JPH0239506B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel bisbibenzyl diether derivatives and salts thereof.

The bisbibenzyl diether derivative of the present invention is
This is a new compound that has not been published in any literature and is represented by the following general formula (1).

[In the formula, R ¹ represents a hydroxyl group, a lower alkoxy group, or a lower alkanoyloxy group. R ² , R ³ , R ⁴ ,
R ⁵ and R ⁶ represent a hydrogen atom, a hydroxyl group, a lower alkoxy group or a lower alkanoyloxy group. R ¹
and R ² may be bonded to each other to form a methylenedioxy group. -E- is bonded to the 2nd or 3rd position of the C ring and the 4' or 5' position of the D ring, and E may or may not be connected through an oxygen atom. Moreover, the -E- bond may not be present. ] In this specification, examples of lower alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy groups, etc., and examples of lower alkanoyloxy groups include:
Examples include formyloxy, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pentanoyloxy, tert-butylcarbonyloxy, and hexanoyloxy groups.

The compound of the present invention represented by the above general formula (1) is:
It has excellent anticancer effects and is useful as an anticancer agent. Furthermore, the compounds of the present invention have low toxicity and
It is characterized by extremely low side effects.

The compound of the present invention is extracted and isolated from, for example, Merchantia polymorpha, Reboulia hemisphaerica, Riccardia multifida, Radula perrottetiana, and the like.

There are no particular limitations on the extraction and isolation method for the compound of the present invention, and ordinary separation means that utilize the physicochemical properties of the compound of general formula (1) above can be used, such as methods that utilize the solubility difference with the solvent. This can be carried out by a solvent extraction method, a column chromatography method that takes advantage of the difference in adsorption affinity for an adsorbent, a countercurrent distribution method that takes advantage of the difference in distribution ratio between two liquid phases, or a suitable combination of these methods. Examples of the extraction solvent include water, lower alcohols such as methanol, ethanol, and isopropanol, ethyl acetate, and mixed solvents thereof. Examples of the adsorbent include activated carbon, silica gel, cation exchange resin, and alumina.

Among the compounds of the above general formula (1), the compound in which at least one of R ¹ to ^{R 6} has a lower alkanoyloxy group is a compound in which at least one of the corresponding R ¹ to ^{R 6} has a hydroxyl group. It is produced by acylating. For this acylation, a wide range of reaction conditions for ordinary acylation reactions can be employed. As the acylating agent, a wide variety of conventionally known ones can be used, and examples thereof include lower alkanoic acid anhydrides such as acetic anhydride, lower alkanoic acid halides such as acetyl chloride, and propionyl bromide. The amount of such an acylating agent to be used is not particularly limited and can be appropriately selected within a wide range, but it is usually used in an amount of at least equimolar to the raw material, usually in excess, to replace one hydroxyl group of the raw material compound. It is better. When using an acid anhydride or an acid halide as an acylating agent, the acylation reaction is preferably carried out in the presence of a basic compound. Examples of basic compounds include alkali metals such as sodium metal and potassium metal, hydroxides of these alkali metals,
Examples include carbonates or bicarbonates, alkyl lithiums, and tertiary amine compounds such as pyridine, N-methylpiperidine, and triethylamine.
The acylation reaction is carried out in any suitable solvent. Examples of solvents include ketones such as acetone and methyl ethyl ketone, ethers such as ether, dioxane, and tenarahydrofuran, aromatic hydrocarbons such as benzene, toluene, and xylene;
Pyridine, dimethylformamide, dimethyl sulfoxide, hexamethyl phosphoric triamide, 1,
Examples include 2-dimethoxyethane.
The reaction proceeds either under cooling, at room temperature, or under heating, but it is usually preferable to carry out the reaction at -10 to 80°C.

The above reaction is generally completed in about 2 to 24 hours.

Among the compounds of the above general formula (1), the compound in which at least one of R ¹ to ^{R 6} has a lower alkoxy group is a compound in which at least one of the corresponding R ¹ to ^{R 6} has a hydroxyl group. Produced by alkylation. For this alkylation, a wide range of reaction conditions for ordinary alkylation reactions can be employed. For example, in the above-mentioned acylation reaction, an appropriate alkylating agent is used instead of the acylating agent, and the reaction temperature is between room temperature and
The reaction conditions for the above acylation reaction can be applied as they are, except that the temperature is 100°C. As the alkylating agent, a wide variety of conventionally known alkylating agents can be used, such as those represented by the general formula R ² 'X (2) [wherein R ² ' represents a lower alkyl group and X represents a halogen atom]. ], diazoalkanes such as diazomethane, dialkyl sulfates such as dimethyl sulfate, Meermein reagents such as trimethyl oxonium fluoroborate, and the like. Specific examples of the compound of general formula (2) include methyl iodide, methyl bromide, ethyl iodide, 1-propyl bromide, and 1-pentyl iodide. When using diazoalkanes or Meerwein's reagent as the alkylating agent, it is preferable to carry out the reaction at -80 to 50°C. Furthermore, when using diazoalkanes as an alkylating agent, compounds such as tetrafluoroboron hydride, p-toluenesulfonic acid, BF ₃ O(C ₂ H ₅ ) ₂ may be present in the reaction system. good.

Among the compounds of general formula (1) above, compounds in which R ¹ and R ² are bonded to each other to represent a methylenedioxy group are produced by subjecting the corresponding compounds in which R ¹ and R ² are hydroxyl groups to a methylene reaction. be done. For this methylenation reaction, the same reaction conditions as for the above-mentioned alkylation reaction can be employed, except that a reagent such as diiodomethane is used and the reaction is carried out at about 80 to 150°C. In this reaction, it is preferable to add a catalyst such as cupric oxide to the reaction system.

Among the compounds of general formula (1) produced in this way,
A compound having an acidic group can easily form a salt with a common pharmaceutically acceptable basic compound. Examples of such basic compounds include strong basic compounds such as sodium hydroxide, calcium hydroxide, and potassium hydroxide.

The compound of the present invention thus obtained can be easily isolated and purified by conventional separation means.
Examples of the separation means include solvent extraction, dilution, recrystallization, column chromatography, preparative thin layer chromatography, and the like.

Examples of manufacturing the compounds of the present invention are listed below.

Production example 1 100g of methanol extract of liverwort in 75cm x 5
Silica gel (Kieselgel) in a cm glass column
60, 35-70 mesh, Merck & Co., Ltd.) on a chromatograph packed with 250 g of n-hexane 1, 5% ethyl acetate/n-hexane 1, 10% 1, 20% 1, 30
%1.5, 50%2, 80%1, ethyl acetate2
It was eluted using Marchantin A, Marchantin B, and Marchantin C are included in the 30% elution fraction. This elution area
The 30 g was divided into 5 times, and the following chromatography was performed using 6 g each time. In other words, CHCl ₃ :CH ₃ OH (1:1V/
Elution was performed using the mixed solvent of V). As a result, a total of 14 g of eluate containing marcantein A, B, and C was obtained. This eluate was transferred to a 70 cm x 4 cm glass column again using silica gel (Kiesel 60, 70-230 mesh,
10 with a column chromatograph packed with 140 g of Merck & Co.
% ethyl acetate/n-hexane 0.5, 20% 1,
Elution was performed using 30% 2, ethyl acetate 1. Marcantein A, B, and C are contained in the 30% ethyl acetate eluate. 13g of this eluate was transferred to a 70cm x 4cm glass column using silica gel (Kieselgel 60, 70-
10% ethyl acetate/benzene 0.2, 30 on a column chromatograph packed with 230 mesh, Merck & Co., Ltd. 200 g.
Eluted with 1%, 1% 40%, and 1% ethyl acetate.
As a result, 0.5 g of Marcantein C was obtained from the 10% ethyl acetate eluate, and 10 g from the 30% ethyl acetate eluate.
1 g of marcantein A and 1 g of marcantein B were isolated from the 40% ethyl acetate eluate.

Marcantein A is represented by the following formula.

The physical properties of Marcantein A are as follows.

High resolution MS: C ₂₈ H ₂₄ O ₅ (M ⁺ , 440.1602, calculated value 440.1617) UV (EtOH): 217 nm (max) log ε4.95 275 nm log ε4.10 279 nm log ε4.07 IR (cm ^-1 ): 3590, 1620 , 1605, 1585, 1520,
1505, 1485, 1470, 1450, 1360, 1220,
1200, 1180, 1135, 1025 PMR (CDCl ₃ , ppm, 360MHz): 2.77 (m, 4H) 3.00 (m, 4H) 5.13 (d, J = 1.8Hz) 6.41 (ddd, J = 7.8, 1.5, 0.7Hz ) 6.47 (d, J = 1.8Hz) 6.55 (ddd, J = 7.8, 2.5, 0.7Hz) 6.58 (d, J = 8.5Hz) 6.58 (dd, J = 2.5, 1.5Hz) 6.87 (dd, J = 7.8 , 1.6Hz) 6.93 (d, J = 8.5Hz) 6.98 (dd, J = 7.8Hz) 7.02 (dd, J = 7.8, 1.6Hz) 7.15 (dd, J = 7.8Hz) Marcantein B is expressed by the following formula. It will be done.

The physical properties of Marcantein B are as follows.

PMR (CDCl ₃ , ppm, 360MHz): 2.78 (m, 4H) 2.95 (m, 4H) 5.13 (d, J = 1.8Hz) 6.41 (ddd, J = 7.8, 1.5, ~1Hz) 6.47 (d, J = 1.8Hz) 6.56 (dd, J = 2.3, 1.5Hz) 6.56 (ddd, J = 7.8, 2.3, ~1Hz) 6.58 (d, J = 8.5Hz) 6.85 (d, J = 8.5Hz) 6.92 (d, J = 8.5Hz) 6.93 (d, J = 8.5Hz) 6.99 (dd, J = 7.8Hz) Marcantein C is expressed by the following formula.

The physical properties of Marcantein C are as follows.

PMR (CDCl ₃ , ppm, 360MHz): 2.77-2.85 (m, 4H) 3.01 (m, 4H) 5.52 (d, J = 2Hz) 6.38 (ddd, J = 7.8, 1.5, 0.7Hz) 6.54 (ddd, J =7.8, 2.5, 0.7Hz) 6.60 (d, J = 8.5Hz) 6.62 (dd, J = 2.5, 1.5Hz) 6.74 (dd, J = 8.1, 2Hz) 6.87 (dd, J = 7.8, 1.6Hz) 6.88 (d, J=8.1Hz) 6.94 (d, J=8.5Hz) 6.98 (dd, J=7.8Hz) 7.02 (dd, J=7.8, 1.6Hz) 7.15 (dd, J=7.8Hz) Manufacturing example 2 Marukan 500 mg of Tein A, 3 ml of acetic anhydride and 3 ml of pyridine were stirred at 0°C for one day and night. The reaction mixture is then poured into water and extracted with ethyl ether. After drying the ethyl ether layer over sodium sulfate, the solvent was distilled off to obtain 480 mg of triacetate of marcantein A as a colorless oil.

The triacetate form of Marcantein A is represented by the following formula.

The physical properties of Marcantein A triacetate are as follows.

MS: C ₃₄ H ₃₀ O ₈ (M ⁺ , 566, 6.5%) m/z 43 (100%) 211 (44.5%) 227 (37.1%) 424 (31%) 440 (86.4%) 482 (78.3%) 508 (30.5%) 524 (50.5%) IR (cm ^-1 ): 1770, 1600, 1505, 1465, 1450,
1370, 1265, 1225, 1180 PMR (CDCl ₃ , ppm): 1.63 (s, 3H) 2.24 (s, 3H) 2.28 (s, 3H) 2.74 (m, 2H) 2.90 (m, 2H) 3.05 (bs, 4H) ) 5.69 (d, J=2) 6.41-7.10 (m, 12H) Production Example 3 500 mg of Marcantein A, 3 ml of methyl iodide, 2 g of potassium carbonate and 8 ml of acetone are refluxed for 8 hours. Thereafter, the solution is filtered and the solvent is distilled off. Water is then added to the residue and extracted with ether. The ether layer was dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain white crystals of trimethyl form of marcantein A.
Get 450mg.

The trimethyl form of Marcantein A is represented by the following formula.

The physical properties of the trimethyl form of Marcantein A are as follows.

MS: C ₃₁ H ₃₀ O ₅ (M ⁺ , 482, 100%) m/z 438 (1.4%) 451 (3%) 452 (3.3%) 453 (2.1%) 454 (1%) 467 (3.9%) IR (cm ^-1 ): 1615, 1590, 1510, 1475, 1450,
1425, 1350, 1335, 1265, 950, 900, 880 PMR (CDCl ₃ , ppm): 2.80 (bs, 4H) 3.00 (s, 4H) 3.62, 3.84, 3.86 (s, each3H) 5.28 (d, J = 2 , 1H) 6.30-7.10 (m, 12H) Production example 4 Marcantein A 500mg, potassium carbonate 1g,
Add 100 mg of cupric oxide and 1 ml of diiodomethane to 10 ml of dimethylformamide, and react at 120°C for 3 hours. After the reaction is complete, the reaction mixture is poured into water and extracted with ether. After drying the ether layer over anhydrous sodium sulfate, the solvent was distilled off to obtain 200 mg of methylenedioxy compound of marcantein A.

The methylenedioxy form of Marcantein A is represented by the following formula.

The physical properties of the methylenedioxy compound of Marcantein A are as follows.

MS: C ₂₉ H ₂₄ O ₅ (M ⁺ , 452, 100%) m/z 18 (30%) 104 (10.8%) 134 (20.8%) 211 (26.8%) 227 (20.2%) 241 (43.5%) PMR (CDCl ₃ , ppm) 2.74 (bs, 4H) 2.98 (bs, 4H) 4.86 (s, 1H, OH) 5.10 (d, J=2, 1H) 6.37−7.13 (m, 12H) 5.93 (s, 2H ) Production example 5 10g of methanol extract of C.
Using a chromatograph packed with 200 g of silica gel (Kieselgel 60, 35-70 mesh, Merck & Co.) in a cm x 5 cm glass column, 1 part of n-hexane, 1 part of 5% ethyl acetate/1 part of n-hexane, 1 part of 10%, 1 part of 20%,
Elution was performed using 50% 1, 80% 1, and ethyl acetate 1. Riccardin A (Riccardin A) is 10% ethyl acetate eluent, Riccardin B (Riccardin B)
are contained in the 20% ethyl acetate elution fraction. 1.5 g of the crude ricardein A eluate was transferred to a 40 cm x 2 cm glass column again using silica gel (Kieselgel 60, 70
0.3 g of ricardein A was isolated using a chromatograph packed with 80 g of 5% ethyl acetate/n-hexane as eluant. 2 g of the crude ricardein B eluate was transferred to a 40 cm x 2 cm glass column using silica gel (Kieselgel 60, 70-230).
In a chromatograph packed with 80g of
Ricardine B, 0.8 g, was isolated by elution with 10% ethyl acetate/n-hexane.

Ricardine A is represented by the following formula.

The physical properties of Ricardine A are as follows.

PMR (ppm, 400MHz): 5.33 (d, J=1.9, 1H) 5.35 (OH) 5.98 (OH) 6.18 (dd, J=7.7, 1.5, 1H) 6.36 (d, J=1.5, 1H) 6.69 (dd, J=8.1, 1.9, 1H) 6.70 (br, 2H) 6.75 (br, 1H) 6.75 (d, J=7.7, 1H) 6.82 (dd, J=8.5, 2.9, 1H) 6.83 (br, 1H) 6.88 (d, J=8.1, 1H) 6.98 (d, J=2.9, 1H) 7.05 (d, J=8.5, 1H) 2.88 (m, 2H) 3.04 (m, 1H) 2.65 (m, 1H) 2.70 (m, 2H) 2.60 (m, 2H) 3.82 (s, 3H) Ricardine B is represented by the following formula.

The physical properties of Ricardine B are as follows.

PMR (ppm, 400MHz): 2.70 (s, 4H) 2.78 (m, 4H) 5.64 (OH) 5.77 (OH) 5.98 (dd, J = 8.3, 1.9, 1H) 6.02 (d, J = 2.1, 1H) 6.03 (dd, J=2.4, 2.4, 1H) 6.17 (d, J=8.3, 1H) 6.63 (d, J=8.6, 2H) 6.67 (dd, J=8.3, 1.9, 1H) 6.70 (d, J=8.6 , 2H) 6.90 (dd, J = 8.3, 2.1, 1H) 6.93 (ddd, J = 7.8, 2.4, 0.8, 1H) 6.95 (d, J = 8.3, 1H) 7.06 (ddd, J = 7.8, 2.4, 0.8 , 1H) 7.32 (dd, J = 7.8, 7.8, 1H) Production Example 6 Ricardine B is treated in the same manner as in Production Example 3 to obtain the dimethyl form of Ricardine B.

The dimethyl form of Ricardine B is represented by the following formula.

The physical properties of the dimethyl form of Ricardine B are as follows.

PMR (ppm, 400MHz): 2.77 (s, 4H) 2.80 (bs, 4H) 3.77 (s, 3H) 3.85 (s, 3H) 5.98 (dd, J = 2.4, 2.4, 1H) 5.99 (dd, J = 8.0 , 1.9, 1H) 6.02 (d, J = 2.1, 1H) 6.17 (d, J = 8.0) 6.59 (d, J = 8.6, 2H) 6.66 (d, J = 1.9, 1H) 6.71 (d, J = 8.6 , 2H) 6.94 (d, J = 8.3, 1H) 6.95 (ddd, J = 8.0, 2.4, 1.1, 1H) 7.00 (dd, J = 8.3, 2.1, 1H) 7.04 (ddd, J = 8.0, 2.4, 1.1 , 1H) 7.31 (dd, J = 8.0, 8.0, 1H) Production example 7 10g of methanol extract of Zingasago moss was placed in a 70cm×
Fill a 5 cm glass column with silica gel (Kiesel gel)
Benzene 1, 5% ethyl acetate / benzene 1, 10% ethyl acetate 1, 20% 1, 30
Elution was performed using 1%, 1% 50%, and 1% ethyl acetate. Riccardin C is contained in the 30% ethyl acetate eluate. 1g of this elution area is again
Sephadex LH on a 70cm x 2cm glass column
- Filled with 20, 30g and CHCl ₃ as elution solvent -
Chromatography was carried out using CH ₃ OH, 1:1 (V/V) and 0.2 g of Ricardine C was isolated.

Ricardine C is represented by the following formula.

The physical properties of Ricardine C are as follows.

MS: C ₂₈ H ₂₄ O ₄ (M ⁺ , 424, 71%) m/z 91 (12%) 107 (17%) 149 (11%) 189 (16%) 197 (11%) 211 (100%) 212 (30%) 213 (27%) 425 [M+1] ⁺ (24%) IR (ν _nax , cm ^-1 ): 3600, 3560, 3400 (OH), 1605, 1590,
1515, 1510, 1490, 850, 818 (aromatic ring),
1445, 1440, 1340, 1270, 1190, 1165,
1110 PMR (δ, ppm): 2.60 (bs, 4H) 2.83 (bs, 4H) 4.95 (bs, 1H) 5.31 (d, 1H, J = 2Hz) 5.70 (bs, 1H) 6.15 (dd, 1H, J = 8.2Hz) 6.31 (d, 1H, J=2Hz) 6.81 (complex m, 10H) Production Example 8 Ricardine C is treated in the same manner as in Production Example 3 above to obtain a trimethyl form of Ricardine C.

The trimethyl form of Ricardine C is represented by the following formula.

The physical properties of the trimethyl form of Ricardine C are as follows.

MS: C ₃₁ H ₃₀ O ₄ (M ⁺ ,466,85%) m/z 90 (15%) 105 (11%) 121 (13%) 211 (16%) 225 (14%) 227 (12%) 233 (14%) 239 (100%) 240 (19%) 467 [M+1] ⁺ (51%) IR (ν _nax , cm ^-1 ): 1610, 1580, 1515, 1510, 1490, 1468,
1445, 1420, 1410, 1260, 1165, 1130,
1040, 1020, 980, 905, 875, 850, 660 PMR (δ, ppm): 2.71 (bs, 4H) 2.85 (bs, 4H) 3.61 (s, 3H) 3.81 (s, 3H) 3.90 (s, 3H) 5.33 (d, 1H, J = 2Hz) 6.18 (dd, 1H, J = 8.2Hz) 6.36 (bs, 1H) 6.58-7.05 (complex m, 10H) Production example 9 5g of methanol extract of P. fasciata was placed in a 70cm x 5
Silica gel (Kieselgel) in a cm glass column
n-hexane 1, 10% 1, 20% on a chromatograph packed with 100 g of n-hexane
Elution was performed using 2, 30% 1, 50% 1, 80% 1, and ethyl acetate 2. Perrottetin E and F are included in the 30% elution fraction. 3 g of this eluate was transferred to a 70 cm x 5 cm glass column filled with 100 g of silica gel (Kieselgel 60, 70-230 mesh, Merck & Co.) using a column chromatograph with 10% ethyl acetate/benzene 1, 20% 1, 30%.
It was eluted using %1. Perotetein E, F is
Contained in the 30% ethyl acetate elution fraction. This elution part 2
g is 80 g of silica gel (Kieselgel 60, 70-230 mesh, Merck & Co.) in a 40 cm x 2 cm glass column.
Chloroform in a column chromatograph packed with 0.5 g
, 5% methanol/chloroform 1, 10% 1
It was eluted. As a result, 0.8 g of perotetein E and 0.6 g of perotetein F were isolated from the 5% eluted portion.

Perotetein E is represented by the following formula.

The physical properties of Perotetein E are as follows.

MS: C ₂₈ H ₂₆ O ₄ (M ⁺ , 426, 29.3%) m/z 77 (14.4%) 79 (5.0%) 91 (11.3%) 105 (8.6%) 106 (5.7%) 107 (46.3%) 121 (14.2%) 199 (17.5%) 211 (21.8%) 212 (8.9%) 213 (5.6%) 319 (100%) 320 (22.2%) IR (cm ^-1 ): 3400, 3040, 2930, 2860, 1697,
1610, 1600, 1590, 1565, 1455, 1435,
1352, 1341, 1275, 1220, 1165, 1110,
1080, 1013, 1000, 945, 880, 830, 820,
802, 782, 755, 692 Perotetein F is represented by the following formula.

The structural formula of Perotetein F is PMR, and the production example is shown below.
It was identified from PMR etc. of the compound obtained in 11 (tetramethyl form of perotetein F).

Production Example 10 Perotetein E is treated in the same manner as in Production Example 3 above to obtain a trimethyl form of Perotetein E.

The trimethyl form of perotetein E is represented by the following formula.

The physical properties of the trimethyl form of perotetein E are as follows.

PMR (CDCl ₃ , ppm, 400NHz): 2.81 (bs, 4H) 2.88 (s, 4H) 6.67 (dd, J=2, ~2Hz) 6.72 (ddd, J=7.3, 2, ~1Hz) 6.73 (ddd, J=2, ~2, ~0.8Hz) 6.73 (ddd, J=7.3, ~2, ~1Hz) 6.74 (ddd, J=7.3, 2, ~1Hz) 6.76 (dd, J= ~1, ~1Hz) 6.79 (ddd, J=7.3, ~2, ~1Hz) 6.83 (d, 2H, J=8.6Hz) 6.90 (dd, J=2, ~1Hz) 6.90 (dd, J=2, ~1Hz) 7.09 (d , 2H, J = 8.6Hz) 7.17 (dd, J = 7.3, 7.3Hz) 7.19 (ddd, J = 7.3, 7.3, ~0.8Hz) Production Example 11 Perotetein F was treated in the same manner as in Production Example 3 above to produce perotetein. A tetramethyl form of F is obtained.

The tetramethyl form of perotetein F is represented by the following formula.

The physical properties of the tetramethyl form of perotetein F are as follows.

PMR (CDCl ₃ , ppm, 400MHz): 2.82 (m, 4H) 2.88 (s, 4H) 6.39 (d, J = 1.9Hz) 6.48 (d, J = 1.9Hz) 6.67 (dd, J = 2, ~2Hz ) 6.71 (dd, J = 2, ~2Hz) 6.72 (ddd, J = 8.1, 2, ~1Hz) 6.72 (ddd, J = 8.1, 2, ~1Hz) 6.73 (dd, J = 7.5, ~2, ~ 1Hz) 6.77 (ddd, J = 7.5, ~2, ~1Hz) 6.85 (d, 2H, J = 8.64Hz) 7.09 (d, 2H, J = 8.64Hz) 7.17 (dd, J = 7.5, 7.5Hz) 7.19 (dd, J=7.3, 7.3Hz) Pharmacological test KB cells were cultured in Eagle's minimal essential medium (Eagle's MEM) containing 10% caly serum. For the test, place 1 ml of culture medium, 0.1 ml of cell suspension, and 0.1 ml of drug solution in a glass test tube with a diameter of 15 mm and a major axis of 150 mm.
The test was carried out using an oblique test tube tube. Three test tubes were used for both the control group and the drug group. Culture is
_CO2 incubator (5% _CO2 in air) at 37℃
I went for 72 hours. Protein content was measured by Oyama and
This was carried out using the Folin-Ciocalteu reagent according to the method of Eagle (1956). Drug treatment of KB cells was performed at the same time as the start of the experiment.
The inhibition rate of protein synthesis is calculated as C-T/C-Co×100, where Co is the protein amount immediately before drug administration, and C and T are the protein amounts at the end of the experiment in the control group and drug administration group, and the 50% inhibition concentration is calculated as C-T/C-Co×100. was determined from the logarithmic concentration response curve. Since the sample was poorly soluble in water, it was dissolved in dimethyl sulfoxide and diluted with medium before use.

The _ED50 value of Marcantein A was 8.39ug/ml.

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ represents a hydroxyl group, a lower alkoxy group, or a lower alkanoyloxy group. R ² , R ³ , R ⁴ ,
R ⁵ and R ⁶ represent a hydrogen atom, a hydroxyl group, a lower alkoxy group or a lower alkanoyloxy group. R ¹
and R ² may be bonded to each other to form a methylenedioxy group. -E- is bonded to the 2nd or 3rd position of the C ring and the 4' or 5' position of the D ring, and E may or may not be connected through an oxygen atom. Moreover, the -E- bond may not be present. ] Bisbibenzyl diether derivatives and salts thereof.