CN101225049A - Beta-elemene amino acid derivatives as well as synthetic method and use thereof - Google Patents
Beta-elemene amino acid derivatives as well as synthetic method and use thereof Download PDFInfo
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Abstract
The invention discloses Beta-elemene amino acid derivatives as shown in the formula I and the salt accepted pharmaceutically, the synthesis method of the Beta-elemene amino acid derivatives and the usage in preparing anticancer drugs; wherein, in the formula I, R[1], R[2] are independently H or amino acid with one hydrogen atom substituted on amino; the condition is H when R[1] and R[2] are different. The synthesis method of the Beta-elemene amino acid derivatives in the formula I and the salt accepted pharmaceutically has the advantages of having good water soluble and biocompatibility and higher anticancer activity compared with Beta-elemene and an important reaction intermediate. The synthesis method can be used as synthesizing other Beta-elemene derivatives.
Description
Technical field
The present invention relates to a kind of cancer therapy drug, relate in particular to a kind of beta-elemene amino acid derivative and preparation method and use thereof.
Background technology
Cancer is the common disease of present serious harm people life and health, and (β-Elemene) is the anticancer effective component at first extracted from zingiberaceous plant RADIX CURCUMAE (warm curcuma zedoary) rhizome of China in recent years to beta-elemene, and its molecular formula is C
15H
24, structural formula is as follows:
Dong Jinhua etc. have reported a series of beta-elemene anticancer compounds (Dong Jinhua, the research of beta-elemene series anticancer compound, Dalian Inst of Chemicophysics, Chinese Academy of Sciences's Ph D dissertation, 1995); The CN1462745 patent application discloses the beta-elemene pyridine derivatives; CN1462746 discloses beta-elemene penta azacyclo derivative and synthetic method thereof; The CN1153168 patent disclosure elemene hydroxyls derivs and as cancer therapy drug.Gong Guoliang has synthesized piperidyl and morpholinyl beta-elemene derivative, has carried out the synthetic exploration of series derivates, for synthesizing of fragrant heterocyclic substituted beta-elemene individual isomer, Chu Changhu has done useful exploration, obtained the individual isomer compound, productive rate is higher, and purity is also fine.The Xiao Yuan triumph has been synthesized a series of derivatives with the method for combinatorial chemistry, and one of them important intermediate is the beta-elemene bridged piperazine derivatives.Beta-elemene has been applied to clinical as Chinese medicine, but because water-soluble extreme difference, has limited its clinical application, therefore, how to improve it and water-solublely receives much attention always.Amino acid is proteinic essentially consist unit, plays an important role in the human life activity.Introduce the amino acid structure unit, one side can be improved water-soluble, can strengthen the absorption of beta-elemene in tumour cell on the other hand.
Summary of the invention
The technical problem to be solved in the present invention promptly is by will introducing amino acid group in the beta-elemene molecule, preparing a series of beta-elemene amino acid derivatives with good water-solubility and biocompatibility.
Thus, the invention provides the beta-elemene amino acid derivative shown in the formula I or its pharmacy acceptable salt,
Wherein, R
1, R
2For on H or the amino hydrogen atom substituted amino acid being arranged, condition is R independently
1, R
2Be not H simultaneously.
Amino acid of the present invention is meant and has at least one amino (NH in the structural formula
2) and at least one carboxyl (compound COOH), it can be natural amino acid, comprise the neutral amino acids such as α-An Jibingsuan (L-L-Ala), the phenylalanine etc. that have nonpolar group, have polar group but uncharged neutral amino acids such as Serine etc., and acidic amino acid and basic aminoacids.
Described amino acid can be NH for molecular formula also
2(CH
2)
nThe alpha-non-natural amino acid of COOH, wherein n is 2～10 integer, for example n is 2 β-An Jibingsuan (Beta-alanine), or n is γ-Gamma Amino Butyric Acid of 3; Or NH
2(CH
2)
mC
6H
5The non-natural die aromatischen Aminosaeuren of COOH, wherein m is 0～3 integer, preferred m=1 is as 4-(Metylamino)-benzoic acid.
Described salt can be various salt, as the N on organic acid or mineral acid and the beta-elemene amino acid derivative, or the various salt of organic bases or mineral alkali and COOH formation.
In addition, the present invention also provides the synthetic method of above-mentioned beta-elemene amino acid derivative.Same prior art (as the patent documentation of mentioning in the above-mentioned background technology) is similar, synthetic method of the present invention also is to go out to send synthetic from formula II compound beta-elemene chloro thing (chloro beta-elemene), comprise formula II compound beta-elemene chloro thing and amino acid are dissolved in the ethanol, add basic catalyst, reacted 1～48 hour down at 10～100 ℃;
Wherein, X
1, X
2Be H or Cl by oneself, condition is X
1, X
2Be not H simultaneously.
In the synthetic method of the present invention, the amount of substance of amino acid and beta-elemene chloro thing preferably is 1: 1～3 than (mol ratio) no particular requirement.
Described basic catalyst can be various inorganic alkaline catalysts, as KOH or NaOH, and the organic basic catalyzer, as 1,8-diaza-bicyclo [5.4.0]-7-hendecene (DBU) and 1, one or more in 5-diaza-bicyclo [4.3.0]-5-octene (DBN).Described beta-elemene chloro thing can be 1: 0.35 with the amount of substance of basic catalyst than (mol ratio)～and 1.10.
Preferably, the preferred 70～80v/v% of the alcohol concn described in the synthetic method of the present invention, preferred 60～70 ℃ of temperature of reaction, the reaction times can be 8～48 hours.
After using synthetic method reaction of the present invention to finish, boil off solvent, add methylene dichloride, transferring pH is 1～2, as precipitation occurring, then filters the throw out that obtains and is pure beta-elemene amino acid derivative, as precipitation not occurring, then, can obtain pure beta-elemene amino acid derivative with methylene dichloride and methanol-eluted fractions further through silica gel column chromatography with chloroform or dichloromethane extraction.
In the prior art, utilize Elemenum with contain the synthetic Elemenum of aminocompound reaction contain aminocompound the time, all be with Elemenum chloro thing directly and ammoniac compounds in ethanol, reflux, do not add alkali, and require solvent anhydrous, and the present invention adds basic catalyst, and so not harsh to the requirement of solvent, has avoided handling the overwork amount that solvent brought.
Beta-elemene amino acid derivative provided by the present invention contains active carboxyl, can be used for synthesizing other beta-elemene derivative, is the important reaction intermediate of a class.
Beta-elemene amino acid derivative of the present invention has good water-solubility and biocompatibility, can improve drug effect and bioavailability, has better characteristics such as antitumor drug effect than beta-elemene.In vitro tests to JEG-3 shows, introduces the antitumour activity that amino acid structure has strengthened compound in the beta-elemene structure.
Embodiment
Further specify the present invention with embodiment below, but the present invention is not limited.
Raw material beta-elemene chloro thing used in the following example can be synthetic according to prior art, and is synthetic voluntarily as each part document of mentioning in the above-mentioned background technology content; Amino acid is ACROS company product; The condition that other not concrete medicines that indicate or experiment condition are advised according to normal condition or its manufacturer of this area.
1. formula II compound beta-elemene chloro thing is synthetic
According to document (Jia Weimin, synthetic, the structure and the structure of PTS beta-elemene and derivative thereof are imitated research, Dalian Inst of Chemicophysics, Chinese Academy of Sciences's Ph D dissertation, 1991) synthetic beta-elemene chloro thing, concrete steps are as follows: the 0.01mol beta-elemene is dissolved in the 10mL methylene dichloride, adds 2mL formic acid, temperature is controlled at 0～5 ℃, in 2 hours, slowly drip the 15mL chlorine bleach liquor, continue reaction 3～5 hours.Reaction finishes, add saturated sodium bicarbonate aqueous solution and regulate pH to 7～8, with the reaction mixture static layering, tell organic phase, water is with the dichloromethane extraction of 3 * 10mL, merge organic phase, and use anhydrous sodium sulfate drying, filter, remove methylene chloride, get faint yellow oily thing, behind silica gel column chromatography, can obtain colorless oil, through gas chromatographic analysis is chloro beta-elemene mixture, is the mixture of beta-elemene chloro thing and beta-elemene, and the content of beta-elemene chloro thing is about 40～50%.Beta-elemene chloro thing wherein contains following three kinds of compounds, mainly is mono-substituted, i.e. formula 1 and formula 2 compounds, and wherein again based on formula 1 compound, the content of formula 2 compounds is seldom.
Because the beta-elemene in this chloro beta-elemene mixture is not easily separated, and after reaction finishes,, very easily separate because the polarity of the polarity of beta-elemene and final product of the present invention differs greatly.So same prior art, this chloro beta-elemene mixture can be directly used in building-up reactions of the present invention, and participates in the formula that is mainly 1 compound of reaction, so following embodiment reaction formula is that example illustrates with it.
Synthesizing of embodiment 1 beta-elemene γ-Gamma Amino Butyric Acid derivative
With 0.1481g (1.4mmol) γ-Gamma Amino Butyric Acid, 0.0609g NaOH adds 5mL CH
3CH
2OH and 1.6mL H
2O at room temperature is stirred to dissolving fully, adds 0.64g (2.7mmol) chloro beta-elemene mixture then.Stir at 65 ℃ oil bath lower magnetic forces, heated 44 hours, the transparent cyan that is of solution, reaction finishes to steam and desolventizes, and adds CH
2Cl
2, be 1～2 with the hydrochloric acid adjust pH, precipitation does not appear, then use CHCl
3Extraction (10mL * 3) gets yellow oily liquid.
Adopt CH by silicagel column
2Cl
2: CH
3OH=10: 1 (v/v) separates product, is CH at developping agent
2Cl
2: CH
3OH=5: during 1 (v/v), product Rf value is 0.59.
Characterize: IR V
Max: 3080 (C=C-H), 1709 (C=O);
1H-NMR(CDCl
3，TMS，500MHz)，δ0.99(s，3H，CH
3)，1.20-1.79(m，6H)，1.70(s，3H，CH
3)，1.92-2.24(m，4 H)，2.45(s，2H)，3.06(s，2H)，3.45-3.70(m，2H)，4.53-4.75(m，1H)，4.77-5.01(m，3H)，5.05-5.48(m，2H)，5.72-5.90(m，1H)，8.74(s，2H，HN and COOH)；
13C-NMR(CD
3OD，TMS，125MHz)，δ17.36，23.53，25.66，28.49，34.58，37.10，41.05，41.16，43.96，51.81，54.00，110.93，113.21，114.20，147.67，148.95，151.55，181.00。
Synthesizing of embodiment 2 beta-elemene beta-alanine derivatives
With 0.1378g (1.5mmol) β-Ala, 0.1281g NaOH adds 5mL CH
3CH
2OH and 1.8mL H
2O at room temperature is stirred to dissolving fully, adds 0.70g (3.0mmol) chloro beta-elemene mixture then.Stir at 65 ℃ oil bath lower magnetic forces, heated 48 hours, solution is transparent to be yellow, and reaction finishes to steam and desolventizes, and adds CH
2Cl
2, be 1～2 with the hydrochloric acid adjust pH.Precipitation do not occur, then use CHCl
3Extraction (10mL * 3) gets yellow oily liquid.
Adopt CH by silicagel column
2Cl
2: CH
3OH=10: 1 separates product, is CH at developping agent
2Cl
2: CH
3OH=5: 1 o'clock, product Rf value was 0.59.
Characterize: IR V
Max: 3080 (C=C-H), 1719 (C=O), 1637 (C=C);
1H-NMR(CDCl
3，TMS，500MHz)，δ0.99(s，3 H，CH
3)，1.20-1.35(m，1H)，1.36-1.78(m，5H)，1.73(s，3H，CH
3)，1.99-2.19(m，2H)，2.76(s，2H)，3.20(s，2H)，3.68(s，2H)，4.97-4.57(4H，m)，5.08-5.49(2H，m)，5.80(dd，J＝17.58，6.93，1H)；
1H-NMR(CD
3OD，TMS，500MHz)，δ1.06(s，3H)，1.30-1.35(m，1H)，1.48-1.56(m，2H)，1.59-1.69(m，3H)，1.75(s，3H)，2.07-2.16(m，2H)，2.69-2.74(m，2H)，3.24-3.28(m，2H)，3.73(s，2H)，4.64(s，1H)，4.86-4.98(m，3H)，5.32(s，1H)，5.25(s，1H)，5.87(dd，J＝17.56，10.8，1H)；
13C-NMR(CD
3OD，TMS，125MHz)，δ16.46，20.96，24.83，26.91，32.75，39.54，39.59，41.94，43.09，51.13，52.20，110.09，112.25，114.58，144.29，147.15，149.73，175.00。
Synthesizing of embodiment 3 beta-elemene L-alanine derivatives
With 0.7543g (8.4mmol) α-Bing Ansuan, 0.5774g NaOH adds 15mLCH
3CH
2OH and 5mL H
2O at room temperature is stirred to dissolving fully, adds 4g (16.8mmol) chloro beta-elemene mixture then.Stir at 66 ℃ oil bath lower magnetic forces, heated 28 hours, solution is transparent to be yellow, and reaction finishes to steam and desolventizes, and adds CH
2Cl
2, be 1～2 with the hydrochloric acid adjust pH.There is insolubles to occur, then this solution filtered, obtain white solid, productive rate 57.4%.
Characterize: IR V
Max: 3080 (C=C-H), 1637 (C=O);
1H-NMR(CD
3OD，TMS，500MHz)，δ0.99(s，3H)，1.39-1.58(m，6H)，1.59(d，J＝6.07，3H)，1.70(s，3H)，2.01-2.10(m，2H)，3.59-3.63(m，1H)，3.74-3.83(m，2H)，4.57(s，1H)，4.82(s，1H)，4.89(s，1H)，4.91(d，J＝3.34，1H)，5.21(s，1H)，5.28(s，1H)，5.80(dd，J＝17.94，10.9，1H)。
Synthesizing of embodiment 4 beta-elemene L-phenylalanine derivatives
With 0.2079g (1.25mmol) L-phenylalanine, 0.1058g NaOH adds 9mlCH
3CH
2OH and 2.8ml H
2O at room temperature is stirred to dissolving fully, adds 0.837g (3.5mmol) chloro beta-elemene mixture then.Stir at 66 ℃ oil bath lower magnetic forces, heated 8 hours, reaction finishes to steam and desolventizes, and adds CH
2Cl
2, be 1～2 with the hydrochloric acid adjust pH, extraction is dry, steam desolventize yellow crude product.Use silica gel column chromatography, elutriant is a methylene dichloride: methyl alcohol (volume ratio 15: 1) gets product 0.462g, productive rate 46.5%.
1H-NMR(CD
3OD，TMS，500MHz)，δ0.90(s，3H)，1.21-1.58(m，6H)，1.67(s，3H)，1.84-2.05(m，2H)，3.21(s，1H)，3.27-3.50(m，3H)，3.81(s，1H)，4.52(s，1H)，4.67-4.97(m，3H)，5.06(s，2H)，5.74(dd，J＝17.31，10.92，1H)，7.23-7.34(m，5H)。
Synthesizing of embodiment 5 beta-elemene L-serine derivatives
With 0.1822g (1.7mmol) L-Serine, 0.1417g NaOH adds 10ml CH
3CH
2OH and 2.5ml H
2O at room temperature is stirred to dissolving fully, adds 0.96g (4.0 mmol) chloro beta-elemene mixture then.Stir at 67 ℃ oil bath lower magnetic forces, heated 18 hours, steaming desolventized after reaction finished, and added CH
2Cl
2, be 1～2 with the hydrochloric acid adjust pH, extraction is dry, steam desolventize yellow crude product.Use silica gel column chromatography, elutriant is a methylene dichloride: methyl alcohol (volume ratio 10: 1) gets product 0.187g, productive rate 35%.
1H-NMR(CD
3OD，TMS，500MHz)，δ0.98(s，3H)，1.26-1.61(m，6H)，1.70(s，3H)，1.94-2.27(m，2H)，3.62-3.81(m，3H)，4.00-4.23(m，2H)，4.57(s，1H)，4.81(s，1H)，4.83-4.91(m，2H)，5.20-5.47(m，2H)，5.56-5.59(m，1H)。
Synthesizing of embodiment 6 beta-elemene glycine derivatives
With 0.3751g (5.0mmol) glycine, 0.1417g NaOH adds 10ml CH
3CH
2OH and 2.5ml H
2O at room temperature is stirred to dissolving fully, adds 2.385g (10mol) chloro beta-elemene mixture then.Stir at 67 ℃ oil bath lower magnetic forces, heated 18 hours, steaming desolventized after reaction finished, and added CH
2Cl
2, be 1～2 with the hydrochloric acid adjust pH, extraction is dry, steam desolventize yellow crude product.Use silica gel column chromatography, elutriant is a methylene dichloride: methyl alcohol (volume ratio 10: 1), get product 0.6231g, productive rate 42%.
1H-NMR(CDCl
3，TMS，500MHz)，δ0.96(s，3H，CH
3)，1.30-1.62(m，6H)，1.66(s，3H，CH
3)，1.94-2.03(m，1H)，2.08--2.19(m，1H)，3.09(s，2H)，3.18(s，2H)，4.58(s，1H)，4.78(s，1H)，4.85(d，J＝4.51，1H)，4.89(s，1H)，4.91(s，2H)，5.80(dd，J＝17.92，10.41，1H)。
Synthesizing of embodiment 7 beta-elemene 4-(Metylamino)-benzoic acid derivatives
With 0.7581g (5.0mmol) 4-(Metylamino)-benzoic acid, 0.1417g NaOH adds 10mlCH
3CH
2OH and 2.5ml H
2O at room temperature is stirred to dissolving fully, adds 2.385g (10mol) chloro Elemenum mixture then.Stir at 67 ℃ oil bath lower magnetic forces, heated 18 hours, steaming desolventized after reaction finished, and added CH
2Cl
2, be 1～2 with the hydrochloric acid adjust pH, extraction is dry, steam desolventize yellow crude product.Use silica gel column chromatography, elutriant is a methylene dichloride: methyl alcohol (volume ratio 10: 1) gets product 0.7805g, productive rate 41%.
1H-NMR(CDCl
3，TMS，500MHz)，δ0.94(s，3H)，1.32-1.38(m，2H)，1.43-1.52(m，3H)，1.55-1.62(m，1H)，1.65(s，3H)，1.97-2.09(m，2H)，3.59(s，2H)，4.19(s，2H)，4.57(s，1H)，4.78(s，1H)，4.85(d，J＝6.03，1H)，4.88(s，1H)，5.17(s，1H)，5.19(s，1H)，5.79(dd，J＝17.01，10.62，1H)。
HRMS(EI)m/z 355.2497，C
23H
31NO
2 requires M+2，355.2511。
Experimental example 1 external antitumour activity test
1. to the restraining effect of people's chronic leukemia K562 cell strain.
The K562 cell of taking the logarithm vegetative period with carrying out cell counting after the RPMI1640 suspension, adds 96 well culture plates, every hole 90 μ l (1 * 104 cell), add different concns (100,10,1 then, 0.1,0.01 the beta-elemene amino acid derivative of embodiment 3-6 μ M) (using the DMSO hydrotropy, final concentration 0.5 w/v%) 10 μ l establish 5 concentration altogether, each concentration is established 2 multiple holes, puts into 37 ℃ CO
2Case continues to cultivate 24h.Add 10 μ l WST-1 (water-soluble tetrazole) solution then, continue in the incubator to cultivate 2h, place the microplate reader reading, the mensuration wavelength is 450nm, calculates inhibiting rate, tries to achieve equation of linear regression, calculates IC
50
2. to human cervical carcinoma Hela cell's restraining effect.
After human cervical carcinoma Hela cell's recovery, the cell that is in logarithmic phase is got in the cultivation of going down to posterity, and carries out cell counting after 0.25% trysinization, joins 96 well culture plates, and every hole 100 μ l (5 * 103 cells) spend the night in 37 ℃ of incubators.Sop up substratum next day, adds the medicine with the different concns of substratum preparation then, and all the other steps are the same.The results are shown in Table 1.
Table 1 beta-elemene amino acid derivative is to leukemia cell K562 and human cervical carcinoma Hela cell's external antiproliferative activity
| Compound | IC 50(μmol/ml) | |
| HeLa | K562 | |
| Beta-elemene embodiment 3 embodiment 4 embodiment 5 embodiment 6 | 236.2 102.2 87.5 189.1 97.4 | 220.1 110.2 78.6 156.4 101.3 |
Observed of the vitro inhibition effect of the derivative of beta-elemene amino acid, and adopted WST-1 staining pair cell survival rate to detect, calculated IC human leukemia cell line K562 and s strain
50The result shows, by in the beta-elemene structure, introducing the antitumour activity that amino acid structure can strengthen compound really.
Conclusion:
The external antitumour activity of beta-elemene amino acid derivative increases than beta-elemene itself.
Claims (10)
1. beta-elemene amino acid derivative or its pharmacy acceptable salt shown in the formula I,
Wherein, R
1, R
2For on H or the amino hydrogen atom substituted amino acid being arranged, condition is R independently
1, R
2Be not H simultaneously.
2. beta-elemene amino acid derivative as claimed in claim 1 is characterized in that: described amino acid is natural amino acid.
3. beta-elemene amino acid derivative as claimed in claim 1 is characterized in that: described amino acid is that molecular formula is NH
2(CH
2)
nCOOH or NH
2(CH
2)
mC
6H
5The alpha-non-natural amino acid of COOH, wherein n is 2～10 integer, m is 0～3 integer.
4. beta-elemene amino acid derivative as claimed in claim 3 is characterized in that: n is 2～3, m=1.
5. the synthetic method of each described beta-elemene amino acid derivative of claim 1～4, this synthetic method comprises formula II compound beta-elemene chloro thing and amino acid is dissolved in the ethanol, add basic catalyst, reacted 1～48 hour down at 10～100 ℃;
Wherein, X
1, X
2Be H or Cl by oneself, condition is X
1, X
2Be not H simultaneously.
6. synthetic method as claimed in claim 5 is characterized in that: the mol ratio of amino acid and beta-elemene chloro thing is 1: 1～3.
7. synthetic method as claimed in claim 5 is characterized in that: described basic catalyst is inorganic alkaline catalyst and/or organic basic catalyzer, and the mol ratio of beta-elemene chloro thing and described basic catalyst is 1: 0.35～1.10.
8. synthetic method as claimed in claim 7 is characterized in that: described inorganic alkaline catalyst is KOH and/or NaOH; Described organic basic catalyzer is 1,8-diaza-bicyclo [5.4.0]-7-hendecene and/or 1,5-diaza-bicyclo [4.3.0]-5-octene.
9. synthetic method as claimed in claim 5 is characterized in that: described alcohol concn is 70～80v/v%, and temperature of reaction is 60～70 ℃, reacts 8～48 hours.
10. each described beta-elemene amino acid derivative of claim 1～4 or its pharmacy acceptable salt purposes in synthetic other beta-elemene derivative or preparation cancer therapy drug.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102070482A (en) * | 2010-12-31 | 2011-05-25 | 中山大学 | Derivatives of natural product S6-2, and preparation method and use thereof as anti-tumor medicines |
| CN112707833A (en) * | 2019-10-24 | 2021-04-27 | 沈阳药科大学 | Histone deacetylase inhibitor and preparation and application thereof |
| CN113801073A (en) * | 2021-10-11 | 2021-12-17 | 杭州师范大学 | 14-chloro-beta-elemene nitric oxide donor type derivative and preparation and application thereof |
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| CN1052716C (en) * | 1995-12-26 | 2000-05-24 | 中国科学院大连化学物理研究所 | Elemene hydroxyls derivs. and their use as anticancer drugs |
| CN1066444C (en) * | 1995-12-26 | 2001-05-30 | 中国科学院大连化学物理研究所 | Nitrogenous derivs. of elemene and their use as anticancer drugs |
| CN1844084B (en) * | 2006-05-10 | 2012-02-22 | 沈阳药科大学 | Beta-elemene amino acid or carboxylic acid derivatives and preparation process and use thereof |
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Cited By (3)
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| CN102070482A (en) * | 2010-12-31 | 2011-05-25 | 中山大学 | Derivatives of natural product S6-2, and preparation method and use thereof as anti-tumor medicines |
| CN112707833A (en) * | 2019-10-24 | 2021-04-27 | 沈阳药科大学 | Histone deacetylase inhibitor and preparation and application thereof |
| CN113801073A (en) * | 2021-10-11 | 2021-12-17 | 杭州师范大学 | 14-chloro-beta-elemene nitric oxide donor type derivative and preparation and application thereof |
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