CN101161670A - Ursolic acid chemical modified compound amine having antitumor activity - Google Patents
Ursolic acid chemical modified compound amine having antitumor activity Download PDFInfo
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- CN101161670A CN101161670A CNA2007101583854A CN200710158385A CN101161670A CN 101161670 A CN101161670 A CN 101161670A CN A2007101583854 A CNA2007101583854 A CN A2007101583854A CN 200710158385 A CN200710158385 A CN 200710158385A CN 101161670 A CN101161670 A CN 101161670A
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- ursolic acid
- alkene
- compound
- acyl
- amine
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Abstract
An amine as a chemical decorative compound with anti-tumor activity is provided, which relates to a natural product and the semi-complex thereof, wherein the present invention carries out chemical decoration for a natural product of ursolic acid to obtain a series of analogs of ursolic acid, i.e., and an amine as a chemical decorative compound with anti-tumor activity. Based on pharmaceutical researches, the amine as the chemical decorative compound of ursolic acid has the significant suppressive activity on Hela cells from Human cervical cancer and SKOV3 cells from ovarian cancer, with advantageous effect on both lines compared with ursolic acid as the parent compound.
Description
Technical field
The present invention relates to a kind of natural product and its semisynthetic, particularly relate to a kind of ursolic acid chemical modified compound amine with anti-tumor activity.
Background technology
(ursolic acid, UA) (compound 1) has another name called urson, ursonic acid to ursolic acid, belongs to pentacyclic triterpenoid, and be widely distributed at occurring in nature, and have the various biological effect.Neural system had obviously stable and cooling effect; External to G
+And G
-Bacterium and yeast all have anti-microbial activity; Have reducing blood-fat, study of anti-atherogenic effect; Protect the liver in addition, antihepatitic activity.
The chemical structural formula of ursolic acid:
Studies show that ursolic acid not only has resistant function to multiple carcinogenic, short cancer thing, and multiple malignant tumour such as P-388 and L-1210 leukemia cell, A-549 human lung adenocarcinoma cell are had the growth of inhibition effect; Can induce the F9 teratocarcinoma cell to become the endoderm cell; T cell lymphoma Jurkat cell strain had the restraining effect of killing and wounding; In addition, also has the effect that antineoplastic vascular generates.
Summary of the invention
The object of the present invention is to provide a kind ofly to have multiple bioactive ursolic acid, design a kind of ursolic acid chemical modified compound amine with anti-tumor activity as lead compound.
The objective of the invention is to be achieved through the following technical solutions:
A kind of ursolic acid chemical modified compound amine with anti-tumor activity, its structural formula is as follows:
R wherein
1Be hydroxyl, acyloxy, alkoxyl group or carbonyl.
Aforesaid a kind of ursolic acid chemical modified compound amine with anti-tumor activity is prepared by following steps:
(1) ursolic acid 1 and corresponding anhydride reaction get 3 β-acyloxy-ursane type-12-alkene-28-carboxylic acid compound 2～4;
The reaction of (2) 3 β-acyloxy-ursane type-12-alkene-28-carboxylic acid compound and oxalyl chloride, again with corresponding amine react N-(3 β-acyloxy-ursane type-12-alkene-28-acyl)-aminated compounds 5～8;
(3) N-(3 β-propionyloxy-ursane type-12-alkene-28-acyl)-morpholine hydrolysis under alkaline condition, 3 hydroxyls are free, get N-[3 β-acyloxy or alkoxyl group-ursane type-12-alkene-28-acyl with Benzoyl chloride or halohydrocarbons reaction again]-morpholine;
(4) N-(3 β-oxyethyl group-ursane type-12-alkene-28-acyl)-aminated compounds 5～6 hydrolysis under alkaline condition gets N-(3 beta-hydroxies-ursane type-12-alkene-28-acyl)-aminated compounds 13,14;
(5) 3 hydroxyl oxidizes with ursolic acid and N-(3 beta-hydroxies-ursane type-12-alkene-28-acyl)-aminated compounds are that carbonyl gets compound 15～19.
Aforesaid a kind of ursolic acid chemical modified compound amine with anti-tumor activity, it has anti-tumor activity, can be used for treating tumor disease.
Advantage of the present invention and effect are:
The present invention carries out chemically modified to the natural product ursolic acid, obtain the analog of a series of ursolic acid, show that through pharmacological testing they have the obvious suppression effect to human body s and ovarian cancer SKOV3 cell, and all are better than the parent compound ursolic acid.
Embodiment
Below the present invention is described in detail.
The present invention finishes through the following steps:
1. the extraction using alcohol medicinal extract of Loquat Leaf is with sherwood oil, 1% sodium hydroxide with to be washed to elutant colourless, the dehydrated alcohol heating for dissolving, and activated carbon decolorizing, filtrate placement is separated out white crystals, gets ursolic acid (compound 1) with recrystallization from hot methanol.
Compound 1 and diacetyl oxide, propionic anhydride or butyryl oxide react compound 2～4
3. compound 2～4 at room temperature reacts with oxalyl chloride, 3-alkanoyloxy-ursane type-12 alkene-28-acyl chlorides, again with the compound 5～8 of corresponding amine reaction.
R wherein
1Be acyloxy, R
2Be substituted-amino
4. compound 7 hydrolysis under alkaline condition, again with corresponding halohydrocarbon or Benzoyl chloride react compound 9～12.
R wherein
1Be alkoxyl group or acyloxy, R
2Be substituted-amino or morpholinyl.
5. compound 5～6 hydrolysis in the methyl alcohol/tetrahydrofuran solution of sodium hydroxide gets compound 13,14.
R wherein
1Be hydroxyl, R
2Be amido
6. 3 hydroxyl oxidizes with ursolic acid and 3-hydroxyl-ursane type-12-alkene-28-amides are that carbonyl gets compound 15～19.
R wherein
1Be carbonyl, R
2Be amido or morpholinyl.
With the positive contrast of taxol, adopt mtt assay that synthesize is carried out preliminary anti tumor activity in vitro test to ursolic acid and institute's synthetic compound.Studies show that part of compounds is better than ursolic acid to the growth-inhibiting effect of human body s, ovarian cancer SKOV3 cell, compound structure and vitro test result are as shown in Table 1 and Table 2.
Table 1 target compound is to Hela cells in vitro anti-tumor activity
The a compound concentration is 10
-5The inhibiting rate that records during mol/L
BIC
50The expression half effective inhibition concentration
Table 2 target compound is to SKOV3 cells in vitro anti-tumor activity
The a compound concentration is 10
-5The inhibiting rate that records during mol/L
BIC
50The expression half effective inhibition concentration
Further specify enforcement of the present invention with example below
Embodiment 1
The preparation of 3 β-acetoxyl group-ursane type-12-alkene-28-carboxylic acid (compound 2):
To magnetic agitation and ursolic acid (200mg are housed, 0.44mmol) 50mL single port bottle in add tetrahydrofuran (THF) 20mL, ursolic acid dissolving back adds pyridine 1mL under room temperature, diacetyl oxide (180mg, 1.76mmol) and a small amount of DMAP, stir under the room temperature, with TLC detection reaction terminal point (developping agent: petrol ether/ethyl acetate=3/1, developer are 10% ethanol solution of sulfuric acid), reaction finishes, steam and remove reaction solvent, with water dispersible solid, 2N hydrochloric acid is transferred pH3～4, suction filtration, filter cake is washed to neutrality, natural drying at room temperature gets white solid 210mg, the crude product silica gel chromatography, eluent is petrol ether/ethyl acetate=10/1 (V/V), get compound 2, white solid 182.2mg, productive rate are 83.6%.mp?285～288℃；
1HNMR(300MHz，CDCl
3)：5.23(s，1H，H-12)，4.47～4.52(t，1H，J＝7.9，H-3)，2.19(m，1H，H-18)，2.04(s，3H，CH
3CO)，1.07(s，3H，CH
3)，0.95(s，6H，CH
3×2)，0.86(s，3H，CH
3)，0.84(m，6H，CH
3×2)，0.76(s，3H，CH
3)；IR(KBr)：3445，2926，1735，1694，1460，1383，1246cm
-1。
Embodiment 2:
N-[3 β-acetoxyl group-ursane type-12-alkene-28-acyl]-preparation of hexahydroaniline (compound 5):
Compound 2 (0.20mmol) is dissolved in the 3mL methylene dichloride, add oxalyl chloride (0.8mmol), stirring at room 24 hours, generate 3-acetoxyl group-ursane type-12-alkene-28-acyl chlorides, steam and remove reaction solvent and oxalyl chloride, resistates adds the 2mL hexanaphthene, removes hexanaphthene under reduced pressure, repeatable operation 2 times.Add the 2mL methylene dichloride in acyl chlorides, adding triethylamine accent pH is 8～9, stirs to add hexahydroaniline (0.8mmol) after 5 minutes, and reaction is 1.5 hours under the room temperature, with TLC detection reaction terminal point (developping agent: sherwood oil/acetone=3/1).After reaction finishes, in reaction solution, add 3mL water, transfer pH to 3, remove methylene dichloride under reduced pressure with 2N hydrochloric acid, separate out white solid, suction filtration, the washing filter cake is to neutrality, drying at room temperature, crude product is through silica gel column chromatogram separating purification, get compound 5, the Powdered solid 56mg of white powder solid white, productive rate 48.3%.
1H?NMR(300MHz，CDCl
3)：5.66～5.64(d，1H，J＝7.5，NH)，5.28(s，1H，H-12)，4.52～4.47(t，1H，J＝7.6，H-3)，3.71(m，1H，NH
CH)，2.05(s，3H，CH
3CO)，1.09(s，3H，CH
3)，0.96(s，6H，CH
3×2)，0.88～0.86(m，9H，CH
3×3)，0.83(s，3H，CH
3)；IR(KBr)：3366，2928，1736，1638，1520，1453，1370，1246cm
-1.ESI-MS：580.6(M+H)
+。
Embodiment 3:
The preparation of N-(3 β-oxyethyl group-ursane type-12-alkene-28-acyl)-morpholine (compound 10):
With N-(3 beta-hydroxies-ursane type-12-alkene-28-acyl)-morpholine (80mg, 0.15mmol) be dissolved in the 3mL dry DMF, stir and add the 100mg sodium hydride down, add the 0.5mL monobromethane, be warming up to 70 ℃, with TLC detection reaction terminal point, reaction in 3 hours finishes, remove DMF under reduced pressure, adding water dispersible solid, is 4～5 with 2N hydrochloric acid adjust pH, filters, the washing filter cake is to neutral, filter cake is dried in air, and crude product is through silica gel column chromatogram separating purification, and eluent is petrol ether/ethyl acetate=6/1 (V/V), get white powder solid 36.5mg, yield 43.3%.mp?197～199℃；
13C?NMR(75MHz，CDCl
3)：175.4(CONH)，138.6(C-13)，125.3(C-12)，86.7(C-3)，66.8(
CH
2O
CH
2)，65.1(O
CH
2CH
3)；IR(KBr)：3431，2923，1623，1459，1387，1118cm
-1；ESI-MS：630.6(M+H)
+。
Embodiment 4:
N-[3-oxo-ursane type-12-alkene-28-acyl]-preparation of hexahydroaniline (compound 17):
(90mg 0.17mmol) joins in the mixed solution of 2mL tetrahydrofuran (THF) and 15mL methylene dichloride and dissolves, and adds diatomite, PDC (0.68mmol) successively with compound 13.Stir under the room temperature, with TLC detection reaction terminal point, the 2h reaction finishes, suction filtration, and filter cake is with washed with dichloromethane (5mL * 2), merging filtrate and washing lotion, be concentrated into 1mL, silica gel chromatography, eluent is petrol ether/ethyl acetate=4/1 (V/V), get white powder solid 54.9mg, productive rate 61.2%.
1H?NMR(300MHz，CDCl
3)：5.66(m，1H，NH)，5.30(s，1H，H-12)，3.72(m，1H，NH
CH)，2.51(m，1H，
H-2a)，2.42(m，1H，
H-2b)，1.10，1.09，1.05(m，9H，CH
3×3)，0.95(s，3H，CH
3)，0.88(m，9H，CH
3×3)；IR(KBr)：3358，2928，1705，1634，1522，1453，1384；ESI-MS：536.3(M+H)
+，558.2(M+Na)
+。
Claims (3)
1. ursolic acid chemical modified compound amine with anti-tumor activity is characterized in that structural formula is as follows:
R wherein
1Be hydroxyl, acyloxy, alkoxyl group or carbonyl.
2. a kind of ursolic acid chemical modified compound amine with anti-tumor activity according to claim 1 is characterized in that being prepared by following steps:
(1) ursolic acid 1 and corresponding anhydride reaction get 3 β-acyloxy-ursane type-12-alkene-28-carboxylic acid compound 2～4;
The reaction of (2) 3 β-acyloxy-ursane type-12-alkene-28-carboxylic acid compound and oxalyl chloride, again with corresponding amine react N-(3 β-acyloxy-ursane type-12-alkene-28-acyl)-aminated compounds 5～8;
(3) N-(3 β-propionyloxy-ursane type-12-alkene-28-acyl)-morpholine hydrolysis under alkaline condition, 3 hydroxyls are free, get N-[3 β-acyloxy or alkoxyl group-ursane type-12-alkene-28-acyl with Benzoyl chloride or halohydrocarbons reaction again]-morpholine;
(4) N-(3 β-oxyethyl group-ursane type-12-alkene-28-acyl)-aminated compounds 5～6 hydrolysis under alkaline condition gets N-(3 beta-hydroxies-ursane type-12-alkene-28-acyl)-aminated compounds 13,14;
(5) 3 hydroxyl oxidizes with ursolic acid and N-(3 beta-hydroxies-ursane type-12-alkene-28-acyl)-aminated compounds are that carbonyl gets compound 15～19.
3. a kind of ursolic acid chemical modified compound amine with anti-tumor activity according to claim 1 is characterized in that it has anti-tumor activity, can be used for treating tumor disease.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2007101583854A CN101161670B (en) | 2007-11-20 | 2007-11-20 | Ursolic acid chemical modified compound amine having antitumor activity |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2007101583854A CN101161670B (en) | 2007-11-20 | 2007-11-20 | Ursolic acid chemical modified compound amine having antitumor activity |
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| Publication Number | Publication Date |
|---|---|
| CN101161670A true CN101161670A (en) | 2008-04-16 |
| CN101161670B CN101161670B (en) | 2011-07-27 |
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|---|---|---|---|
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101891794A (en) * | 2010-07-29 | 2010-11-24 | 福州大学 | Ursolic acid piperazine derivative having antitumor activity and preparation method thereof |
| CN101928322A (en) * | 2010-03-02 | 2010-12-29 | 福州大学 | Ursolic acid modifier polyol monoesters with anti-cancer activity |
| CN102532245A (en) * | 2011-12-31 | 2012-07-04 | 中国人民解放军第三军医大学 | Ursolic acid derivative and preparation method thereof |
| CN113896757A (en) * | 2020-07-07 | 2022-01-07 | 中国科学院上海药物研究所 | Pentacyclic triterpene carbon glycoside compounds, and preparation method and application thereof |
-
2007
- 2007-11-20 CN CN2007101583854A patent/CN101161670B/en not_active Expired - Fee Related
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101928322A (en) * | 2010-03-02 | 2010-12-29 | 福州大学 | Ursolic acid modifier polyol monoesters with anti-cancer activity |
| CN101891794A (en) * | 2010-07-29 | 2010-11-24 | 福州大学 | Ursolic acid piperazine derivative having antitumor activity and preparation method thereof |
| CN102532245A (en) * | 2011-12-31 | 2012-07-04 | 中国人民解放军第三军医大学 | Ursolic acid derivative and preparation method thereof |
| CN102532245B (en) * | 2011-12-31 | 2013-05-15 | 中国人民解放军第三军医大学 | Ursolic acid derivative and preparation method thereof |
| CN113896757A (en) * | 2020-07-07 | 2022-01-07 | 中国科学院上海药物研究所 | Pentacyclic triterpene carbon glycoside compounds, and preparation method and application thereof |
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| CN101161670B (en) | 2011-07-27 |
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Granted publication date: 20110727 Termination date: 20211120 |