酸体とする。ラクトン化は
モノヒドロキシカルボン酸体を２，４，６−トリクロロ
ベンゾイルクロリドを用いて混合酸無水物とした後、高
希釈条件下４−ジメチルアミノピリジンを用いてエステ
ル化を行うヤマグチ法（Inanaga, J. et al., Bull. Ch
em. Soc. Jap., 52, 1989 (1979)）に従う。また、２級
水酸基の脱保護は酸性条件下フッ素陰イオンにより行
い、３級水酸基のエーテル型保護基の脱離にはトリフェ
ニルカルベニウムテトラフロロボレートを用いる。The novel okadaic acid derivative represented by the general formula (1) of the present invention can be synthesized by the following procedure. That is, the carboxyl group of okadaic acid is esterified and reacted with a large excess of a silylating agent to obtain a trisilyl compound in which all secondary hydroxyl groups are protected by silyl groups. Then, a trisilylmethyl thiomethyl ether body in which the tertiary hydroxyl group is also protected by acting acetic anhydride in DMSO, and then tetrabutylammonium fluoride is allowed to act at a low temperature to give C2.
Only the 4-position hydroxyl group is deprotected, and then the ester is hydrolyzed to give a monohydroxycarboxylic acid body. For the lactonization, the monohydroxycarboxylic acid is converted to a mixed acid anhydride using 2,4,6-trichlorobenzoyl chloride, and then esterified with 4-dimethylaminopyridine under a high dilution condition (Inanaga, Inanaga, J. et al., Bull. Ch
em. Soc. Jap., 52, 1989 (1979)). Further, deprotection of the secondary hydroxyl group is carried out with a fluorine anion under acidic conditions, and triphenylcarbenium tetrafluoroborate is used for elimination of the ether type protective group of the tertiary hydroxyl group.

【００１２】本発明における前記一般式（１）に含まれ
る化合物としては具体的には、Specific examples of the compound contained in the above general formula (1) in the present invention include:

【００１３】[0013]

【化４】 [Chemical 4]

【化５】 [Chemical 5]

【化６】 [Chemical 6]

【００１４】などを例示することができる。The following can be exemplified.

【００１５】[0015]

【実施例】以下、実施例及び試験例により本発明を詳細
に説明するが、本発明はこれらに限定されるものではな
い。The present invention will be described in detail below with reference to examples and test examples, but the present invention is not limited thereto.

【００１６】実施例１ Ｃ２−メチルチオメチル−Ｃ７，Ｃ２７−ジシリルラク
トン体（４）の合成Example 1 Synthesis of C2-methylthiomethyl-C7, C27-disilyllactone (4)

【００１７】[0017]

【化７】 [Chemical 7]

【００１８】ｔ−ブチルジメチルシリルクロリド５５
９．９ｍｇ（３．７２ｍｍｏｌ）をナス型フラスコにと
りアルゴン置換した後、ジメチルホルムアミド２０ｍＬ
に溶解させた。既知のメチルエステル体（５）（Tachib
ana, K. et al., J. Am. Chem.Soc., 103, 2496 (198
1)）５０．３ｍｇ（６１．５μｍｏｌ）を枝付きフラス
コにとり、ベンゼンを加え３回ロータリーエバポレータ
で減圧濃縮した。４−ジメチルアミノピリジン３００．
４ｍｇ（２．４６ｍｍｏｌ）をいれ、アルゴン置換した
後、ジメチルホルムアミド２ｍＬを加え攪はんし、先の
ｔ−ブチルジメチルシリルクロリドのジメチルホルムア
ミド溶液１２．７ｍＬ（ｔ−ブチルジメチルシリルクロ
リド２．３６ｍｍｏｌ）を加え室温で４０時間攪はんし
た。反応終了後、水を加え酢酸エチル−ヘキサン（１：
４）混合溶媒で３回抽出した。有機層を無水硫酸ナトリ
ウムに通した後減圧濃縮した。薄層クロマトグラフィー
（展開溶媒、メタノール：ベンゼン＝１．５：９８．
５）で精製して、Ｃ７，Ｃ２４，Ｃ２７−トリシリル体
（６）６４．９ｍｇ（５５．９μｍｏｌ）を得た。T-Butyldimethylsilyl chloride 55
After 9.9 mg (3.72 mmol) was placed in an eggplant-shaped flask and purged with argon, 20 mL of dimethylformamide was added.
Dissolved in. Known methyl ester (5) (Tachib
ana, K. et al., J. Am. Chem. Soc., 103, 2496 (198
1)) 50.3 mg (61.5 μmol) was placed in a side-branched flask, benzene was added, and the mixture was concentrated under reduced pressure three times with a rotary evaporator. 4-dimethylaminopyridine 300.
After adding 4 mg (2.46 mmol) and substituting with argon, 2 mL of dimethylformamide was added and stirred, and 12.7 mL of a dimethylformamide solution of the above t-butyldimethylsilyl chloride (t-butyldimethylsilyl chloride 2.36 mmol). Was added and the mixture was stirred at room temperature for 40 hours. After the reaction was completed, water was added and ethyl acetate-hexane (1:
4) The mixed solvent was extracted 3 times. The organic layer was passed through anhydrous sodium sulfate and then concentrated under reduced pressure. Thin layer chromatography (developing solvent, methanol: benzene = 1.5: 98.
Purification in 5) yielded 64.9 mg (55.9 μmol) of C7, C24, C27-trisilyl compound (6).

【００１９】1H-NMR(CDCl3,400MHz) :δ5.39(1H,s,H-4
1), 5.06(1H,s,H-41), 4.21(1H,br.t,J=9.6Hz,H-27),
4.06(1H,d,J=8.8Hz,H-26), 3.92(1H,d,J=9.6Hz,H-24),
3.46(1H,dd,J=5.6,11.2Hz,H-7). 1 H-NMR (CDCl 3 , 400 MHz): δ5.39 (1H, s, H-4
1), 5.06 (1H, s, H-41), 4.21 (1H, br.t, J = 9.6Hz, H-27),
4.06 (1H, d, J = 8.8Hz, H-26), 3.92 (1H, d, J = 9.6Hz, H-24),
3.46 (1H, dd, J = 5.6,11.2Hz, H-7).

【００２０】[0020]

【化８】 [Chemical 8]

【００２１】Ｃ７，Ｃ２４，Ｃ２７−トリシリル体
（６）６４．９ｍｇ（６１．５μｍｏｌ）を５０ｍＬの
枝付きフラスコにとり、ベンゼンを加え減圧濃縮した。
アルゴン置換した後、ジメチルスルホキシド４．２５ｍ
Ｌを加え攪はんした。無水酢酸１２．７ｍｌを加え室温
で４８時間攪はんした。反応終了後、無水酢酸を留去す
るためにトルエンを加え減圧濃縮した。水を加え酢酸エ
チル−ヘキサン（１：４）混合溶媒で３回抽出した。有
機層を無水硫酸ナトリウムに通した後減圧濃縮した。薄
層クロマトグラフィー（展開溶媒、メタノール：ベンゼ
ン＝１：９９）で精製して、Ｃ２−メチルチオメチル−
Ｃ７，Ｃ２４，Ｃ２７−トリシリル体（７）５４．１ｍ
ｇ（４４．３μｍｏｌ）を得た。64.9 mg (61.5 μmol) of C7, C24, C27-trisilyl compound (6) was placed in a 50 mL side-armed flask, benzene was added and the mixture was concentrated under reduced pressure.
After substituting with argon, dimethyl sulfoxide 4.25 m
L was added and stirred. 12.7 ml of acetic anhydride was added, and the mixture was stirred at room temperature for 48 hours. After the reaction was completed, toluene was added to distill off acetic anhydride, and the mixture was concentrated under reduced pressure. Water was added, and the mixture was extracted 3 times with a mixed solvent of ethyl acetate-hexane (1: 4). The organic layer was passed through anhydrous sodium sulfate and then concentrated under reduced pressure. Purification by thin-layer chromatography (developing solvent, methanol: benzene = 1: 99) gave C2-methylthiomethyl-
C7, C24, C27-trisilyl compound (7) 54.1 m
g (44.3 μmol) was obtained.

【００２２】1H-NMR(CDCl3,400MHz) :δ5.30(1H,s,H-4
1), 4.98(1H,s,H-41), 4.52(1H,d,J=10.6Hz,2-O-CH2),
4.41(1H,d,J=10.6Hz,2-O-CH2), 4.20(1H,br.t,J=8.8Hz,
H-27),4.04(1H,d,J=8.1Hz,H-26), 3.90(1H,d,J=9.5Hz,H
-24), 3.46(1H,dd,J=5.6,11.4Hz,H-7), 2.16(3H,s,S-M
e), 1.45(3H,s,2-Me). 1 H-NMR (CDCl 3 , 400 MHz): δ5.30 (1H, s, H-4
1), 4.98 (1H, s, H-41), 4.52 (1H, d, J = 10.6Hz, 2-O-CH 2 ),
4.41 (1H, d, J = 10.6Hz, 2-O-CH 2 ), 4.20 (1H, br.t, J = 8.8Hz,
H-27), 4.04 (1H, d, J = 8.1Hz, H-26), 3.90 (1H, d, J = 9.5Hz, H
-24), 3.46 (1H, dd, J = 5.6,11.4Hz, H-7), 2.16 (3H, s, SM
e), 1.45 (3H, s, 2-Me).

【００２３】[0023]

【化９】 [Chemical 9]

【００２４】Ｃ２−メチルチオメチル−Ｃ７，Ｃ２４，
Ｃ２７−トリシリル体（７）５４．１ｍｇ（４４．３μ
ｍｏｌ）を３０ｍＬ容のナス型フラスコにとりジメチル
ホルムアミド３ｍＬを加え、−６０℃で攪はんした。テ
トラブチルアンモニウムフロリド（１Ｍテトラヒドロフ
ラン溶液）２．０ｍＬを加え２時間で−６０℃から−５
℃まで温度を上げながら攪はんした。その後薄層クロマ
トグラフィーにより反応を確認しつつ温度を−５℃に保
ち更に２時間攪はんした。テトラヒドロフランを留去す
るために反応液を減圧濃縮した。その後水を加え酢酸エ
チル−ヘキサン（１：４）混合溶媒で３回抽出した。有
機層を無水硫酸ナトリウムに通した後減圧濃縮した。薄
層クロマトグラフィー（展開溶媒、酢酸エチル：ベンゼ
ン＝１：９）で精製して、Ｃ２−メチルチオメチル−Ｃ
７，Ｃ２７−ジシリル体（８）３８．０ｍｇ（３４．４
μｍｏｌ）を得た。C2-methylthiomethyl-C7, C24,
54.1 mg (44.3 μ) of C27-trisilyl compound (7)
(mol) was placed in a 30 mL eggplant-shaped flask, 3 mL of dimethylformamide was added, and the mixture was stirred at -60 ° C. Tetrabutylammonium fluoride (1M tetrahydrofuran solution) (2.0 mL) was added, and the temperature was changed from -60 ° C to -5 in 2 hours.
The mixture was stirred while raising the temperature to ℃. Then, while confirming the reaction by thin layer chromatography, the temperature was kept at -5 ° C and further stirred for 2 hours. The reaction solution was concentrated under reduced pressure to distill off tetrahydrofuran. After that, water was added and the mixture was extracted 3 times with a mixed solvent of ethyl acetate-hexane (1: 4). The organic layer was passed through anhydrous sodium sulfate and then concentrated under reduced pressure. Purification by thin layer chromatography (developing solvent, ethyl acetate: benzene = 1: 9) gave C2-methylthiomethyl-C.
7, C27-disilyl compound (8) 38.0 mg (34.4)
μmol) was obtained.

【００２５】1H-NMR(CDCl3,400MHz) :δ5.31(1H,s,H-4
1), 5.01(1H,s,H-41), 4.52(1H,d,J=10.6Hz,2-O-CH2),
4.45(1H,d,J=10.6Hz,2-O-CH2), 4.15(1H,br.t,J=7.9Hz,
H-27),4.06(1H,d,J=7.4Hz,H-26), 4.02(1H,d,J=8.1Hz,H
-24), 3.46(1H,dd,J=5.6,11.4Hz,H-7), 2.17(3H,s,S-M
e), 1.46(3H,s,2-Me). 1 H-NMR (CDCl 3 , 400 MHz): δ5.31 (1H, s, H-4
1), 5.01 (1H, s, H-41), 4.52 (1H, d, J = 10.6Hz, 2-O-CH 2 ),
4.45 (1H, d, J = 10.6Hz, 2-O-CH 2 ), 4.15 (1H, br.t, J = 7.9Hz,
H-27), 4.06 (1H, d, J = 7.4Hz, H-26), 4.02 (1H, d, J = 8.1Hz, H
-24), 3.46 (1H, dd, J = 5.6,11.4Hz, H-7), 2.17 (3H, s, SM
e), 1.46 (3H, s, 2-Me).

【００２６】[0026]

【化１０】 [Chemical 10]

【００２７】Ｃ２−メチルチオメチル−Ｃ７，Ｃ２７−
ジシリル体（８）３０．０ｍｇ（２７．１μｍｏｌ）を
３０ｍＬ容のナス型フラスコにとりジオキサン１．８ｍ
Ｌを加え、室温で攪はんした。水酸化リチウム水溶液
（０．３７Ｍ）０．６ｍＬを加え６時間攪はんした。反
応終了後、飽和塩化アンモニウム水溶液を加えｐＨを７
から８にした。ジオキサンを留去するために反応液を減
圧濃縮した。水を加えクロロホルムで３回抽出した。有
機層を無水硫酸ナトリウムに通した後減圧濃縮した。薄
層クロマトグラフィー（展開溶媒、メタノール：クロロ
ホルム＝２：９８）で精製して、モノヒドロキシカルボ
ン酸体（９）２６．８ｍｇ（２４．５μｍｏｌ）を得
た。C2-methylthiomethyl-C7, C27-
30.0 mg (27.1 μmol) of the disilyl compound (8) was placed in a 30 mL eggplant-shaped flask and 1.8 m of dioxane was added.
L was added and the mixture was stirred at room temperature. 0.6 mL of an aqueous lithium hydroxide solution (0.37M) was added, and the mixture was stirred for 6 hours. After the reaction was completed, saturated aqueous ammonium chloride solution was added to adjust the pH to 7
Changed to 8. The reaction solution was concentrated under reduced pressure to distill off dioxane. Water was added and the mixture was extracted 3 times with chloroform. The organic layer was passed through anhydrous sodium sulfate and then concentrated under reduced pressure. Purification by thin layer chromatography (developing solvent, methanol: chloroform = 2: 98) gave 26.8 mg (24.5 μmol) of monohydroxycarboxylic acid compound (9).

【００２８】1H-NMR(CDCl3,400MHz) :δ5.34(1H,s,H-4
1), 5.01(1H,s,H-41), 4.63(1H,d,J=10.3Hz,2-O-CH2),
4.48(1H,d,J=10.3Hz,2-O-CH2), 4.15(1H,br.t,J=8.1Hz,
H-27),4.06(1H,d,J=7.4Hz,H-26), 3.96(1H,d,J=9.5Hz,H
-24), 3.46(1H,dd,J=5.6,11.4Hz,H-7), 2.17(3H,s,S-M
e), 1.37(3H,s,2-Me). 1 H-NMR (CDCl 3 , 400 MHz): δ5.34 (1H, s, H-4
1), 5.01 (1H, s, H-41), 4.63 (1H, d, J = 10.3Hz, 2-O-CH 2 ),
4.48 (1H, d, J = 10.3Hz, 2-O-CH 2 ), 4.15 (1H, br.t, J = 8.1Hz,
H-27), 4.06 (1H, d, J = 7.4Hz, H-26), 3.96 (1H, d, J = 9.5Hz, H
-24), 3.46 (1H, dd, J = 5.6,11.4Hz, H-7), 2.17 (3H, s, SM
e), 1.37 (3H, s, 2-Me).

【００２９】[0029]

【化１１】 [Chemical 11]

【００３０】モノヒドロキシカルボン酸体（９）２６．
８ｍｇ（２４．５μｍｏｌ）を枝付きフラスコにとり、
ベンゼンを加え減圧濃縮した。アルゴン置換した後、テ
トラヒドロフラン４．８ｍＬを加え室温で攪はんした。
塩基性アルミナを通したトリエチルアミン０．３６ｍＬ
（２．３ｍｍｏｌ）を加え室温で１時間攪はんした。
２，４，６−トリクロロベンゾイルクロリドのテトラヒ
ドロフラン溶液０．５９ｍＬ（２，４，６−トリクロロ
ベンゾイルクロリド９４．４μｍｏｌ相当）を先の反応
容器に加え、室温で攪はんし、１２．５時間後薄層クロ
マトグラフィー（展開溶媒、酢酸エチル：ベンゼン＝
１：９）により原料のスポットが消失したことを確認し
た。Monohydroxycarboxylic acid derivative (9) 26.
Take 8 mg (24.5 μmol) in a sidearm flask,
Benzene was added and the mixture was concentrated under reduced pressure. After replacing with argon, 4.8 mL of tetrahydrofuran was added and the mixture was stirred at room temperature.
0.36 mL of triethylamine through basic alumina
(2.3 mmol) was added, and the mixture was stirred at room temperature for 1 hr.
0.54 mL of a solution of 2,4,6-trichlorobenzoyl chloride in tetrahydrofuran (corresponding to 2,4,6-trichlorobenzoyl chloride 94.4 μmol) was added to the above reaction vessel and stirred at room temperature for 12.5 hours. Thin layer chromatography (developing solvent, ethyl acetate: benzene =
It was confirmed that the spot of the raw material disappeared by 1: 9).

【００３１】４−ジメチルアミノピリジン１２９．１ｍ
ｇ（１．９６ｍｍｏｌ）を三口フラスコにとり、アルゴ
ン置換した後、トルエン４５ｍＬを加え、９２℃で１２
時間加温攪はんした。その後７２℃まで温度を下げて３
時間攪はんした。先の反応容器中にトルエン１５５ｍＬ
を加えて、４−ジメチルアミノピリジンを含むトルエン
溶液に高希釈条件下滴下した。滴下終了後７２℃で５日
間攪はんした。薄層クロマトグラフィーにより反応が完
了したことを確認した後に、反応溶液に水を加え水で３
回洗浄した。この洗浄液（水）を更にクロロホルムで３
回抽出した。トルエン層とクロロホルム抽出液を合わせ
て無水硫酸ナトリウムに通した後減圧濃縮して白色粉末
を得た。薄層クロマトグラフィー（展開溶媒、酢酸エチ
ル：ベンゼン＝１：９）で精製して、Ｃ２−メチルチオ
メチル−Ｃ７，Ｃ２７−ジシリルラクトン体（４）１
０．８ｍｇ（１０．１μｍｏｌ）を得た。4-Dimethylaminopyridine 129.1 m
g (1.96 mmol) was placed in a three-necked flask and purged with argon, then 45 mL of toluene was added, and the mixture was added at 92 ° C. for 12 hours.
Heated and stirred for hours. Then lower the temperature to 72 ° C and
I stirred the time. 155 mL of toluene in the previous reaction vessel
And was added dropwise to a toluene solution containing 4-dimethylaminopyridine under high dilution conditions. After the completion of dropping, the mixture was stirred at 72 ° C for 5 days. After confirming the completion of the reaction by thin layer chromatography, water was added to the reaction solution and the mixture was mixed with water.
Washed twice. This washing solution (water) was further mixed with chloroform to 3 times.
Extracted twice. The toluene layer and the chloroform extract were combined, passed through anhydrous sodium sulfate, and concentrated under reduced pressure to give a white powder. Purification by thin layer chromatography (developing solvent, ethyl acetate: benzene = 1: 9) to give C2-methylthiomethyl-C7, C27-disilyl lactone (4) 1.
0.8 mg (10.1 μmol) was obtained.

【００３２】1H-NMR(CDCl3,400MHz) :δ5.69(1H,dd,J=
6.6,15.0Hz,H-14), 5.49(1H,dd,J=8.1,15.0Hz,H-15),
5.27(1H,d,J=10.3Hz,H-24), 5.21(1H,s,H-41), 2.02(1
H,s,H-41), 4.52(1H,d,J=10.6Hz,2-O-CH2), 4.49(1H,d,
J=10.6Hz,2-O-CH2), 4.16(1H,br.t,J=7.7Hz,H-27), 4.0
6(1H,d,J=6.9Hz,H-26), 3.50(1H,dd,J=5.8,10.7Hz,H-
7), 2.18(3H,s,S-Me), 1.56(3H,s,2-Me). FAB-MS(m/z): 1027(M++1-48). 1 H-NMR (CDCl 3 , 400 MHz): δ5.69 (1 H, dd, J =
6.6,15.0Hz, H-14), 5.49 (1H, dd, J = 8.1,15.0Hz, H-15),
5.27 (1H, d, J = 10.3Hz, H-24), 5.21 (1H, s, H-41), 2.02 (1
H, s, H-41), 4.52 (1H, d, J = 10.6Hz, 2-O-CH 2 ), 4.49 (1H, d,
J = 10.6Hz, 2-O-CH 2 ), 4.16 (1H, br.t, J = 7.7Hz, H-27), 4.0
6 (1H, d, J = 6.9Hz, H-26), 3.50 (1H, dd, J = 5.8,10.7Hz, H-
7), 2.18 (3H, s, S-Me), 1.56 (3H, s, 2-Me). FAB-MS (m / z): 1027 (M + + 1-48).

【００３３】実施例２ Ｃ２−メチルチオメチルラクトン体（３）の合成Example 2 Synthesis of C2-methylthiomethyl lactone (3)

【００３４】[0034]

【化１２】 [Chemical 12]

【００３５】アセトニトリル８．６ｍＬを三角フラスコ
にとり、水０．９ｍＬと４６％フッ化水素水溶液０．５
ｍＬを加えた溶液を調製した。Ｃ２−メチルチオメチル
−Ｃ７，Ｃ２７−ジシリルラクトン体（４）９．３ｍｇ
（８．６μｍｏｌ）をナス型フラスコにとりテトラヒド
ロフラン１．０ｍＬを加え室温で攪はんした。反応溶液
中に先の含水フッ化水素アセトニトリル溶液２．０ｍＬ
を加え、更に室温で４時間攪はんした。薄層クロマトグ
ラフィーにより反応が完了したことを確認した後に、飽
和塩化アンモニウム水溶液を加えｐＨを７から８にし
た。反応溶液を減圧濃縮した。水を加えクロロホルムで
３回抽出した。有機層を無水硫酸ナトリウムに通した後
減圧濃縮した。薄層クロマトグラフィー（展開溶媒、メ
タノール：クロロホルム＝４：９６）で精製して、Ｃ２
−メチルチオメチルラクトン体（３）３．７ｍｇ（４．
４μｍｏｌ）を得た。Transfer 8.6 mL of acetonitrile to an Erlenmeyer flask and add 0.9 mL of water and 0.5% of 46% hydrogen fluoride aqueous solution.
A solution containing mL was prepared. C2-methylthiomethyl-C7, C27-disilyl lactone form (4) 9.3 mg
(8.6 μmol) was placed in an eggplant-shaped flask, 1.0 mL of tetrahydrofuran was added, and the mixture was stirred at room temperature. 2.0 mL of the above hydrous hydrogen fluoride acetonitrile solution in the reaction solution
Was added, and the mixture was further stirred at room temperature for 4 hours. After confirming the completion of the reaction by thin layer chromatography, a saturated aqueous ammonium chloride solution was added to adjust the pH to 7-8. The reaction solution was concentrated under reduced pressure. Water was added and the mixture was extracted 3 times with chloroform. The organic layer was passed through anhydrous sodium sulfate and then concentrated under reduced pressure. Purified by thin layer chromatography (developing solvent, methanol: chloroform = 4: 96) to obtain C2
-Methylthiomethyl lactone form (3) 3.7 mg (4.
4 μmol) was obtained.

【００３６】1H-NMR(CDCl3,400MHz) :δ5.69(1H,dd,J=
7.2,15.2Hz,H-14), 5.49(1H,dd,J=8.2,15.2Hz,H-15),
5.43(1H,d,J=9.5Hz,H-24), 5.36(1H,s,H-41), 5.05(1H,
s,H-41),4.56(1H,d,J=10.3Hz,2-O-CH2), 4.51(1H,d,J=1
0.3Hz,2-O-CH2), 4.13(1H,br.t,J=9.9Hz,H-27), 3.97(1
H,d,J=9.2Hz,H-26), 3.44(1H,dd,J=4.8,11.0Hz,H-7),
2.19(3H,s,S-Me), 1.58(3H,s,2-Me). FAB-MS(m/z): 869(M++Na), 847(M++1), 829(M++1-18),
811(M++1-18-18), 781(M++1-48-18), 763(M++1-48-18-1
8). 1 H-NMR (CDCl 3 , 400 MHz): δ5.69 (1 H, dd, J =
7.2,15.2Hz, H-14), 5.49 (1H, dd, J = 8.2,15.2Hz, H-15),
5.43 (1H, d, J = 9.5Hz, H-24), 5.36 (1H, s, H-41), 5.05 (1H,
s, H-41), 4.56 (1H, d, J = 10.3Hz, 2-O-CH 2 ), 4.51 (1H, d, J = 1
0.3Hz, 2-O-CH 2 ), 4.13 (1H, br.t, J = 9.9Hz, H-27), 3.97 (1
H, d, J = 9.2Hz, H-26), 3.44 (1H, dd, J = 4.8,11.0Hz, H-7),
2.19 (3H, s, S-Me), 1.58 (3H, s, 2-Me). FAB-MS (m / z): 869 (M + + Na), 847 (M + +1), 829 (M + + 1-18),
811 (M + + 1-18-18), 781 (M + + 1-48-18), 763 (M + + 1-48-18-1
8).

【００３７】実施例３ オカダ酸ラクトン（２）の合成Example 3 Synthesis of okadaic acid lactone (2)

【００３８】[0038]

【化１３】 [Chemical 13]

【００３９】Ｃ２−メチルチオメチルラクトン体（３）
２．８ｍｇ（３．３μｍｏｌ）を枝付きフラスコにと
り、ベンゼンを加え減圧濃縮した。アルゴン置換した
後、塩基性アルミナを通したジクロロメタン１．０ｍＬ
を加え室温で１５分間攪はんした。トリフェニルカルベ
ニウムテトラフロロボレートのジクロロメタン溶液０．
１ｍＬ（トリフェニルカルベニウムテトラフロロボレー
ト３．７１μｍｏｌ）を先の反応容器へ加え攪はんし
た。３時間後、さらにトリフェニルカルベニウムテトラ
フロロボレートのジクロロメタン溶液０．１ｍＬ（トリ
フェニルカルベニウムテトラフロロボレート３．９７μ
ｍｏｌ）を先の反応容器へ加え攪はんした。２時間後、
反応溶液に水を加えクロロホルムで３回抽出した。クロ
ロホルム抽出液を無水硫酸ナトリウムに通した後減圧濃
縮して白色粉末を得た。薄層クロマトグラフィー（展開
溶媒、メタノール：クロロホルム＝４：９６）で精製し
て、オカダ酸ラクトン（２）１．３ｍｇ（１．７μｍｏ
ｌ）を得た。C2-methylthiomethyl lactone form (3)
2.8 mg (3.3 μmol) was placed in a side-armed flask, benzene was added, and the mixture was concentrated under reduced pressure. After substituting with argon, 1.0 mL of dichloromethane passed through basic alumina
Was added and the mixture was stirred at room temperature for 15 minutes. Triphenylcarbenium tetrafluoroborate solution in dichloromethane
1 mL (triphenylcarbenium tetrafluoroborate 3.71 μmol) was added to the above reaction vessel and stirred. After 3 hours, 0.1 mL of a solution of triphenylcarbenium tetrafluoroborate in dichloromethane (triphenylcarbenium tetrafluoroborate 3.97 μm) was added.
(mol) was added to the above reaction vessel and stirred. Two hours later,
Water was added to the reaction solution and the mixture was extracted 3 times with chloroform. The chloroform extract was passed through anhydrous sodium sulfate and then concentrated under reduced pressure to obtain a white powder. Purification by thin layer chromatography (developing solvent, methanol: chloroform = 4: 96) gave 1.3 mg (1.7 μmo) of okadaic acid lactone (2).
l) was obtained.

【００４０】1H-NMR(CDCl3,400MHz) :δ5.69(1H,dd,J=
7.7,15.4Hz,H-14), 5.49(1H,dd,J=8.1,15.4Hz,H-15),
5.40(1H,d,J=9.9Hz,H-24), 5.33(1H,s,H-41), 5.02(1H,
s,H-41),4.11(1H,br.t,J=9.9Hz,H-27), 3.96(1H,d,J=9.
8Hz,H-26), 3.39(1H,dd,J=4.7,10.5Hz,H-7), 1.53(3H,
s,2-Me). FAB-MS(m/z): 809(M++Na), 769(M++1-18), 751(M++1-18
-18). 1 H-NMR (CDCl 3 , 400 MHz): δ5.69 (1 H, dd, J =
7.7,15.4Hz, H-14), 5.49 (1H, dd, J = 8.1,15.4Hz, H-15),
5.40 (1H, d, J = 9.9Hz, H-24), 5.33 (1H, s, H-41), 5.02 (1H,
s, H-41), 4.11 (1H, br.t, J = 9.9Hz, H-27), 3.96 (1H, d, J = 9.
8Hz, H-26), 3.39 (1H, dd, J = 4.7,10.5Hz, H-7), 1.53 (3H,
FAB-MS (m / z): 809 (M + + Na), 769 (M + + 1-18), 751 (M + + 1-18)
-18).

【００４１】試験例１ マウスリンパ性白血病細胞（Ｐ３８８）を２−ヒドロキ
シエチルジスルフィド５μＭ、硫酸カナマイシン１００
μｇ／ｍＬを添加した１０％牛胎児血清含有のＲＰＭＩ
−１６４０培地に加え、培養細胞を１ｘ１０4 個／ｍＬ
に調製し、前記（２）及びオカダ酸を所定の濃度になる
ように添加し、ＣＯ2 培養器（ＣＯ2 ５％、湿度１００
％、３７℃）で４日間培養した。ＭＴＴ比色法により生
存細胞数を計測して、対照群に対する増殖阻害率から５
０％細胞増殖阻害濃度（ＩＣ50）を求めたところ、ＩＣ
50は３６μｇ／ｍＬであった。Test Example 1 Mouse lymphocytic leukemia cells (P388) were treated with 2-hydroxyethyl disulfide 5 μM and kanamycin sulfate 100.
RPMI containing 10% fetal bovine serum supplemented with μg / mL
Add 1 × 10 4 cells / mL to -1640 medium
And adding the above (2) and okadaic acid to a predetermined concentration, and adding a CO 2 incubator (CO 2 5%, humidity 100).
%, 37 ° C.) for 4 days. The number of surviving cells was measured by the MTT colorimetric method, and the growth inhibition rate was 5 based on
When the 0% cell growth inhibitory concentration (IC 50 ) was determined, IC
50 was 36 μg / mL.

【００４２】[0042]

【発明の効果】本発明のオカダ酸ラクトン誘導体は弱い
ながら抗腫瘍活性を示す。したがって、抗腫瘍剤、とく
に、生体内のエステラーゼ活性の高い部位もしくは塩基
加水分解の起こり得る部位（例えば腸管内）等で特異的
に高い抗腫瘍活性が発現されると考えられ、局所抗腫瘍
剤として有用と期待される。また、マスクされたオカダ
酸として働き、生体内において局在するプロティンフォ
スファターゼ１、２Ａの特定と機能の関係を解明するた
めの試薬としても利用しうる。The okadaic acid lactone derivative of the present invention exhibits antitumor activity although it is weak. Therefore, it is considered that an antitumor agent, in particular, a high antitumor activity is specifically expressed at a site having a high esterase activity in a living body or a site where base hydrolysis may occur (for example, in the intestinal tract), and a local antitumor agent. Expected to be useful as It also acts as a masked okadaic acid and can be used as a reagent for elucidating the relationship between the identification and function of protein phosphatases 1 and 2A localized in vivo.

Claims (1)

【特許請求の範囲】[Claims] 【請求項１】 一般式 【化１】 （式中、Ｒ1 、Ｒ2 、Ｒ3 は水素原子または水酸基の保
護基を表す）で表されるオカダ酸ラクトン誘導体。1. A general formula: (In the formula, R 1 , R 2 , and R 3 represent a hydrogen atom or a hydroxyl-protecting group), and an okadaic acid lactone derivative represented by the formula.
JP6064410A 1994-03-09 1994-03-09 Okadaic acid lactone derivative Pending JPH07247291A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP6064410A JPH07247291A (en) 1994-03-09 1994-03-09 Okadaic acid lactone derivative

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
JP6064410A JPH07247291A (en) 1994-03-09 1994-03-09 Okadaic acid lactone derivative

Publications (1)

Publication Number Publication Date
JPH07247291A true JPH07247291A (en) 1995-09-26

Family

ID=13257511

Family Applications (1)

Application Number Title Priority Date Filing Date
JP6064410A Pending JPH07247291A (en) 1994-03-09 1994-03-09 Okadaic acid lactone derivative

Country Status (1)

Country Link
JP (1) JPH07247291A (en)

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