CN102180939B - Ursolic acid chemical modifier with antitumor activity and preparation method thereof - Google Patents
Ursolic acid chemical modifier with antitumor activity and preparation method thereof Download PDFInfo
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Abstract
The invention provides an ursolic acid chemical modifier with an antitumor activity and a preparation method thereof, relating to a structure modification technology for natural product ursolic acid. After a hydroxyl group at the C3-position of ursolic acid is oxidized or acetylized, or oximido or acetyloxy imino is formed, and after a carbonyl group is formed at the C11 position, carboxyl at the C28 position is subjected to condensation reaction with amine, amino acid methyl ester, alkamine and the like so as to modify the structure of the ursolic acid, thus a series of ursolic acid derivatives (I1-11, II1-3, III1-5, IV-3 and V1-9) are obtained. Detection proves that the ursolic acid derivatives have a certain inhibition effect on human cervical carcinoma HeLa cells, human ovarian caner SKOV3 cells, human liver cancer HepG2 cells and gastric cancer BGG-823 cells. The structures of the ursolic acid derivatives are shown in the specification.
Description
Technical field
The present invention relates to a kind of structure of modification technology of natural product ursolic acid, particularly relate to acid as chemical modifier for ursolic of a kind of anti-tumor activity and preparation method thereof.
Background technology
Ursolic acid (Ursolic acid, UA) has another name called ursonic acid, urson, chemistry 3 β by name-Hydroxy-urs-12 – en-28-oic acid, molecular formula C
30H
48O
3, relative molecular mass 456.68,285 ~ 291 ℃ of fusing points.The formal distribution that UA is combined into glycosides with free form or with sugar belongs to 62 kind of plant in about 7 46 of sections.Modern study proves, ursolic acid has the various biological effect such as antibacterial, the anti-hepatitis of anti-inflammatory, anti-diabetic, AIDS virus resisting, blood fat reducing and arteriosclerosis and obvious anti-oxidant function.Ursolic acid has obvious carcinogenesis, anti-promoting, induces the effects such as the differentiation of F9 teratocarcinoma cell and angiogenesis inhibitor simultaneously, has the antitumour activity of wide spectrum, good prospect in medicine and exploitation value.
The chemical structural formula of ursolic acid:
In recent years, ursolic acid comes into one's own day by day to inhibition and the lethal effect of tumour.Studies show that, ursolic acid is except suppressing archaeal dna polymerase and DNA topological enzyme activity, suppressing the propagation of cell, can also improve the intracellular calcium level, activate the proteolysis cascade reaction of caspase (caspase), induce the kinds of tumor cells apoptosis such as lung carcinoma cell A-549, leukemia cell P-388.
Be lead compound to having multiple bioactive ursolic acid, the chemical modification object that designs serial ursolic acid is present very important problem.
Summary of the invention
The object of the present invention is to provide acid as chemical modifier for ursolic of a kind of anti-tumor activity and preparation method thereof, to have multiple bioactive ursolic acid as lead compound, design the chemical modification object of a series of ursolic acid.
The objective of the invention is to be achieved through the following technical solutions:
A kind of acid as chemical modifier for ursolic of anti-tumor activity, described acid as chemical modifier for ursolic comprises:
The following ursolic acid derivative of one class formation formula:
Wherein: R1 is carbonyl or alkanoyloxy or oximido or alkyloyloxyethyl imino-; R2 is carbonyl or hydrogen; R3 is fatty amido, aryl amine and substituted aromatic amines base, and phenylhydrazino, alcohol is amino, benzyloxy, morpholinyl, ester is amino;
Ursolic acid modifier:
Wherein: R1 is carbonyl, when R2 is hydrogen, is compound,
Wherein: R3 is-NHC
4H
9,-NHC
6H
4(
p-Cl) ,-NHC
6H
4(
p-CH
3) ,-NHC
6H
4(
p-OCH
3) ,-NHC
6H
3(
p-Cl) (
o-F) ,-NHNHC
6H
5,-NHCH
2CH
2OH ,-NH (CH
2)
3OH ,-NHCH (CH
3) CH
2OH ,-NHCH (CH
2C
6H
5) COO CH
3,-NHCH
2CH
2COOCH
3;
R1 is carbonyl, when R2 is carbonyl, is compound ii,
Wherein: R3 is-NHC
6H
11,-NHCH (CH
3) CH
2OH,
R1 is acetoxyl group, when R2 is carbonyl, is the compound III,
Wherein: R3 is-NHC
6H
5,-NHC
6H
11,-NHCH (CH
3) CH
2OH,
-NHCH(COOCH
3)CH
2CH(CH
3)
2；
R1 is oximido, when R2 is hydrogen, is compounds Ⅳ,
Wherein: R3 is-OBn-NHNHC
6H
5,-NHC
6H
11;
R1 is the acetyl oxyimino group, when R2 is hydrogen, is the compound V,
Wherein: R3 is-OBn-OC
6H
4(
o-NO
2) ,-NH (CH
2)
3CH
3,-NHC
6H
5,-N (CH
2CH
2CH
2CH
3)
2,-NHCH
2CH
2OH ,-NHC
6H
4(
o-CH
2OH),
A kind of preparation method of acid as chemical modifier for ursolic of anti-tumor activity, this preparation method may further comprise the steps:
(1) ursolic acid and Jones reagent react get 3-oxo ursolic acid;
(2) 3-oxo ursolic acid and oxalyl chloride reaction is reacted to get compound with aliphatic amide, substituted aromatic amines, phenylhydrazine, amino alcohol, amino acid methyl ester again
I 1-11
(3) 3-oxo ursolic acid and CrO
3React to get intermediate 3 in the acetum of 5% aceticanhydride, 11-dioxo ursolic acid with the oxalyl chloride reaction, reacts to get compound with aliphatic amide, amino alcohol and heterocyclic amine more again
II 1-3
(4) ursolic acid and aceticanhydride react to get 3-acetoxyl group ursolic acid under DMAP catalysis, again with CrO
3In the acetum of 5% aceticanhydride, react to get intermediate 3-acetoxyl group-11-carbonyl ursolic acid;
(5) 3-acetoxyl group-11-carbonyl ursolic acid and oxalyl chloride reaction is reacted to get compound with arylamine, aliphatic amide, amino alcohol, heterocyclic amine and amino acid methyl ester again
III 1-5
(6) 3-oxo ursolic acid and oxammonium hydrochloride react to get 3-oximido ursolic acid in pyridine, react with the bromobenzyl reaction or with oxalyl chloride, react to get compound with phenylhydrazine and hexahydroaniline again
IV 1-3
(7) 3-oximido ursolic acid and aceticanhydride react to get 3-acetyl oxyimino group ursolic acid under DMAP catalysis
V 1
(8) 3-acetyl oxyimino group ursolic acid and bromobenzyl react or react with oxalyl chloride, react to get compound with p-NP, aliphatic amide, arylamine, amino alcohol and heterocyclic amine again
V 2-9
Embodiment
Below the present invention is described in detail.
1. the extraction using alcohol medicinal extract of Loquat Leaf is colourless to elutant with sherwood oil, 1% sodium hydroxide and water, the dehydrated alcohol heating for dissolving, activated carbon decolorizing, filtrate is placed and to be separated out white crystals, with recrystallization from hot methanol get ursolic acid (
UA).
2.
UAWith the reaction under 0 ℃ of Jones reagent, after the oxalyl chloride activation, further under alkaline condition, react to get compound with aliphatic amide, substituted aromatic amines, phenylhydrazine, amino alcohol, amino acid methyl ester
I 1-11
Wherein: R1 is carbonyl, and R2 is hydrogen, and R3 is-NHC
4H
9,-NHC
6H
4(
p-Cl) ,-NHC
6H
4(
p-CH
3) ,-NHC
6H
4(
p-OCH
3) ,-NHC
6H
3(
p-Cl) (
o-F) ,-NHNH C
6H
5,-NHCH
2CH
2OH ,-NH (CH
2)
3OH ,-NHCH (CH
3) CH
2OH ,-NHCH (CH
2C
6H
5) COOCH
3,-NHCH
2CH
2COOCH
3
3. 3,11-dioxo ursolic acid and oxalyl chloride at room temperature react, and further react to get compound with aliphatic amide, amino alcohol and heterocyclic amine under alkaline condition
II 1-3
Wherein: R1 is carbonyl, and R2 is carbonyl, and R3 is-NHC
6H
11,-NHCH (CH
3) CH
2OH,
4. 3-acetoxyl group-11-carbonyl ursolic acid and oxalyl chloride at room temperature react, and further react to get compound with arylamine, aliphatic amide, amino alcohol, heterocyclic amine and amino acid methyl ester under alkaline condition
III 1-5
Wherein: R1 is acetoxyl group, and R2 is carbonyl, and R3 is-NHC
6H
5,-NHC
6H
11,-NHCH (CH
3) CH
2OH,
,-NHCH (COOCH
3) CH
2CH (CH
3)
2
5. 3-oximido ursolic acid and bromobenzyl react or at room temperature react with oxalyl chloride, further react to get compound with phenylhydrazine and hexahydroaniline under alkaline condition
IV 1-3
Wherein: R1 is oximido, and R2 is hydrogen, and R3 is-OBn-NHNHC
6H
5,-NHC
6H
11
6. 3-acetyl oxyimino group ursolic acid and bromobenzyl react or react at normal temperatures with oxalyl chloride, further react to get compound with p-NP, aliphatic amide, arylamine, amino alcohol and heterocyclic amine under alkaline condition
V 2-9
6.
Wherein: R1 is the acetyl oxyimino group, and R2 is hydrogen, and R3 is-OBn-OC
6H
4(
p-NO
2) ,-NH (CH
2)
3CH
3,-NHC
6H
5,-N (CH
2CH
2CH
2CH
3)
2,-NHCH
2CH
2OH ,-NHC
6H
4(
o-CH
2OH),
With Gefitinib and the positive contrast of VP-16, adopt mtt assay that ursolic acid and the compound that synthesize are carried out preliminary anti tumor activity in vitro and test.Studies show that the compound that is synthesized has certain restraining effect to Human Cervical (HeLa) cell, human ovarian cancer (SKOV3) cell, human liver cancer cell (HepG2) and cancer of the stomach (BGC-823) cell, compound structure and in vitro tests result are shown in table 1, table 2, table 3 and table 4.
Table 1 target compound is to the anti tumor activity in vitro of HeLa cell
Annotate: a. compound concentration is 10
-5The inhibiting rate that records during mol/L; B. IC
50The expression half effective inhibition concentration.
Table 2 target compound is to the anti tumor activity in vitro of SKOV3 cell
Annotate: a. compound concentration is 10
-5The inhibiting rate that records during mol/L, b. IC
50The expression half effective inhibition concentration.
Table 3 target compound is to the anti tumor activity in vitro of HepG2 cell
Annotate: a. compound concentration is 10
-5The inhibiting rate that records during mol/L, b. IC
50The expression half effective inhibition concentration.
Table 4 target compound is to the anti tumor activity in vitro of BGC-823 cell
Annotate: a. compound concentration is 10
-5The inhibiting rate that records during mol/L, b. IC
50The expression half effective inhibition concentration.
The present invention will be further described below in conjunction with embodiment:
Embodiment 1
N-[3-oxo-Ursane-12-alkene-28-acyl]-monoethanolamine (compound
I 7 ) preparation.
With ursolic acid (0.100g, 0.22mmol) be dissolved in the 1.5mL acetone, in the time of 0 ℃ Jones reagent (0.4mL) is slowly dripped, rise to room temperature reaction, TLC controls reaction end, then is cooled to 0 ℃, adds its oxidisability of Virahol (5mL) stirring at room 30min cancellation, decompress filter, collect filtrate, steam except reaction solvent, behind an amount of saturated salt solution 5mL of adding, add again 10 mL ethyl acetate extractions, extract 3 times, merge organic phase, concentrated, vacuum-drying gets white solid 3-oxo ursolic acid 90.4 mg.With its (50mg, 0.1099mmol) be dissolved in the 4mL methylene dichloride, add oxalyl chloride (0.4396mmol), stirring at room 20 hours, generate 3-oxo-Ursane-12-alkene-28-acyl chlorides, steam except reaction solvent and unreacted oxalyl chloride, resistates adds the 2mL hexanaphthene, remove hexanaphthene under reduced pressure, repeatable operation 2 times.After adding 2mL methylene dichloride made it to dissolve fully in the acyl chlorides, adding triethylamine accent pH was 9～10, stirs after 5 minutes, adds thanomin (26.82mg, 0.4396mmol), reacts under the room temperature, with TLC detection reaction terminal point.After reaction finishes, add 2mL water in reaction solution, transfer pH to 3～4 with 2mol/L hydrochloric acid, standing demix separates organic phase, adds the 3mL methylene dichloride to water again, extracts three times, merges organic phase.Underpressure distillation gets white solid N-[3-oxo-Ursane-12-alkene-28-acyl]-monoethanolamine.Crude product silica gel chromatography, eluent are petrol ether/ethyl acetate=2.5/1(V/V), get white powder solid 28.60mg, productive rate 52.3%.mp 160~162℃;
1H-NMR (300MHz, CDCl
3): δ 6.38 (s, 1H, N
H), 5.37(s, 1H, H-12), 3.71(t, 2H, C
H 2OH), 3.43(m, 1H, NHC
Ha), 3.32(m, 1H, NHC
Hb), 2.51 (m, 1H, H-2b), 2.42 (m, 1H, H-2a), 1.13 (s, 3H, CH
3), 1.11(s, 3H, CH
3), 1.07 (s, 3H, CH
3), 1.02 (d, 3H, CH
3), 0.88 (s, 3H, CH
3); ESI-MS: 498.6(M+H)
+。
Embodiment 2
N-[3,11-dioxo-Ursane-12-alkene-28-acyl]-morpholine (compound
II 3 ) synthetic.
Ursolic acid (UA) (228mg, 0.5mmol) is dissolved in the acetic acid solution of 15mL 5% diacetyl oxide and adds CrO
399.6mg reaction mixture stirred 4 hours.Add 20mL water and 20mL methylene dichloride, after the layering, water layer merges organic phase, with saturated NaHCO with 20mL dichloromethane extraction twice
3Washing soln is washed to neutrality, anhydrous Na again to slight alkalinity
2SO
4Drying, decompress filter, the filtrate decompression precipitation obtains green jelly.Get product 3,11-dioxo-Ursane-12-alkene-28-carboxylic acid through column chromatography (petrol ether/ethyl acetate=3/1 (V/V)) purifying.It is dissolved in the 5mL methylene dichloride, adds oxalyl chloride (0.2mmol), stirring at room 20 hours, generate 3,11-dioxo-Ursane-12-alkene-28-acyl chlorides, steam except reaction solvent and unreacted oxalyl chloride, resistates adds the 5mL hexanaphthene, removes hexanaphthene under reduced pressure, twice of repeatable operation.Add the 5mL methylene dichloride in the acyl chlorides, add triethylamine and transfer pH to 9～10, stir after 5 minutes, add morpholine (0.3mmol), react under the room temperature, with TLC detection reaction terminal point.Reaction removes methylene dichloride under reduced pressure after finishing, and adds the 5mL salt solution in the reaction solution, transfers pH to 3～4 with 2mol/L hydrochloric acid, separates out white solid, decompress filter, and the washing filter cake is to neutral.Drying at room temperature, crude product get white powder solid 29.4mg through silica gel chromatography.Productive rate: 51.6%.mp: 246～248℃.
1H-NMR (300MHz, CDCl
3): δ 5.60 (s, 1H, H-12), 3.66~3.68 (m, 8H, N-C
H 2×4), 3.00 (m, 1H, H-18),2.67 (m, 1H, H-2), 2.36 (m, 1H, H-9), 1.19 (s, 3H, CH
3), , 0.98 (d, 3H, CH
3)0.87 (d, 3H, CH
3) ; ESI-MS: 538.5 (M+H)
+。
Embodiment 3
N-[3 β-acetoxyl group-Ursane-11-carbonyl-12-alkene-28-acyl]-leucine methyl ester hydrochloride (compound
III 5 ) preparation.
To magnetic agitation and ursolic acid (300mg are housed, 0.66mmol) eggplant-shape bottle in add tetrahydrofuran (THF) 10mL, after the ursolic acid dissolving, under room temperature, add pyridine 1mL, diacetyl oxide (19.8 mmol) and a small amount of DMAP, stir under the room temperature, react complete, remove reaction solvent under reduced pressure, with water dispersible solid, 2mol/L hydrochloric acid is transferred pH3～4, suction filtration, filter cake is washed to neutrality, and natural drying at room temperature gets white solid 310mg, the crude product silica gel chromatography, eluent is petrol ether/ethyl acetate=10/1(V/V), get white solid 3-acetoxyl group ursolic acid 228.4mg, and productive rate is 86.6%.Get in the acetic acid solution that above-mentioned product 100mg (0.2mmol) is dissolved in 15mL 5% diacetyl oxide and add CrO
399.6mg reaction mixture stirred 4 hours.Add 20mL water and 20mL methylene dichloride, after the layering, water layer merges organic phase, with saturated NaHCO with 20mL dichloromethane extraction twice
3Washing soln is washed to neutrality, anhydrous Na again to slight alkalinity
2SO
4Drying, decompress filter, the filtrate decompression precipitation obtains the light green thing.Get product 3 β-acetoxyl group-Ursane-11-carbonyl-12-alkene-28-carboxylic acid through column chromatography (petrol ether/ethyl acetate=3/1 (V/V)) purifying, get its (50mg, 0.1mmol) be dissolved in the 5mL methylene dichloride, add oxalyl chloride (0.2mmol), stirring at room 20 hours, generate 3 β-acetoxyl group-Ursane-11-carbonyl-12-alkene-28-acyl chlorides, steam except reaction solvent and unreacted oxalyl chloride, resistates adds the 5mL hexanaphthene, remove hexanaphthene under reduced pressure, twice of repeatable operation.Add the 5mL methylene dichloride in the acyl chlorides, add triethylamine and transfer pH to 9～10, stir after 5 minutes, add leucine methyl ester hydrochloride (0.3mmol), react under the room temperature, with TLC detection reaction terminal point.Reaction removes methylene dichloride under reduced pressure after finishing, and adds the 5mL salt solution in the reaction solution, transfers pH to 3～4 with 2mol/L hydrochloric acid, separates out white solid, decompress filter, and the washing filter cake is to neutral.Drying at room temperature, crude product get white powder solid N-[3 β-acetoxyl group-Ursane-11-carbonyl-12-alkene-28-acyl through silica gel chromatography]-leucine methyl ester hydrochloride 30mg.Productive rate: 49.1%.mp: 135~138℃.
1H-NMR (300MHz, CDCl
3):δ 6.38 (s, 1H, N
H),5.67 (s,1H,H-12), 4.53 (m, 1H, H-3), 3.70 (m, H, NC
H), 1.10 (s, 3H, CH
3), 0.90 (d, 3H, CH
3) , 0.81 (d, 3H, CH
3), 0.70~0.76 (d, 6H, CH
3×2); ESI-MS: 626.4 (M+H)
+。
Embodiment 4
N-[3-oximido-Ursane-12-alkene-28-acyl]-hexahydroaniline (compound
IV 3 ) preparation.
With 3-oxo ursolic acid (50 mg, 0.11 mmol) be dissolved in an amount of pyridine, add hydrochloric acid azanol (100 mg, 1.44 mmol), 115 ℃ of lower backflows 1.5 hours, react complete, pour in the frozen water, produce a large amount of white precipitates, suction filtration, the washing filter cake, dry white solid 3-oximido ursolic acid 42.8 mg that get, productive rate is 82.96%.mp 215.6～218℃；IR (KBr): 3417, 2919, 2850, 1688, 1649,1277,1183cm
-1; ESI-MS: 468.2(M-H)
-
With 3-oximido ursolic acid (50mg, 0.1066mmol) be dissolved in the 4mL methylene dichloride, add oxalyl chloride (0.4264mmol), stirring at room 20 hours, generate 3-oximido-Ursane-12-alkene-28-acyl chlorides, steam except reaction solvent and unreacted oxalyl chloride, resistates adds the 2mL hexanaphthene, remove hexanaphthene under reduced pressure, repeatable operation 2 times.After adding 2mL methylene dichloride made it to dissolve fully in the acyl chlorides, adding triethylamine accent pH was 9～10, stirs after 5 minutes, adds hexahydroaniline (42.21mg, 0.4264mmol), reacts TLC monitoring reaction terminal point under the room temperature.Reaction removes methylene dichloride under reduced pressure after finishing, and adds 2mL water in reaction solution, transfers pH to 3～4 with 2mol/L hydrochloric acid, separates out white solid, decompress filter, and the washing filter cake is to neutral.Drying at room temperature crude product silica gel chromatography, eluent are petrol ether/ethyl acetate=5/1 (V/V), get white powder solid 19.4mg, and productive rate is 33.05%.mp 96.6~98.9℃；IR (KBr): 3357, 2927, 2853, 1732, 1634,1454cm
-1;
1H-NMR (300MHz, CDCl
3): δ 7.73(s, 1H, CON
H), 5.37(s, 1H, H-12), 3.37~3.39 (m, 1H, NC
H), 2.58(d, 1H, H-18), 2.29(s, 1H, O
H), 1.645~1.665(m, 10H, C
H 2×5), 1.33~1.38 (m, 2H, H-2), 1.11 (s, 6H, CH
3×2), 1.07 (s, 3H, CH
3), 1.05 (s,3H, CH
3), 0.98(s,3H,CH
3), 0.89 (d, 3H, CH
3), 0.85(s, 3H, CH
3); ESI-MS: 587.5 (M+Cl)
+。
Embodiment 5
N-[3-acetyl oxyimino group-Ursane-12-alkene-28-acyl]-morpholine (compound
V 9 ) preparation.
With 3-oximido ursolic acid (50mg, 0.1066mmol) be dissolved in the 4mL tetrahydrofuran (THF) (THF), then under room temperature, add pyridine 0.25mL, diacetyl oxide (0.337g, 3.3mmol) and a small amount of DMAP, stir under the room temperature, with TLC detection reaction terminal point, react complete, remove reaction solvent under reduced pressure, with water dispersible solid, 2mol/L hydrochloric acid is transferred pH3～4, suction filtration, and filter cake is washed to neutrality, natural drying at room temperature, crude product silica gel chromatography, eluent are petrol ether/ethyl acetate=10/1 (V/V), get 3-acetyl oxyimino group ursolic acid
V 1 40.2mg productive rate is 73.80%.mp 87.5～91.4℃；IR (KBr): 3290, 2926, 2855, 1747, 1696, 1653, 1233cm
-1;
1H-NMR (300MHz, CDCl
3): δ 11.0(s, 1H, COO
H),5.29 (s, 1H,H-12), 2.55 (d,1H,H-18), 2.18(s,3H,C
H 3COON), 1.33~1.38 (m, 2H, H-2), 1.11 (s, 6H, CH
3×2), 1.07 (s, 3H, CH
3), 1.05 (s, 3H, CH
3), 0.98 (s, 3H, CH
3), 0.89 (d, 3H, CH
3), 0.85(s, 3H, CH
3); ESI-MS: 510.5(M-H)
-。
With 3-acetyl oxyimino group ursolic acid (50mg, 0.0978mmol) be dissolved in the 4mL methylene dichloride, add oxalyl chloride (0.3914mmol), stirring at room 20 hours, generate 3-acetyl oxyimino group-Ursane-12-alkene-28-acyl chlorides, steam except reaction solvent and unreacted oxalyl chloride, resistates adds the 2mL hexanaphthene, remove hexanaphthene under reduced pressure, repeatable operation 2 times.After adding 2mL methylene dichloride made it to dissolve fully in the acyl chlorides, adding triethylamine accent pH was 9～10, stir after 5 minutes, the adding morpholine (33.64,0.3912mmol), react TLC monitoring reaction terminal point under the room temperature.Reaction removes methylene dichloride under reduced pressure after finishing, and adds 2mL water in reaction solution, transfers pH to 3～4 with 2mol/L hydrochloric acid, separates out white solid, decompress filter, and the washing filter cake is to neutral.Drying at room temperature, the crude product silica gel chromatography, eluent is petrol ether/ethyl acetate=10/1 (V/V), gets white solid 20.7mg, productive rate 36.0%.mp 129.8~131.2℃; IR (KBr): 1745, 1634, 1233, 1117, 1044, 852 cm
-1;
1H-NMR (300MHz, CDCl
3): δ 5.35(s, 1H, H-12), 3.61~3.66(m, 8H, N
4 H 8NO), 3.00(d, 1H, H-18), 2.15(s, 3H, C
H 3COON); ESI-MS: 603.5(M+Na)
+。
Claims (2)
1. the acid as chemical modifier for ursolic of an anti-tumor activity is characterized in that, described acid as chemical modifier for ursolic is:
Wherein:
R1 is the acetyl oxyimino group, and when R2 was hydrogen, R3 was-NHC
6H
5,-NHC
6H
4(
o-CH
2OH),
2. the preparation method of the acid as chemical modifier for ursolic of an anti-tumor activity is characterized in that, the preparation of N-[3-acetyl oxyimino group-Ursane-12-alkene-28-acyl]-morpholine comprises the steps:
50mg, 0.1066mmol 3-oximido ursolic acid are dissolved in the 4mL tetrahydrofuran (THF) (THF), then under room temperature, add pyridine 0.25mL and 0.337g, 3.3mmol diacetyl oxide and a small amount of DMAP, stir under the room temperature, with TLC detection reaction terminal point, react complete, remove reaction solvent under reduced pressure, with water dispersible solid, 2mol/L hydrochloric acid is transferred pH3～4, suction filtration, and filter cake is washed to neutrality, natural drying at room temperature, crude product silica gel chromatography, eluent are petrol ether/ethyl acetate=10/1 (V/V), get 3-acetyl oxyimino group ursolic acid 40.2mg;
50mg, 0.0978mmol 3-acetyl oxyimino group ursolic acid are dissolved in the 4mL methylene dichloride, add the 0.3914mmol oxalyl chloride, stirring at room 20 hours, generate 3-acetyl oxyimino group-Ursane-12-alkene-28-acyl chlorides, steam except reaction solvent and unreacted oxalyl chloride, resistates adds the 2mL hexanaphthene, removes hexanaphthene under reduced pressure, repeatable operation 2 times; After adding 2mL methylene dichloride made it to dissolve fully in the acyl chlorides, adding triethylamine accent pH was 9～10, stirs after 5 minutes, adds 33.64,0.3912mmol morpholine, reacts TLC monitoring reaction terminal point under the room temperature; Reaction removes methylene dichloride under reduced pressure after finishing, and adds 2mL water in reaction solution, transfers pH to 3～4 with 2mol/L hydrochloric acid, separates out white solid, decompress filter, and the washing filter cake is to neutral; Drying at room temperature, the crude product silica gel chromatography, eluent is petrol ether/ethyl acetate=10/1 (V/V), gets white solid 20.7mg.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110078125 CN102180939B (en) | 2011-03-30 | 2011-03-30 | Ursolic acid chemical modifier with antitumor activity and preparation method thereof |
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| CN 201110078125 CN102180939B (en) | 2011-03-30 | 2011-03-30 | Ursolic acid chemical modifier with antitumor activity and preparation method thereof |
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| Publication Number | Publication Date |
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| CN102180939A CN102180939A (en) | 2011-09-14 |
| CN102180939B true CN102180939B (en) | 2013-02-20 |
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| WO2018069086A1 (en) | 2016-10-13 | 2018-04-19 | Vivacell Biotechnology España S.L. | Hydroxamate triterpenoid derivatives |
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| 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 |
| CN102675406A (en) * | 2012-06-04 | 2012-09-19 | 福州大学 | Ursolic acid nitrogen heterocyclic ring structure modifiers with antitumor activity and preparation method for ursolic acid nitrogen heterocyclic ring structure modifiers |
| CN102993018B (en) * | 2012-08-10 | 2015-08-05 | 浙江工业大学 | A kind of 5-nitro coffeic acid Buddha's warrior attendant alcohol ester and preparing the application in antitumor drug |
| CN103626828A (en) * | 2013-11-20 | 2014-03-12 | 沈阳化工大学 | Anti-tumor active ursolic acid chemical modifier and preparation method thereof |
| US10343997B1 (en) | 2018-12-04 | 2019-07-09 | King Saud University | Ursolic acid derivatives |
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| CN1887898A (en) * | 2006-07-19 | 2007-01-03 | 沈阳化工学院 | Amino acid as chemical modifier for ursolic acid |
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| Chao-Mei Ma,et al.The cytotoxic activity of ursolic acid derivatives.《European Journal of Medicinal Chemistry》.Elsevier,2005,第40卷(第6期),582–589. |
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| WO2018069086A1 (en) | 2016-10-13 | 2018-04-19 | Vivacell Biotechnology España S.L. | Hydroxamate triterpenoid derivatives |
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