CN102180939A - 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 PDF

Info

Publication number
CN102180939A
CN102180939A CN2011100781252A CN201110078125A CN102180939A CN 102180939 A CN102180939 A CN 102180939A CN 2011100781252 A CN2011100781252 A CN 2011100781252A CN 201110078125 A CN201110078125 A CN 201110078125A CN 102180939 A CN102180939 A CN 102180939A
Authority
CN
China
Prior art keywords
ursolic acid
nhc
acid
react
ursolic
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN2011100781252A
Other languages
Chinese (zh)
Other versions
CN102180939B (en
Inventor
孟艳秋
白忠伟
夏燕
白洁
焉兆凯
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shenyang University of Chemical Technology
Original Assignee
Shenyang University of Chemical Technology
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shenyang University of Chemical Technology filed Critical Shenyang University of Chemical Technology
Priority to CN 201110078125 priority Critical patent/CN102180939B/en
Publication of CN102180939A publication Critical patent/CN102180939A/en
Application granted granted Critical
Publication of CN102180939B publication Critical patent/CN102180939B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

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

Acid as chemical modifier for ursolic of a kind of anti-tumor activity and preparation method thereof
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 UA) has another name called ursonic acid to ursolic 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.UA is with free form or be distributed in 46 of about 7 sections with form that sugar is combined into glycosides and belong to 62 kind of plant.Modern study proves that ursolic acid has various biological effect and tangible anti-oxidant functions such as antibacterial, the anti-hepatitis of anti-inflammatory, anti-diabetic, AIDS virus resisting, blood fat reducing and arteriosclerosis.Ursolic acid has tangible carcinogenesis, anti-promoting, induces effects such as 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:
Figure 124566DEST_PATH_IMAGE001
。
In recent years, ursolic acid comes into one's own day by day to the 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 kinds of tumor cells apoptosis such as lung carcinoma cell A-549, leukemia cell P-388.
To having multiple bioactive ursolic acid is lead compound, and 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, is lead compound to have multiple bioactive ursolic acid, designs 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 ursolic acid derivative that one class formation formula is following:
Figure 105685DEST_PATH_IMAGE002
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 amino;
Ursolic acid modifier:
Wherein: R1 is a carbonyl, when R2 is hydrogen, is compound,
Figure 326711DEST_PATH_IMAGE003
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 a carbonyl, when R2 is carbonyl, is compound ii,
Figure 765301DEST_PATH_IMAGE004
Wherein: R3 is-NHC 6H 11,-NHCH (CH 3) CH 2OH,
Figure 777427DEST_PATH_IMAGE005
R1 is an acetoxyl group, when R2 is carbonyl, is the compound III,
Figure 481727DEST_PATH_IMAGE006
Wherein: R3 is-NHC 6H 5,-NHC 6H 11,-NHCH (CH 3) CH 2OH,
Figure 987401DEST_PATH_IMAGE007
-NHCH(COOCH 3)CH 2CH(CH 3) 2；
R1 is an oximido, when R2 is hydrogen, is the compound 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,
Figure 424646DEST_PATH_IMAGE009
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),
Figure 800263DEST_PATH_IMAGE010
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 the reaction, again with aliphatic amide, substituted aromatic amines, phenylhydrazine, amino alcohol, amino acid methyl ester react compound I 1-11
(3) 3-oxo ursolic acid and CrO 3In the acetum of 5% aceticanhydride, react intermediate 3,11-dioxo ursolic acid, again with oxalyl chloride reaction, again with aliphatic amide, amino alcohol and heterocyclic amine react compound II 1-3
(4) ursolic acid and aceticanhydride under DMAP catalysis, react 3-acetoxyl group ursolic acid, again with CrO 3In the acetum of 5% aceticanhydride, react intermediate 3-acetoxyl group-11-carbonyl ursolic acid;
(5) 3-acetoxyl group-11-carbonyl ursolic acid and oxalyl chloride the reaction, again with arylamine, aliphatic amide, amino alcohol, heterocyclic amine and amino acid methyl ester react compound III 1-5
(6) 3-oxo ursolic acid and oxammonium hydrochloride in pyridine, react 3-oximido ursolic acid, with bromobenzyl reaction or with the oxalyl chloride reaction, again with phenylhydrazine and hexahydroaniline react compound IV 1-3
(7) 3-oximido ursolic acid and aceticanhydride under DMAP catalysis, react 3-acetyl oxyimino group ursolic acid V 1
(8) reaction of 3-acetyl oxyimino group ursolic acid and bromobenzyl or with oxalyl chloride reaction, again with p-NP, aliphatic amide, arylamine, amino alcohol and heterocyclic amine react compound V201110078125.2 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, and activated carbon decolorizing, filtrate placement is separated out white crystals, gets ursolic acid (UA) with recrystallization from hot methanol.
2. UA and Jones reagent is 0 ℃ of down reaction, after the oxalyl chloride activation further under alkaline condition with aliphatic amide, substituted aromatic amines, phenylhydrazine, amino alcohol, amino acid methyl ester react compound I 1-11
Figure 651239DEST_PATH_IMAGE011
Wherein: R1 is a carbonyl, and R2 is a 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, further under alkaline condition with aliphatic amide, amino alcohol and heterocyclic amine react compound II 1-3
Figure 497710DEST_PATH_IMAGE012
Wherein: R1 is a carbonyl, and R2 is a 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, further under alkaline condition with arylamine, aliphatic amide, amino alcohol, heterocyclic amine and amino acid methyl ester react compound III 1-5
Figure 477003DEST_PATH_IMAGE013
Wherein: R1 is an acetoxyl group, and R2 is a carbonyl, and R3 is-NHC 6H 5,-NHC 6H 11,-NHCH (CH 3) CH 2OH,
Figure 389727DEST_PATH_IMAGE014
,-NHCH (COOCH 3) CH 2CH (CH 3) 2
5. 3-oximido ursolic acid and bromobenzyl reaction or at room temperature react with oxalyl chloride, further under alkaline condition with phenylhydrazine and hexahydroaniline react compound IV 1-3
Figure 74392DEST_PATH_IMAGE015
Wherein: R1 is an oximido, and R2 is a hydrogen, and R3 is-OBn-NHNHC 6H 5,-NHC 6H 11
6. 3-acetyl oxyimino group ursolic acid and bromobenzyl reaction or react at normal temperatures with oxalyl chloride, further under alkaline condition with p-NP, aliphatic amide, arylamine, amino alcohol and heterocyclic amine react compound V 2-9
6.
Figure 545694DEST_PATH_IMAGE016
Wherein: R1 is the acetyl oxyimino group, and R2 is a 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),
Figure 287383DEST_PATH_IMAGE017
With Gefitinib and the positive contrast of VP-16, adopt mtt assay that ursolic acid and institute's synthetic compound are carried out preliminary anti tumor activity in vitro test.Studies show that institute's synthetic compound has certain restraining effect to human body cervical cancer (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 HeLa cells in vitro anti-tumor activity
Figure 440016DEST_PATH_IMAGE018
Figure 247697DEST_PATH_IMAGE019
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 SKOV3 cells in vitro anti-tumor activity
Figure 147313DEST_PATH_IMAGE021
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 HepG2 cells in vitro anti-tumor activity
Figure 401839DEST_PATH_IMAGE022
Figure 890458DEST_PATH_IMAGE023
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 BGC-823 cells in vitro anti-tumor activity
Figure 880060DEST_PATH_IMAGE024
Figure 955595DEST_PATH_IMAGE025
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 type-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, is cooled to 0 ℃ then, adds its oxidisability of Virahol (5mL) stirring at room 30min cancellation, decompress filter, collect filtrate, steam and remove reaction solvent, behind an amount of saturated salt solution 5mL of adding, add 10 mL ethyl acetate extractions again, extract 3 times, merge organic phase, concentrate, 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 type-12-alkene-28-acyl chlorides, steam and remove 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, and (26.82mg 0.4396mmol), reacts under the room temperature, with TLC detection reaction terminal point to add thanomin.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 again to water, extracts three times, merges organic phase.Underpressure distillation gets white solid N-[3-oxo-ursane type-12-alkene-28-acyl]-monoethanolamine.Crude product silica gel chromatography, eluent are petrol ether/ethyl acetate=2.5/1(V/V), 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 type-12-alkene-28-acyl]-morpholine (compound 〉 II 3 ) synthetic.
(228mg 0.5mmol) is dissolved in the acetic acid solution of 15mL 5% diacetyl oxide and adds CrO with ursolic acid (UA) 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 type-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 type-12-alkene-28-acyl chlorides is steamed and is removed 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 type-11-carbonyl-12-alkene-28-acyl]-the 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, treat that ursolic acid dissolving back adds pyridine 1mL under room temperature, diacetyl oxide (19.8 mmol) and a small amount of DMAP, stir under the room temperature, reaction finishes, 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 a petrol ether/ethyl acetate=10/1(V/V), white solid 3-acetoxyl group ursolic acid 228.4mg, 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 type-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 generates 3 β-acetoxyl group-ursane type-11-carbonyl-12-alkene-28-acyl chlorides, steam and remove 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 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 type-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 type-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 oxammonium hydrochloride (100 mg, 1.44 mmol), 115 ℃ were refluxed 1.5 hours down, reaction finishes, and pours in the frozen water, produces 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 type-12-alkene-28-acyl chlorides, steam and remove 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, and (42.21mg 0.4264mmol), reacts under the room temperature, TLC monitoring reaction terminal point to add hexahydroaniline.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 type-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), under room temperature, add pyridine 0.25mL, diacetyl oxide (0.337g then, 3.3mmol) and a small amount of DMAP, stir under the room temperature, with TLC detection reaction terminal point, reaction finishes, and removes 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 type-12-alkene-28-acyl chlorides, steam and remove 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 comprises:
The ursolic acid derivative that one class formation formula is following:
Figure 2011100781252100001DEST_PATH_IMAGE002
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 amino;
Ursolic acid modifier:
Wherein: R1 is a carbonyl, when R2 is hydrogen, is compound,
Figure 2011100781252100001DEST_PATH_IMAGE004
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 a carbonyl, when R2 is carbonyl, is compound ii,
Figure 2011100781252100001DEST_PATH_IMAGE006
Wherein: R3 is-NHC 6H 11,-NHCH (CH 3) CH 2OH,
Figure 2011100781252100001DEST_PATH_IMAGE008
R1 is an acetoxyl group, when R2 is carbonyl, is the compound III,
Figure 2011100781252100001DEST_PATH_IMAGE010
Wherein: R3 is-NHC 6H 5,-NHC 6H 11,-NHCH (CH 3) CH 2OH,
-NHCH(COOCH 3)CH 2CH(CH 3) 2；
R1 is an oximido, when R2 is hydrogen, is the compound IV,
Figure 2011100781252100001DEST_PATH_IMAGE014
Wherein: R3 is-OBn-NHNHC 6H 5,-NHC 6H 11;
R1 is the acetyl oxyimino group, when R2 is hydrogen, is the compound V,
Figure 2011100781252100001DEST_PATH_IMAGE016
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),
Figure 2011100781252100001DEST_PATH_IMAGE018
2. the preparation method of the acid as chemical modifier for ursolic of an anti-tumor activity is characterized in that, 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 the reaction, again with aliphatic amide, substituted aromatic amines, phenylhydrazine, amino alcohol, amino acid methyl ester react compound I 1-11
(3) 3-oxo ursolic acid and CrO 3In the acetum of 5% aceticanhydride, react intermediate 3,11-dioxo ursolic acid, again with oxalyl chloride reaction, again with aliphatic amide, amino alcohol and heterocyclic amine react compound II 1-3
(4) ursolic acid and aceticanhydride under DMAP catalysis, react 3-acetoxyl group ursolic acid, again with CrO 3In the acetum of 5% aceticanhydride, react intermediate 3-acetoxyl group-11-carbonyl ursolic acid;
(5) 3-acetoxyl group-11-carbonyl ursolic acid and oxalyl chloride the reaction, again with arylamine, aliphatic amide, amino alcohol, heterocyclic amine and amino acid methyl ester react compound III 1-5
(6) 3-oxo ursolic acid and oxammonium hydrochloride in pyridine, react 3-oximido ursolic acid, with bromobenzyl reaction or with the oxalyl chloride reaction, again with phenylhydrazine and hexahydroaniline react compound IV 1-3
(7) 3-oximido ursolic acid and aceticanhydride under DMAP catalysis, react 3-acetyl oxyimino group ursolic acid V 1
(8) reaction of 3-acetyl oxyimino group ursolic acid and bromobenzyl or with oxalyl chloride reaction, again with p-NP, aliphatic amide, arylamine, amino alcohol and heterocyclic amine react compound V 2-9
CN 201110078125 2011-03-30 2011-03-30 Ursolic acid chemical modifier with antitumor activity and preparation method thereof Active CN102180939B (en)

Priority Applications (1)

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

Applications Claiming Priority (1)

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

Publications (2)

Publication Number Publication Date
CN102180939A true CN102180939A (en) 2011-09-14
CN102180939B CN102180939B (en) 2013-02-20

Family

ID=44567250

Family Applications (1)

Application Number Title Priority Date Filing Date
CN 201110078125 Active CN102180939B (en) 2011-03-30 2011-03-30 Ursolic acid chemical modifier with antitumor activity and preparation method thereof

Country Status (1)

Country Link
CN (1) CN102180939B (en)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
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
CN102993018A (en) * 2012-08-10 2013-03-27 浙江工业大学 5-nitro caffeic acid adamantanol ester and application thereof to preparation of antitumor drugs
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

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018069086A1 (en) 2016-10-13 2018-04-19 Vivacell Biotechnology España S.L. Hydroxamate triterpenoid derivatives

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1887898A (en) * 2006-07-19 2007-01-03 沈阳化工学院 Amino acid as chemical modifier for ursolic acid

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1887898A (en) * 2006-07-19 2007-01-03 沈阳化工学院 Amino acid as chemical modifier for ursolic acid

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
《European Journal of Medicinal Chemistry》 20050208 Chao-Mei Ma,et al The cytotoxic activity of ursolic acid derivatives Elsevier 582-589 1 第40卷, 第6期 *
《Journal of Steroid Biochemistry and Molecular Biology》 20110112 Denise V. Kratschmar,et al Characterization of activity and binding mode of glycyrrhetinic acid derivatives inhibiting 11beta-hydroxysteroid dehydrogenase type 2 Elsevier 129-142 1 第125卷, 第1-2期 *
《Molecules》 20100604 Yanqiu Meng,et al Synthesis and in vitro Cytotoxicity of Novel Ursolic Acid Derivatives 4033-4040 1-2 第15卷, 第6期 *
CHAO-MEI MA,ET AL: "The cytotoxic activity of ursolic acid derivatives", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
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
CN102993018A (en) * 2012-08-10 2013-03-27 浙江工业大学 5-nitro caffeic acid adamantanol ester and application thereof to preparation of antitumor drugs
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

Also Published As

Publication number Publication date
CN102180939B (en) 2013-02-20

Similar Documents

Publication Publication Date Title
CN102180939B (en) Ursolic acid chemical modifier with antitumor activity and preparation method thereof
CN101157715B (en) Ursolic acid chemical modified compound amino alcohol having antitumor activity
CN105418721B (en) A kind of oleanolic acid chemical modification object with antitumor activity and preparation method thereof
EP2758058B1 (en) Substituted pyrimidines
BRPI0707689A2 (en) viral polymerase inhibitors
WO2013002357A1 (en) Hiv replication inhibitor
WO2008040236A1 (en) Flavones derivatives, preparation methods and uses thereof
CA3029911C (en) Antimetastatic 2h-selenopheno[3,2-h]chromenes, synthesis thereof, and methods of using same agents
CN110407806B (en) Carboxamide compounds, preparation method and application thereof
Xu et al. New modification strategy of matrine as Hsp90 inhibitors based on its specific L conformation for cancer treatment
CN103626828A (en) Anti-tumor active ursolic acid chemical modifier and preparation method thereof
CN102827116B (en) Alpha-aryl-gamma-methylene butene lactone compounds, and synthesis method and application thereof
CN101161670B (en) Ursolic acid chemical modified compound amine having antitumor activity
WO2013040789A1 (en) Substituted pyrimidines
CN102391351B (en) Asiatic acid modifier with anti-tumor activity and preparation method of the same
WO2015149656A1 (en) 2,2'-tandem dithiazole compound, preparation method therefor, and use thereof
Zhou et al. Design, synthesis and anti-tumor activities of carbamate derivatives of cinobufagin
CN103524598A (en) Cyclic peptide compound and preparation method thereof as well as medicinal composition and application thereof
CN102516350B (en) Glycyrrhetinic acid modifier with antitumor activity and preparation method thereof
CN109776411B (en) Nitrogen mustard carbostyril derivative and preparation method and application thereof
CN114539110B (en) HDAC inhibitor containing RAS/RAF protein interfering group and preparation method thereof
CN115322077B (en) Alkylphenol compounds and preparation method thereof
WO1997044313A1 (en) N,N'-Di(2-HYDROXYBENZYL)ETHYLENEDIAMINE-N,N'-DIACETIC ACID DERIVATIVES
EP2411364A1 (en) Anticancer compounds, preparation thereof, and therapeutic use thereof
CN109705057B (en) Histone deacetylase inhibitor and preparation method and application thereof

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant