KR100417624B1 - Novel Decursin Derivatives - Google Patents

Abstract

The present invention relates to a novel decusin derivative, which is an anticancer agent, wherein 3-methylbut-2-enoic acid-7-hydroxy-2,2-dimethylchroman-3-ester is prepared by the method of synthesizing deckersin. , Cis-2-methylbut-2-enoic acid-7-hydroxy-2,2-dimethylchroman-3-yl ester, and trans-2-methylbut-2-enoic acid-7-hydr Roxy-2,2-dimethylchroman-3-ylester, the novel decusin derivatives of the present invention do not have cytotoxicity against K562 cell lines and can inhibit the differentiation of K562 cell lines by pobolesters. That has an outstanding effect.

Description

Novel Decursin Derivatives

The present invention relates to a novel decusin derivative, and more particularly, the present invention relates to 3-methylbut-2-enoic acid-7-hydroxy-2,2-dimethylchrome prepared by a method for synthesizing the anticancer agent decusin. Man-3-ester, cis-2-methylbut-2-enoic acid-7-hydroxy-2,2-dimethylchroman-3-yl ester, and trans-2-methylbut-2-enoic It relates to a novel decusin derivative represented by EXID-7-hydroxy-2,2-dimethylchroman-3-ylester.

Deckersin was first isolated from the body sprouts, and has also been isolated from the fruit of Korean oil sprouts. The pyranocmarin family of decusin exhibits a strong lethal action on cancer cells, while a much lower lethal action on cancer cells compared to that on cancer cells.

In order to utilize such decosin, the present inventors have applied for a decosin presynthesis process in which decosin can be prepared by using a chemical synthesis method instead of obtaining a decosin from an existing herbal medicine (Patent Application No. 2000-35749 (6, 2000). May 27).

The present invention synthesizes compounds of novel chemical structure by using intermediates generated during the whole synthesis process of Deckerin disclosed in Patent Application No. 2000-35749 (June 27, 2000), and their anticancer activity and PKC The ability to bind is to be demonstrated using the differentiation of K562 cell lines by Fourbolester.

Accordingly, an object of the present invention is to provide a novel decusin derivative, which is an anticancer agent, and another object of the present invention is to provide a compound having a novel structure which binds to PKC but does not have cytotoxicity, and uses it as a signaling modulator in cancer cells. To provide usability.

The above object of the present invention is a novel decusin derivative, 3-methylbut-2-enoic acid-7-hydroxy-2,2-dimethylchroman-3-ester, cis-2-methylbut-2- Enoxy EX-7-Hydroxy-2,2-dimethylchroman-3-yl ester, and trans-2-methylbut-2-enoic EX-7-Hydroxy-2,2-dimethylchroman Achieved by providing -3-yl ester.

Hereinafter, the configuration and operation of the present invention.

1 is a graph showing the cytotoxicity of the Dekerin derivatives according to the present invention against K562 cell line.

Figure 2 is a graph showing the inhibition of differentiation of K562 cell line by the decusin derivative according to the present invention.

The present invention is a novel decusin derivative, 3-methylbut-2-enoic acid-7-hydroxy-2,2-dimethylchroman-3-ester, cis-2-methylbut-2-enoic acid -7-hydroxy-2,2-dimethylchroman-3-yl ester, and trans-2-methylbut-2-enoic acid-7-hydroxy-2,2-dimethylchroman-3- It's about one ester.

The novel decusin derivative 3-methylbut-2-enoic acid-7-hydroxy-2,2-dimethylchroman-3-ester (SDC) (compound 12) according to the invention has the formula .

Other novel decusin derivatives cis-2-methylbut-2-enoic acid-7-hydroxy-2,2-dimethylchroman-3-yl ester (SDA) according to the present invention (Compound 13) Has the formula (2).

Another decusin derivative trans-2-methylbut-2-enoic acid-7-hydroxy-2,2-dimethylchroman-3-ylester (SDT) according to the present invention (compound 14) is Has 3.

The method for synthesizing a novel decusin derivative according to the present invention is 7-hydroxy-2,2-dimethylchroman-4-one (hereinafter referred to as "Compound 2"). "Synthesis"; Synthesizing 2,2-dimethylchroman-4,7-diol (hereinafter referred to as "compound 3"); 2,2 synthesizing the dimethyl -2 H- chromen-7-ol (2,2-dimethyl-2 H- chromen -7-ol) ( hereinafter referred to as "compound 4"hereinafter); 7-acetoxy-2,2-step of the synthesis of dimethyl -2 H- chromen (7-acetoxy-2,2-dimethyl -2 H -chromen) ( hereinafter referred to as "compound 5"hereinafter); (3 S) -2,2- dimethyl-chroman-3,7-diol for the synthesis of ((3 S) -2,2-dimethylchroman -3,7-diol) ( hereinafter referred to as "compound 7a") step; (3 R) -2,2- dimethyl-chroman-3,7-diol for the synthesis of ((3 R) -2,2-dimethylchroman -3,7-diol) ( hereinafter referred to as "compound 7b") step; 7- ( t -butyldimethylsilanyloxy) -2,2-dimethylchroman-3-ol (7- ( tert- butyldimethylsilanyloxy) -2,2-dimethylchroman-3-ol) (hereinafter "Compound 8"Synthesizing); 3-Methylbut-2-enoic acid-7- ( t -butyldimethylsilanyloxy) -2,2-dimethylchroman-3-yl ester (3-Methylbut-2-enoic acid-7- ( tert- butylsilanyloxy) -2,2-dimethylchroman-3-yl ester) (hereinafter referred to as "Compound 9"); Cis-2-methylbut-2-enoic acid-7- ( t -butyldimethylsilanyloxy) -2,2-dimethylchroman-3-yl ester ( cis- 2-methylbut-2-enoic acid Synthesizing -7- ( tert- butyldimethylsilanyloxy) -2,2-dimethylchroman-3-yl ester) (hereinafter referred to as "Compound 10"); Trans-2-methylbut-2-enoic acid-7- ( t -butyldimethylsilanyloxy) -2,2-dimethylchroman-3-yl ester ( cis- 2-methylbut-2-enoic acid Synthesizing -7- ( tert- butyldimethylsilanyloxy) -2,2-dimethylchroman-3-yl ester) (hereinafter referred to as "Compound 11"); 3-methylbut-2-enoic acid-7-hydroxy-2,2-dimethylchroman-3-ester (3-methylbut-2-enoic acid-7-hydroxy-2,2-dimethylchroman-3- yl ester) (hereinafter referred to as "Compound 12"); Cis-2-methylbut-2-enoic acid-7-hydroxy-2,2-dimethylchroman-3-yl ester ( cis- 2-methylbut-2-enoic acid-7-hydroxy-2,2 -dimethylchroman-3-yl ester) (hereinafter referred to as "Compound 13"); And trans-2-methylbut-2-enoic acid-7-hydroxy-2,2-dimethylchroman-3-ylester ( trans- 2-methylbut-2-enoic acid-7-hydroxy-2, 2 -dimethylchroman-3-ylester) (hereinafter referred to as "Compound 14").

The synthesis process of the novel Decusin derivative according to the present invention is shown below.

The novel decusin derivatives according to the present invention do not have anticancer activity against K562 cell lines in the investigation of anticancer activity using K562 cell lines, and in particular, compounds that do not have cytotoxicity can bind to PKC. It is a fact. This fact shows that novel decusin derivatives can inhibit the differentiation of K562 cell lines by pobolesters.

Hereinafter, the specific configuration and operation of the present invention will be described in detail by way of examples, but the scope of the present invention is not limited only to these embodiments.

Example 1 Synthesis of Decasin Derivatives

First Step: Synthesis of 7-hydroxy-2,2-dimethylchroman-4-one

Resorcinol (1) (resorcinol, 10.0 g, 91 mmol) and 3,3-dimethyl in a solution of phosphorus pentoxide (7.75 g, 60.0 mmol) in methanesulfonic acid (0.14 L) Acrylic acid (3,3-dimethylacrylic acid, 9.1 g, 91 mmol) is added at 0 ° C. and stirred. The mixture was refluxed at 70 DEG C for one hour under nitrogen gas, poured into ice water, cooled, extracted with ether, dehydrated with anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting crystals were dissolved in ethyl acetate and hexane and recrystallized to obtain compound 2 (16.80 g, yield 96%). NMR analysis of the compound 2 synthesized in this Example is shown below, and 7-hydroxy-2,2-dimethylchroman-4-one (7-hydroxy-2,2-dimethylchroman-4-one) It was confirmed that.

_{^{1 H NMR (DMSO- d 6)}} δ 7.79 (d, 1H, Ar), 6.47 (dd, 1H, Ar), 6.35 (d, 1H, Ar), 5.97 (s, 1H, OH), 2.68 (s, 2H, CH ₂ ), 1.45 (s, 6H, CH ₃ )

Second Step: Synthesis of 2,2-dimethylchroman-4,7-diol

In a solution of lithium aluminum hydride (LiAlH ₄ , 1.2 g, 31.6 mmol) in purified tetrahydrofuran (25 mL), and purified by tetrahydrofuran (25 mL) while stirring at 0 ° C. under nitrogen gas. A solution of (2 g, 10.4 mmol) was added dropwise and refluxed at 70 ° C. for 3 hours. Cool and add very slowly dropwise 20 mL of saturated aqueous sodium sulfate solution. The mixture was filtered under reduced pressure with washing with ethyl acetate, the filtrate was washed with water, extracted with ethyl acetate, dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate was subjected to silica gel column chromatography in a mixed solvent of ethyl acetate and hexane to obtain compound 3 (1.66 g, yield 83%). NMR analysis of the compound 3 synthesized in this Example is shown below, and confirmed that it is 2,2-dimethylchroman-4,7-diol (2,2-dimethylchroman-4,7-diol).

_{^{1 H NMR (DMSO- d 6)}} δ 7.30 (d, 1H, Ar), 6.43 (dd, 1H, Ar), 6.27 (d, 1H, Ar), 4.79 (q, 1H, OH), 4.77 (s, 1H, OH), 2.15 (dd, 1H, CH ₂ ), 1.84 (dd, 1H, CH ₂ ), 1.43 (s, 3H, CH ₃ ), 1.31 (s, 3H, CH ₃ )

Third Step: 2,2-Dimethyl-2 H- Synthesis of Chromen-7-ol

To a solution of para-toluenesulfonic acid ( p- TsOH, 0.115 g, 0.590 mmol) in purified tetrahydrofuran (50 mL) was added Compound 3 (1.145 g, 5.896 mmol) and stirred for 2 hours under nitrogen gas. Reflux. The mixture was cooled to room temperature, neutralized with 10% aqueous sodium hydroxide solution (pH 7), extracted with ethyl acetate, dehydrated with anhydrous magnesium sulfate, and concentrated under reduced pressure. The concentrate was subjected to silica gel column chromatography in a mixed solvent of ethyl acetate and hexane to obtain compound 4 (0.92 g, yield 88%). It showed for the NMR analysis of the compound 4 synthesized in this embodiment results, 2,2-dimethyl -2 H- chromen-7-ol (2,2-dimethyl-2 H- chromen -7-ol) It was confirmed that.

_{^{1 H NMR (DMSO- d 6)}} δ 6.83 (d, 1H, Ar), 6.33 (d, 1H, Ar), 6.30 (s, 1H, Ar), 6.25 (d, 1H, = CH), 5.46 (d , 1H, = CH), 5.15 (s, 1H, OH), 1.41 (s, 6H, CH ₃ ).

Fourth Step: 7-Acetoxy-2,2-dimethyl-2 H- Synthesis of Chromen

Starting compound 3 (1.12 g, 6.37 mmol), acetic anhydride (0.90 mL, 9.50 mmol), pyridine (1.02 mL, 12.7 mmol), and 4- (dimethylamino) pyridine (4- (dimethylamino) pyridine, 0.04 g, 0.36 mmol) is dissolved in methylene chloride (16.7 mL) and stirred for 3 hours at room temperature under nitrogen gas. Washed with water, extracted with methylene chloride, dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate was subjected to silica gel column chromatography in a mixed solvent of ethyl acetate and hexane to obtain compound 5 (1.36 g, yield 98%). Showed for the NMR analysis of the compound 5 prepared in the present embodiment, 7-acetoxy-2,2-dimethyl -2 H- chromen (7-acetoxy-2,2-dimethyl -2 H -chromen ) Was confirmed.

_{^{1 H NMR (DMSO- d 6)}} δ 6.94 (d, 1H, Ar), 6.56 (dd, 1H, Ar), 6.52 (d, 1H, Ar), 6.29 (d, 1H, = CH), 5.57 (d , 1H, = CH), 2.27 (s, 3H, CH ₃ ), 1.42 (s, 6H, CH ₃ ).

5th step: (3 S Synthesis of) -2,2-dimethylchroman-3,7-diol

Compound 5 synthesized in Example 4 was immediately subjected to the following reaction using a buffer solution. Acetonitrile (25 mL) in 5 (0.50 g, 2.29 mmol), Jacobsen's ( S, S ) -salen-manganese (III) catalyst (0.058 g, 0.092 mmol) and ammonium tetrabutyl sulfate (0.028 g) , 0.082 mmol) in a solution of 0.05 M buffer solution (solution made by dissolving sodium tetraborate decahydrate (0.48 g) in an aqueous solution of 4 × 10 ^-4 M Na ₂ EDTA (EDTA disodium salt) (25 mL)) Add mL under stirring at 0 ° C. under nitrogen gas. 1,1,1-trifluoroacetone (1,1,1-trifluoroacetone, 0.3 mL) was added and oxone (oxone, 5.35 g, 8.7 mmol) in 4 × 10 ^-4 M Na ₂ EDTA aqueous solution (25 mL) The solution was dissolved in 25 mL of water and a solution of sodium carbonate (1.67 g, 19.92 mmol) was added dropwise at the same time to 1 mL per 5 minutes. Washed with water, extracted with ether, and when the concentration was dehydrated with anhydrous magnesium sulfate under reduced pressure the epoxidation (3 S, 4 S) -7- acetoxy-3,4-epoxy-2,2-dimethyl-chroman ((3 R, 4 R) -7-acetoxy-3,4-epoxy-2,2-dimethylchroman, 6a) to obtain a. To a solution of lithium aluminum hydride (0.348 g, 9.16 mmol) in purified tetrahydrofuran (30 mL) was added dropwise with 6a dissolved in purified tetrahydrofuran (20 mL) with stirring at 0 ° C. under nitrogen gas. React for two hours. The reaction was stopped with dropwise addition of water, washed, extracted with ethyl acetate, dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate was subjected to silica gel column chromatography in a mixed solvent of ethyl acetate and hexane to give compound 7a (0.385 g, yield 86.5%). Showed for the NMR analysis results of the synthesized compound 7a in this embodiment, (3 S) -2,2- dimethyl-chroman-3,7-diol ((3 S) -2,2-dimethylchroman- 3,7-diol) was confirmed.

_{^{6a 1 H NMR (DMSO- d 6}} ) δ 7.32 (d, 1H, Ar), 6.67 (dd, 1H, Ar), 6.57 (d, 1H, Ar), 3.90 (d, 1H, CH), 3.48 (d , 1H, CH), 2.26 (s, 3H, CH ₃ ), 1.26 (s, 6H, CH ₃ ).

_{^{7a 1 H NMR (DMSO- d 6}} ) δ 6.91 (d, 1H, Ar), 6.39 (dd, 1H, Ar), 6.32 (d, 1H, Ar), 4.80 (s, 1H, OH), 3.78 (q , 1H, CH), 3.00 (dd, 1H, CH ₂ ), 2.70 (dd, 1H, CH ₂ ), 1.75 (d, 1H, OH), 1.35 (s, 3H, CH ₃ ), 1.30 (s, 3H , CH ₃ )

Sixth Step: (3 R Synthesis of) -2,2-dimethylchroman-3,7-diol

Jacob sen in the (R, R) - salen-manganese (Ⅲ) under the same conditions as the conditions using a catalyst for synthesis of compound 6a (3 R, 4 R) -7- acetoxy-3,4-epoxy-2, 2-dimethyl-chroman compound 7b under the same conditions as the conditions for synthesizing the ((3 R, 4 R) -7-acetoxy-3,4-epoxy-2,2-dimethylchroman, 6b) , and the synthesis of compound 7a Synthesize Showed for the NMR analysis results of the synthesized compound 7b in the present embodiment, (3 S) -2,2- dimethyl-chroman-3,7-diol ((3 S) -2,2-dimethylchroman- 3,7-diol) was confirmed.

_{^{6b 1 H NMR (DMSO- d 6}} ) δ 7.32 (d, 1H, Ar), 6.68 (dd, 1H, Ar), 6.57 (d, 1H, Ar), 3.90 (d, 1H, CH), 3.49 (d , 1H, CH), 2.27 (s, 3H, CH ₃ ), 1.27 (s, 6H. CH ₃ ).

_{^{7b 1 H NMR (DMSO- d 6}} ) δ 6.91 (d, 1H, Ar), 6.39 (dd, 1H, Ar), 6.32 (d, 1H, Ar), 3.78 (t, 1H, CH), 3.00 (dd , 1H, CH ₂ ), 2.70 (dd, 1H, CH ₂ ), 1.36 (s, 3H, CH ₃ ), 1.30 (s, 3H, CH ₃ )

7th step: 7- ( t- Synthesis of Butyldimethylsilanyloxy) -2,2-dimethylchroman-3-ol

In a solution of 7a (0.30 g, 1.54 mmol) in methylene chloride (45 mL), pyridine (0.18 mL) and t -butyldimethylsilyl trifluoromethanesulfonic acid ( tert -butyldimethylsilyl) were stirred at room temperature under nitrogen gas. trifluoromethanesulfonate, 0.407 g, 1.54 mmol) is added and reacted for 3 hours. Washed with water, extracted with methylene chloride, dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate was subjected to silica gel column chromatography in a mixed solvent of ethyl acetate and hexane to obtain compound 8 (0.268 g, yield 56.4%). The NMR analysis of the compound 8 synthesized in this step is shown below, 7- ( t -butyldimethylsilanyloxy) -2,2-dimethylchroman-3-ol (7- ( tert -butyldimethylsilanyloxy) -2,2-dimethylchroman-3-ol).

_{^{1 H NMR (DMSO- d 6)}} δ 6.88 (d, 1H, Ar), 6.39 (dd, 1H, Ar), 6.34 (d, 1H, Ar), 3.78 (q, 1H, CH), 2.99 (dd, 1H, CH ₂ ), 2.69 (dd, 1H, CH ₂ ), 1.81 (d, 1H, OH), 1.34 (s, 3H, CH ₃ ), 1.30 (s, 3H, CH ₃ ), 0.97 (s, 9H , CH ₃ ), 0.18 (s, 6H, CH ₃ ).

Eighth step: 3-methylbut-2-enoic acid-7- ( t -Butyldimethylsilaneyloxy) -2,2

Synthesis of -dimethylchroman-3-yl ester

Pyridine (0.048 mL) and 3,3-dimethylacryloyl chloride (47 mg, 47 mg, stirring a solution of 8 (65 mg, 0.19 mmol) in methylene chloride (12 mL) were stirred. 0.40 mmol) is added and reacted for 12 hours at room temperature under nitrogen gas. After completion of the reaction with water and washing, the mixture was extracted with methylene chloride, dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate was subjected to silica gel column chromatography in a mixed solvent of ethyl acetate and hexane to obtain compound 9 (60 mg, yield%). The NMR analysis of Compound 9 synthesized in this Example is shown below, and 3-methylbut-2-enoic acid-7- ( t -butyldimethylsilanyloxy) -2,2-dimethylchroman 3-yl ester (3-Methylbut-2-enoic acid-7- ( tert -butylsilanyloxy) -2,2-dimethylchroman-3-yl ester) was confirmed.

_{^{1 H NMR (DMSO- d 6)}} δ 6.84 (d, 1H, Ar), 6.37 (dd, 1H, Ar), 6.34 (d, 1H, Ar), 5.68 (d, 1H, = CH), 5.02 (t , 1H, CH), 3.66 (dd, 1H, CH ₂ ), 2.71 (dd, 1H, CH ₂ ), 2.13 (d, 3H, CH ₃ ), 1.31 (s, 6H, CH ₃ ), 1.87 (d, 3H, CH ₃ ), 0.97 (s, 9H, CH ₃ ), 0.18 (s, 6H, CH ₃ )

9th step: cis-2-methylbut-2-enoic acid-7-7 ( t Butyldimethylsilaneyloxy)

Synthesis of -2,2-dimethylchroman-3-yl Ester

Angelic acid (0.173 g, 1.724 mmol), 1,3-dicyclohexyl carbodiimide (1,3-dicyclohexyl carbodiimide, 0.373) while stirring in a solution of 8 (0.266 g, 0.862 mmol) in methylene chloride. g, 1.810 mmol) and 4-dimethylaminopyridine (4-dimethylaminopyridine, 0.021 g, 0.172 mmol) were added and reacted at room temperature for 24 hours under nitrogen gas. The precipitate, dicyclohexylurea, was washed with ethyl acetate, filtered under reduced pressure, concentrated under reduced pressure, dissolved in ethyl acetate, filtered and filtered again with urea, washed twice with water, extracted with ethyl acetate, and extracted with anhydrous sulfuric acid. Dehydrate with magnesium and concentrate under reduced pressure. The concentrate was subjected to silica gel column chromatography in a mixed solvent of ethyl acetate and hexane to obtain compound 10 (0.255 g, yield 76%). NMR analysis of the compound 10 synthesized in this Example is shown below, and cis-2-methylbut-2-enoic acid-7- ( t -butyldimethylsilaneyloxy) -2,2-dimethyl Chroman-3-yl ester ( cis- 2-methylbut-2-enoic acid-7- ( tert -butyldimethylsilanyloxy) -2,2-dimethylchroman-3-yl ester) was confirmed.

_{^{1 H NMR (DMSO- d 6)}} δ 6.87-6.81 (m, 2H, Ar, = CH), 6.40-6.34 (m, 2H, Ar), 5.02 (t, 1H, CH), 3.08 (dd, 1H, CH ₂ ), 2.71 (dd, 1H, CH ₂ ), 1.81 (d, 3H, CH ₃ ), 1.76 (d, 3H, CH ₃ ), 0.97 (s, 9H, CH ₃ ), 0.19 (s, 6H, CH ₃ )

Tenth step: trans-2-methylbut-2-enoic acid-7-7 ( t Butyldimethylsilaneyloxy)

Synthesis of -2,2-dimethylchroman-3-yl Ester

8 (0.10 g, 0.324 mmol) and tiglic acid (tiglic acid, 0.648 g, 6.648 mmol) were reacted in the same manner as in the synthesis of compound 10 to obtain compound 11 (0.087 g, yield 69%).

11th step: 3-methylbut-2-enoic acid-7-hydroxy-2,2-dimethylchroman-3

Synthesis of esters

Tetrabutylammonium fluoride (0.040 g, 0.154 mmol) was added to the solution of 9 (60 mg, 0.154 mmol) in tetrahydrofuran (5 mL), and stirred for 1 hour at room temperature. . Washed with water, extracted with ethyl acetate, dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate was subjected to silica gel column chromatography in a mixed solvent of ethyl acetate and hexane to obtain compound 12 (40 mg, yield 93%). NMR analysis of the compound 12 synthesized in this Example is shown below, 3-methylbut-2-enoic acid-7-hydroxy-2,2-dimethylchroman-3-ester (3-methylbut -2-enoic acid-7-hydroxy-2,2-dimethylchroman-3-yl ester).

_{^{1 H NMR (DMSO- d 6)}} δ 6.63 (d, 1H, Ar), 6.38 (dd, 1H, Ar), 6.34 (d, 1H, Ar), 5.68 (s, 1H, = CH), 5.42 (s , 1H, OH), 5.02 (t, 1H, CH), 3.06 (dd, 1H, CH ₂ ), 2.71 (dd, 1H, CH ₂ ), 2.14 (s, 3H, CH ₃ ), 1.87 (s, 3H , CH ₃ ), 1.32 (s, 3H, CH ₃ ), 1.31 (s, 3H, CH ₃ )

12th Step: cis-2-methylbut-2-enoic acid-7-hydroxy-2,2-dimethylchroman

Synthesis of 3-yl ester

To a solution of 10 (0.255 g, 0.653 mmol) dissolved in purified tetrahydrofuran (10 mL) was added tetrabutylammonium fluoride (0.171 g, 0.653 mmol) while stirring at room temperature for 1 hour. . Washed with water, extracted with ethyl acetate, dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate was subjected to silica gel column chromatography in a mixed solvent of ethyl acetate and hexane to obtain compound 13 (0.113 g, yield 63%). NMR analysis of the compound 13 synthesized in this Example is shown below, and the cis-2-methylbut-2-enoic acid-7-hydroxy-2,2-dimethylchroman-3-yl ester ( cis- 2-methylbut-2-enoic acid-7-hydroxy-2,2-dimethylchroman-3-yl ester).

_{^{1 H NMR (DMSO- d 6)}} δ 6.87 (d, 1H, Ar), 6.84 (dd, 1H, = CH), 6.38 (dd, 1H, Ar), 6.34 (d, 1H, Ar), 5.02 (t , 1H, CH), 4.96 (s, 1H, OH), 3.08 (dd, 1H, CH ₂ ), 2.73 (dd, 1H, CH ₂ ), 1.81 (s, 3H, CH ₃ ), 1.77 (d, 3H , CH ₃ ), 1.33 (s, 3H, CH ₃ ), 1.32 (s, 3H, CH ₃ )

Step 13: trans-2-methylbut-2-enoic acid-7-hydroxy-2,2

Synthesis of -dimethylchroman-3-ylester

Tetrabutylammonium fluoride (0.058 g, 0.223 mmol) was added to the solution of 11 (87 mg, 0.223 mmol) dissolved in purified tetrahydrofuran (8 mL) at room temperature for about an hour. React. Washed with water, extracted with ethyl acetate, dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate was subjected to silica gel column chromatography in a mixed solvent of ethyl acetate and hexane to give compound 14 (34 mg, yield 62%). The NMR analysis of the compound 14 synthesized in this Example is shown below, and trans-2-methylbut-2-enoic acid-7-hydroxy-2,2-dimethylchroman-3-ylester ( trans- 2-methylbut-2-enoic acid-7-hydroxy-2,2-dimethylchroman-3-yl ester).

_{^{1 H NMR (DMSO- d 6)}} δ 6.87-6.82 (m, 2H, Ar, = CH), 6.40 (dd, 1H, Ar), 6.36 (d, 1H, Ar), 5.71 (s, 1H, OH) , 5.03 (t, 1H, CH), 3.07 (dd, 1H, CH ₂ ), 2.73 (dd, 1H, CH ₂ ), 1.81 (s, 3H, CH ₃ ), 1.77 (d, 3H, CH ₃ ), 1.33 (s, 3H, CH ₃ ), 1.32 (s, 3H, CH ₃ )

Example 2: Cytotoxicity Studies in K562 Cell Lines

K562 cell lines incubated in RPMI1640 medium (Gibco BRL) containing 10% fetal bovine serum are dispensed in 12-well plates at a concentration of 1 × 10 ⁵ cells. Compounds 12, 13, and 14 synthesized in Examples 11, 12, and 13 were dissolved in DMSO, and then treated with cells at a concentration of 50 μM, respectively. Cell lines were incubated under conditions of 37 ° C. and 5% carbon dioxide. The final DMSO concentration was 0.1%, and the survival number of cells was measured every 24 hours using trypan blue.

1 shows the cytotoxicity of the decusin derivatives (SDC, SDA, SDT) in the K562 cell line, and all the derivatives were confirmed to have no toxicity in the K562 cell line.

The K562 cell line used in this example is called a human erythroleukemia cell line (Human Erythroleukemia) or a human chronic myelogenous leukemia cell line (Human Chronic Myelogenous Leukemia, CML) and is differentiated into megakaryocytes by Phorbol Ester, a PKC activator.

Example 3: Inhibition of Differentiation of K562 Cell Lines by Fourbolester

K562 cell lines cultured in RPMI1640 medium (Gibco BRL) containing 10% fetal bovine serum are dispensed in 6-well plates at a concentration of 2 × 10 ⁶ cells. The 10 nM PMA and 50 μM derivative dissolved in DMSO are treated. After culturing the cell line for 3 days at 37 ° C. and 5% carbon dioxide, the number of adherent cells and supporting cells was measured. Adhesion inhibition rate was calculated by setting the adhesion cell number of the K562 cell line induced by 10 nM PMA to 100.

2 shows adhesion inhibitory activity of K562 cell line by derivatives (SDC, SDA, SDT), and it was confirmed that 50 μM of SDC inhibited the differentiation of K562 cell line by PAM by 50% or more. SDA and SDT were 18% and 14% lower than SDC.

As described above, the decusin derivatives (SDC, SDA, SDT) of the present invention do not have cytotoxicity against K562 cell lines and are very useful in the pharmaceutical industry because they have the effect of inhibiting the differentiation of K562 cell lines by pobolesters. It is an invention.

Claims (3)

The novel decusin derivative, characterized in that represented by the formula (1). [Formula 1] The novel Decusin derivative, characterized in that represented by the formula (2). [Formula 2] Novel decusin derivative, characterized in that represented by the formula (3). [Formula 3]