CN102329362A - Ursolic acid derivative chemically modified by polyethylene glycol and preparation method of ursolic acid derivative - Google Patents
Ursolic acid derivative chemically modified by polyethylene glycol and preparation method of ursolic acid derivative Download PDFInfo
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Abstract
The invention relates to an ursolic acid derivative chemically modified by polyethylene glycol and a preparation method of the ursolic acid derivative. In the method, a novel ursolic acid derivative with anticancer activity is developed by modifying 28 bits of carboxyl of ursolic acid with butanedioic anhydride, ethylene diamine and polyethylene glycol. As proved by a pharmacological test, the ursolic acid derivative has remarkable in-vitro suppressing capabilities on human liver cancer HepG2 cells, human stomach cancer AGS cells, human stomach cancer BGC-823 cells and human prostatic csarcinoma PC-3 cells.
Description
Technical field
The present invention is specifically related to a kind of ursolic acid verivate through the modification of polyoxyethylene glycol chemistry and preparation method thereof.
Background technology
(Ursolic acid UA), has another name called ursonic acid, urson to ursolic acid, belongs to pentacyclic triterpenoid, chemical name (3 β)-3-Hydroxyurs-12-en-28-oic acid, molecular formula C
30H
48O
3It is wider in distributed in nature, in various plants, exists or be combined into glucoside with sugar with free form to exist.Pharmacological research finds that ursolic acid has biological effect widely, except that protect the liver, anti-inflammatory, antiviral, antibiotic, regulate the effect such as cns, also have significant anticancer function, and spinoff is little, toxicity is low, demonstrates bigger clinical application potentiality.
The chemical structural formula of ursolic acid:
At present, domestic RR to ursolic acid focuses mostly at the extraction and separation process and the pharmaceutical research of ursolic acid, particularly both at home and abroad antitumous effect research of ursolic acid is appeared in the newspapers.Research shows, ursolic acid anti-start sudden change, anti-promoting effect, antioxygenation, CDCC, inducing cancer cell differentiation, blood vessel formation against function, cell death inducing.Yet water-soluble relatively poor this drawback of ursolic acid makes it receive very big restriction at aspects such as reality exploitation and clinical applications.At present, mainly be to improve through the method (as liposome embedded) that adopts covalent linkage that it is water-soluble, also there is report to adopt simultaneously and has certain water miscible ursolic acid verivate with water-soluble strong compound banded method preparation.Among the latter, there is Meng Yanqiu etc. to develop multinomial patents such as series derivates such as ursolic acid modified amino acid, amino alcohol, amine, heterocycle; Yang Dingju etc. have reported the polyglycol supported ursolic acid (" China Medicine University's college journal ", 2008,39 [1]) of biologically active, and have delivered patent " hydrophilic polyglycol supported ursolic acid medicines and preparation method thereof ".Yang Dingju etc. link 3 hydroxyls of PEG and ursolic acid through Succinic Acid.3 hydroxyls of existing bibliographical information ursolic acid are very important to ursolic acid performance antitumous effect, and its 3 hydroxyls are modified, and possibly reduce the anti-tumor activity of gained verivate.
Summary of the invention
Based on the problems referred to above; The invention provides a kind of ursolic acid verivate through the modification of polyoxyethylene glycol chemistry and preparation method thereof; This method adopts 28 carboxyls of Succinic anhydried, quadrol, polyethyleneglycol modified ursolic acid, is intended to research and develop the novel ursolic acid verivate with antitumour activity.
The present invention implements through following technical scheme:
The present invention is lead compound with the ursolic acid, and to the new compound that its structure transformation obtains, the structural formula of this compound is shown in formula I:
（I）
Wherein: R
1Be hydroxyl, acetoxyl group, R
2Be structure shown in the formula (II):
Said R
2Polyoxyethylene glycol, Succinic Acid and quadrol condensation by different polymerization degree form, and the molecular-weight average of used polyoxyethylene glycol is between 200 ~ 60000, and n is any integer, representes its polymerization degree, and n is equivalent to 4 ~ 1300, and preferred n is 4,44,134.
Concrete steps through the preparation method of the ursolic acid verivate of polyoxyethylene glycol chemistry modification are:
1) ursolic acid and acetic anhydride generate compound 2; After the compound 2 process oxalyl chloride activation, generate compound 3 with reacting ethylenediamine; Compound 3 obtains compound 4 through alkaline hydrolysis, acidifying;
2) get the polyoxyethylene glycol PEG (OH) of different polymerization degree
2Being compound 5, is catalyzer with the tosic acid, carries out condensation reaction with the capacity succinyl oxide and prepares Compound P EG (OOCCH
2CH
2COOH)
2Be compound 6; Compound 6 prepares PEG (OOCCH with the oxalyl chloride effect
2CH
2COCl)
2Be compound 7; Compound 7 reacts with compound 3 or 4 respectively, obtains corresponding compounds 8 or 9; Wherein, when 3 of ursolic acid were acetoxyl group, structure was a compound 8 shown in the formula (I); When 3 of ursolic acid were hydroxyl, structure was a compound 9 shown in the formula (I).
Concrete preparation process is following:
A:8-12 g ursolic acid slowly drips 20-30 mL diacetyl oxide with the dissolving of 40-50 mL pyridine under condition of ice bath, drip reaction 6-9 h under the complete room temperature; Stopped reaction removes pyridine under reduced pressure, and resistates dissolves with methylene dichloride; And to use mass concentration successively be 5% hydrochloric acid, zero(ppm) water, saturated nacl aqueous solution washing organic phase, and organic phase with the SODIUM SULPHATE ANHYDROUS 99PCT 1-3 h after-filtration that dewaters, is filtrated and behind 40-50 ℃ of following concentrating under reduced pressure, dried to constant weight again; Bake out temperature is 50-70 ℃; Get bullion, bullion is used the absolute ethyl alcohol recrystallization, gets compound 2;
B: get 4-6 g compound 2 and be dissolved in fully in the 30-50 mL methylene dichloride, slowly splash into 4-7 mL oxalyl chloride under the condition of ice bath, dropwise continued and keep ice bath stirring 0.5-2 h, reaction 12-36 h is continued in the back under room temperature; Reaction finishes, and with above-mentioned solution decompression distillation, gets white foam shape solid; In the white foam shape solid that obtains, add 40-60 mL methylene dichloride and evaporated under reduced pressure solvent, products therefrom is a light yellow solid, with the dissolving of 40-60 mL methylene dichloride, becomes stock solution;
Other gets 10-30 mL anhydrous ethylenediamine and is well-dispersed in the 40-60 mL methylene dichloride, under the ice bath stock solution is slowly splashed into this quadrol/dichloromethane solution; Drip and finish, continue ice bath 30 min, recession removes ice bath, room temperature reaction 8-14 h; Using massfraction is that 5% hydrochloric acid, zero(ppm) water, saturated sodium-chloride wash organic layer successively, until the organic layer clarification and be neutral, and the SODIUM SULPHATE ANHYDROUS 99PCT that adds capacity in the organic layer 1-3 h after-filtration that dewaters, the filtrate decompression distillation obtains compound 3;
C: get 3-5 g compound 3 and be dissolved in fully in the mixing solutions of THF and methyl alcohol, both volumes are 70-90 mL; The 3-5 mol/L aqueous sodium hydroxide solution that adds 10-30 mL, stirred overnight reaction under the room temperature; Remove solvent under reduced pressure, adding 200-300 mL redistilled water fully stirs 0.5-2 h under the room temperature, decompress filter, and filter cake to neutral, removes solvent with the second distillation water washing under reduced pressure, gets compound 4.
D: take by weighing 8-12 mmol PEG, be dissolved in 80-120 mL trichloromethane fully, add 1-4 g succinyl oxide and 0.04-0.08 g tosic acid, more than back flow reaction 48 h; Add 10-30 mL redistilled water, continue backflow 0.5-3 h, backflow finishes, and reaction solution naturally cools to room temperature, standing demix, and organic phase is extremely neutral with the second distillation water washing, again through the saturated common salt water washing; Organic phase concentrates with the SODIUM SULPHATE ANHYDROUS 99PCT 1-4 h that dewaters, and adds anhydrous diethyl ether in the liquid after concentrating rapidly and is settled out product, and product obtains compound 6 with anhydrous diethyl ether crystallization 2 times;
E: get 8-12 mmol compound 6 and be dissolved in fully in the 50-80 mL methylene dichloride, slowly drip 1-3 mL oxalyl chloride under the condition of ice bath, dropwise continued and keep condition of ice bath stirring 0.5-2 h, the back is in continuing under the room temperature more than reaction 24 h; Reaction finishes, and with above-mentioned solution decompression distillation, gets faint yellow gluey thing; Add the methylene dichloride dissolving, and the evaporated under reduced pressure solvent, be cooled to room temperature, obtain compound 7;
F: the compound 7 that step e is obtained is dissolved in the 40-60 mL methylene dichloride fully, becomes reserve liquid 1; Getting 1-3 g compound 3 and be dissolved in fully in the methylene dichloride, is acid binding agent with 1-3 mL triethylamine, under 0 ~ 5 ℃ of condition, reserve liquid 1 is slowly splashed into wherein, and under room temperature, reacts 8-16 h; Steaming desolventizes, and resistates adds the methylene dichloride dissolving, slowly splashes in the ice-cold anhydrous diethyl ether, and the gained deposition with the methylene dichloride dissolving, is used ether sedimentation more afterwards again, and methylene dichloride dissolved step 2 ~ 3 times is used in the deposition repetition that obtains for the first time, compound 8;
G: compound 3 is replaced with compound 4, and the remaining reaction step is identical with f, makes compound 9.
Employed PEG can be PEG200 in the steps d, PEG2000, PEG6000.
The compound 8 that obtains among the step f is for when 3 of ursolic acid are acetoxyl group, suc as formula structure shown in (I).
The compound 9 that obtains among the step f is for when 3 of ursolic acid are hydroxyl, suc as formula structure shown in (I).
Described ursolic acid verivate thing has antitumor action, can be applicable to be fit to adopt ursolic acid to carry out the medical use of antineoplaston.
The invention has the advantages that; The present invention carries out chemical improvement to the natural product ursolic acid; Obtain the structural modification thing of a series of ursolic acid; Show that their human hepatoma HepG2 cells, people's cancer of the stomach ags cell, people's cancer of the stomach BGC-823 cell and human prostata cancer PC-3 cell have obvious in-vitro suppression capacity through pharmacology test.
Description of drawings
Fig. 1 is the present invention's ursolic acid verivate through the modification of polyoxyethylene glycol chemistry with anticancer activity;
Fig. 2 is ursolic acid and structural modification thing thereof the restraining effect (inhibiting rate %) to human colon cancer cell strain HT-29-;
Fig. 3 is ursolic acid and structural modification thing thereof the restraining effect (inhibiting rate %) to human stomach cancer cell line BGC-823;
Fig. 4 is ursolic acid and structural modification thing thereof the restraining effect (inhibiting rate %) to people's liver cancer HepG2;
Fig. 5 is ursolic acid and structural modification thing thereof the restraining effect (inhibiting rate %) to people's cancer of the stomach AGS;
Fig. 6 is ursolic acid and structural modification thing thereof the restraining effect (inhibiting rate %) to human prostata cancer PC-3.
A among Fig. 2-6---the inhibiting rate (%) that corresponding compound concentration records when being 14.4 mg/L;
B---the inhibiting rate (%) that corresponding compound concentration records when being 32 mg/L;
C---the inhibiting rate (%) that corresponding compound concentration records when being 72 mg/L;
D---the inhibiting rate (%) that corresponding compound concentration records when being 20 μ mol/L.
Embodiment
Compound
2Preparation:
10 g ursolic acid dissolve with 45 mL pyridines, under condition of ice bath, slowly drip 25 mL diacetyl oxides, drip reaction 8 h under the complete room temperature.Stopped reaction removes pyridine under reduced pressure, and resistates dissolves with methylene dichloride; And use hydrochloric acid (5%), zero(ppm) water, saturated nacl aqueous solution to wash organic phase successively; Organic phase is filtrated and behind 45 ℃ of following concentrating under reduced pressure, is dried to constant weight with the SODIUM SULPHATE ANHYDROUS 99PCT 2h after-filtration that dewaters, and the thick product of gained is 10.50 g.Crude product is used the absolute ethyl alcohol recrystallization, gets white needle-like crystals 8.59 g.Crystallization yields is 83.3%, and overall yield is 80.5%.mp：282~283℃。
1H?NMR(600MHz,?CDCl
3):?5.32(t,?1H,?
J=3.6?Hz,?H-12),?4.42?(t,?1H,?
J=5.6?Hz,?H-3),?2.22?(d,?1H,?
J=11.2?Hz,?H-18),?2.04?(s,?3H,?CH
3CO),?0.92?(d,?3H,?
J=6.4?Hz,?CH
3),?0.85?(d,?3H,?
J=3.6?Hz,?CH
3),?1.09,?1.00,?0.91,?0.78,?0.74?(s,?15H,?each,?CH
3)。
IR(KBr):?3366,?2972,?2928,?1736,?1700,?1455,?1370,?1246cm
-1。
The preparation of compound 3
5.0 g compound 2 is dissolved in the 40 mL methylene dichloride fully, slowly splashes into 6 mL oxalyl chlorides under the condition of ice bath, dropwises continued and keeps ice bath and stir 1 h, reaction 24 h are continued in the back under room temperature.Reaction finishes, and with above-mentioned solution decompression distillation, gets white foam shape solid.Divide respectively to add a small amount of methylene dichloride and evaporated under reduced pressure solvent 2 times, products therefrom is a light yellow solid, with the dissolving of 50 mL methylene dichloride, is stock solution.
20 mL anhydrous ethylenediamines are well-dispersed in the 50 mL methylene dichloride, slowly splash into above-mentioned stock solution under the ice bath.Drip and finish, continue ice bath 30 min, recession removes ice bath, room temperature reaction 12 h.Wash organic layer successively with 5% hydrochloric acid, zero(ppm) water, saturated sodium-chloride successively, until organic layer clarification and be neutral, the SODIUM SULPHATE ANHYDROUS 99PCT that organic layer the adds capacity 2 h after-filtration that dewater, the filtrate decompression distillation obtains white solid 5.20 g.White solid is used recrystallizing methanol, obtains white needle-like crystals 4.09 g, and overall yield is 75.5%.mp：140~142℃。
1H?NMR(600MHz,?CDCl
3):?6.32?(s,?1H,?CO
NHCH
2),?5.33?(s,?1H,?H-12),?4.49?(t,?1H,?
J=7.6?Hz,?H-3),?3.41~3.38?(m,?1H,?CONH
CH 2 CH
2NH
2a),?3.06~3.04?(m,?1H,?CONH
CH 2 CH
2NH
2b),?2.79?(s,?2H,?
CH 2 NH
2),?2.05?(s,?3H,?CH
3CO),?1.09,?0.95,?0.94,?0.86,?0.85,?0.84,?0.79?(s,?21H,?each,?CH
3)。
IR(KBr):?3365,?2950,?2853,?1728,?1631,?1534,?1452,?1388,?1370,?1252,?1026?cm
-1。
The preparation of compound 4
4.32 the g compound is dissolved in 80 mL THFs/80 mL methyl alcohol fully, adds the 4 mol/L aqueous sodium hydroxide solutions of 20 mL, stirred overnight reaction under the room temperature.Remove solvent under reduced pressure, add 250 mL secondary water, abundant stir about 1 h under the room temperature, decompress filter, filter cake is washed to neutrality with secondary water washing, removes solvent under reduced pressure, obtains white powder solid 3.84 g.White solid is used recrystallizing methanol, obtains white needle-like crystals 3.45 g, and overall yield is 86.7%.mp：145~147℃。
1H?NMR(600MHz,?DMSO-d
6):?7.13?(s,?1H,?CO
NHCH
2),?5.20?(s,?1H,?H-12),?3.5~3.1?(brs,?OH),?3.02~2.98?(m,?2H,?CONH
CH 2 CH
2NH
2),?2.97~2.92(m,2H,?CONHCH
2 CH 2 NH
2),?2.15?(d,?1H,?H-18),?0.82?(d,?3H,?
J=5.2?Hz,?CH
3),?1.03,?0.91,?0.89,?0.85,?0.69,?0.67?(s,?18H,?each,?CH
3)。
IR(KBr):?3362,?2925,?2868,?1640,?1535,?1455,?1389,?1043,?999,?663?cm
-1。
The preparation of compound 6
Take by weighing 60 g PEG6000 (molecular weight is 6000 ~ 7500), be dissolved in 100 mL trichloromethanes fully, add 2.58 g succinyl oxides and 0.06 g tosic acid, more than back flow reaction 48 h.Add 20 mL secondary water, continue 1 h that refluxes.Reaction solution naturally cools to room temperature, standing demix, and organic phase is washed to neutrality with secondary water washing repeatedly, again through the saturated common salt water washing.Organic phase dewaters more than 2 h with SODIUM SULPHATE ANHYDROUS 99PCT, is concentrated into surplus small amount of liquid, adds a large amount of anhydrous diethyl ether depositions rapidly and removes product, and product obtains white powder solid 6c totally 57.40 g, productive rate 92.6% (in PEG6000) with anhydrous diethyl ether crystallization 2 times.
IR(KBr):?3540,?2887,?1735,?1466,?1342,?1278,?1239,?1149,?1112,?1060,?961,?838?cm
-1。
Same method is that raw material makes compound 6a with 2 g PEG200, is faint yellow gluey thing, and thick productive rate is 80.3% (in PEG200), and product is refining without further, directly gets into subsequent step.
IR(KBr):?3435,?2901,?1735,?1454,?1348,?1253,?1160,?992,?863,?829?cm
-1。
Same method is that raw material makes compound 6b with 20g PEG2000, is the white powder solid, and thick productive rate is 80.4% (in PEG2000), and product is refining without further, directly gets into subsequent step.
IR(KBr):?3528,?2881,?1735,?1466,?1342,?1278,?1239,?1149,?1112,?1060,?964,?841?cm
-1。
The preparation of compound 7
9.3 g compound 6c is dissolved in the 70 mL methylene dichloride fully, slowly splashes into 1.5 mL oxalyl chlorides under the condition of ice bath, dropwises continued and keeps ice bath and stir 1 h, the back is in continuing under the room temperature more than reaction 24 h.Reaction finishes, and with above-mentioned solution decompression distillation, gets faint yellow gluey thing.Divide respectively to add a small amount of methylene dichloride and evaporated under reduced pressure solvent 2 times, be cooled to room temperature, the light yellow paste of gained is 7c, and cryodrying is preserved subsequent use, need not be further purified, and directly gets into next step reaction.
Prepare 7a and 7b with method, be faint yellow soup compound.
The preparation of compound 8
8c is an example with the preparation compound.Above-claimed cpd 7c is dissolved in the 50 mL methylene dichloride fully, subsequent use.Getting 1.80 g compounds 3 and be dissolved in fully in the methylene dichloride, is acid binding agent with 1.5 mL triethylamines, and the reserve liquid that under 0 ~ 5 ℃ of condition, will be dissolved with compound 7c slowly splashes into wherein, and the back is reaction 12 h under room temperature.Steaming desolventizes, and resistates adds a small amount of methylene dichloride dissolving, slowly splashes in the ice-cold anhydrous diethyl ether; The gained deposition with a small amount of methylene dichloride dissolving, is used ether sedimentation more afterwards again, repeats 2 ~ 3 times; The In Shade drying of gained solid; Obtaining white powder solid 10.31 g, promptly is compound 8c, and productive rate is 94.8%.
1H?NMR(600MHz,?CDCl
3):?6.68~6.65?(m,?1H,?CO
NHCH
2),?6.41~6.38?(m,?1H,?CO
NHCH
2),
5.33?(s,?1H,?H-12),?4.23~4.22?(m,?4H,?OCH
2 CH 2 OOCCH
2CH
2OOC),?3.7~3.6?(O
CH 2 CH 2 O),?2.69~2.67?(t,?4H,?
J=5.9?Hz,?each,?OOCCH
2 CH 2 CON),
2.47~2.45?(t,?4H,?
J=6.5?Hz,?each,?OOC
CH 2 CH
2CON),?2.05?(s,?6H,?each,?CH
3CO),
1.08,?0.95,?0.93,?0.88,?0.87,?0.85,?0.75?(s,?21H,?each,?CH
3)。
IR(KBr):?3467,?2887,?1734,?1648,?1527,?1468,?1343,?1281,?1242,?1149,?1113,?1060,?963,?842,?528cm
-1
1H?NMR(600MHz,?CDCl
3):?6.64?(s,?1H,?CO
NHCH
2),?6.39?(s,?1H,?CO
NHCH
2),?5.33?(s,?1H,?H-12),?4.23?(s,?4H,?each,?OCH
2 CH 2 OOCCH
2CH
2OOC),?3.7~3.6?(O
CH 2 CH 2 O),
2.68~2.66?(m,?4H,?each,?OOCCH
2 CH 2 CON),?2.46~2.45(t,?4H,?
J=5.6?Hz,?each,?OOC
CH 2 CH
2CON),?2.05?(s,?6H,?each,?CH
3CO),?1.08,?0.95,?0.93,?0.87,?0.86,?0.85,?0.75?(s,?21H,?each,?CH
3)。
IR(KBr):?3523,?2873,?1732,?1650,?1527,?1456,?1351,?1249,?1107,?952,?846,?569?cm
-1。
Prepared compound 8a with method
The preparation of compound 9
9c is an example with the preparation compound.Above-claimed cpd 7c is dissolved in the 50 mL methylene dichloride fully, subsequent use.Getting 1.66 g compounds 4 and be dissolved in fully in the methylene dichloride, is acid binding agent with 1.5 mL triethylamines, and the reserve liquid that under 0 ~ 5 ℃ of condition, will be dissolved with compound 7c slowly splashes into wherein, and the back is reaction 12 h under room temperature.Steaming desolventizes, and resistates adds a small amount of methylene dichloride dissolving, slowly splashes in the ice-cold anhydrous diethyl ether; The gained deposition with a small amount of methylene dichloride dissolving, is used ether sedimentation more afterwards again, repeats 2 ~ 3 times; The In Shade drying of gained solid; Obtaining white powder solid 9.77 g, promptly is compound 9c, and productive rate is 95.7%.
1H?NMR(600MHz,?CDCl
3):?6.63?(m,?1H,?CO
NHCH
2),?6.39?(m,?1H,?CO
NHCH
2),?5.33?(s,?1H,?H-12),?4.23~4.22?(m,?4H,?OCH
2 CH 2 OOCCH
2CH
2OOC),?3.7~3.6?(O
CH 2 CH 2 O),
2.69~2.67?(t,?4H,?
J=5.7?Hz,?each,?OOCCH
2 CH 2 CON),
2.47~2.45?(t,?4H,?
J=6.3?Hz,?each,?OOC
CH 2 CH
2CON),?0.87?(d,?3H,?
J=5.3?Hz,?CH
3),
1.09,?0.98,?0.95,?0.91,?0.78,?0.75?(s,?18H,?each,?CH
3)。
IR(KBr):?3449,?2887,?1736,?1649,?1527,?1468,?1343,?1281,?1243,?1149,?1113,?1060,?963,?842,?528?cm
-1。
1H?NMR?(600MHz,?CDCl
3):?6.66?(s,?1H,?CO
NHCH
2),?6.40?(s,?1H,?CO
NHCH
2),?5.34?(s,?1H,?H-12),?4.23?(s,?4H,?OCH
2 CH 2 OOCCH
2CH
2OOC),?3.7~3.6?(O
CH 2 CH 2 O),
2.69~2.67?(t,?4H,?
J=5.7?Hz?,each,?OOCCH
2 CH 2 CON),
2.47~2.45?(t,?4H,?
J=5.5?Hz,?each,?OOC
CH 2 CH
2CON),?0.87?(d,?3H,?
J=5.3?Hz,?CH
3),
1.09,?0.98,?0.95,?0.91,?0.78,?0.75?(s,?18H,?each,?CH
3)。
IR(KBr):?3449,?2887,?1736,?1649,?1527,?1468,?1343,?1281,?1243,?1149,?1113,?1060,?963,?842,?528?cm
-1。
1H?NMR(600MHz,?CDCl
3):?6.71?(s,?1H,?CO
NHCH
2),?6.42?(s,?1H,?CO
NHCH
2),?5.34?(s,?1H,?H-12),?4.23?(s,?4H,?OCH
2 CH 2 OOCCH
2CH
2OOC),?3.7~3.6?(O
CH 2 CH 2 O),
2.69~2.67?(t,?4H,?
J=5.6?Hz,?each,?OOCCH
2 CH 2 CON),
2.48~2.46?(t,?4H,?
J=5.6?Hz?,each,?OOC
CH 2 CH
2CON),?0.87?(d,?3H,?
J=5.3?Hz,?CH
3),
1.09,?0.98,?0.95,?0.91,?0.78,?0.75?(s,?18H,?each,?CH
3)
IR(KBr):?3447,?2921,?2874,?2677,?2492,?1736,?1650,?1527,?1471,?1352,?1251,?1105,?951,?848,?569?cm
-1。
Antitumour activity through the ursolic acid verivate of polyoxyethylene glycol chemistry modification
37 ℃, 5% CO
2Conventional BGC-823, HepG2, HT-29, AGS and the PC-3 of cultivating under the condition.Cancer cells is inoculated in 96 orifice plates, and cell concn is 10
4Individual/hole, medicine to be measured is used the DMSO hydrotropy, and the DMSO final concentration is no more than 0.5%, adopts the antitumour activity of mtt assay test ursolic acid modifier acidic amino acid.The result sees Fig. 2 ~ 6, and wherein the inhibiting rate of compound 1,3,4 is that concentration is that 20 μ mol/L, action time are the inhibiting rate that 48h records, its IC
50Unit is (μ mol/L); The inhibiting rate of 8b, 8c, 9a, 9b, 9c is to be action time the inhibiting rate of 48 h, and corresponding drug level is respectively 32,72,14.4,32,72 mg/L, its IC
50Unit is (mg/L).
Embodiment 2
A:8 g ursolic acid dissolves with 50 mL pyridines, under condition of ice bath, slowly drips 20 mL diacetyl oxides, drips reaction 9 h under the complete room temperature; Stopped reaction removes pyridine under reduced pressure, and resistates dissolves with methylene dichloride; And to use mass concentration successively be 5% hydrochloric acid, zero(ppm) water, saturated nacl aqueous solution washing organic phase; Organic phase with the SODIUM SULPHATE ANHYDROUS 99PCT 1 h after-filtration that dewaters, is filtrated and behind 50 ℃ of following concentrating under reduced pressure, is dried to constant weight again, bullion; Bullion is used the absolute ethyl alcohol recrystallization, gets compound 2;
B: get 4 g compounds 2 and be dissolved in fully in the 50 mL methylene dichloride, slowly splash into 4 mL oxalyl chlorides under the condition of ice bath, dropwise continued and keep ice bath and stir 0.5 h, reaction 12 h are continued in the back under room temperature; Reaction finishes, and with above-mentioned solution decompression distillation, gets white foam shape solid; Add a small amount of 40 mL methylene dichloride and evaporated under reduced pressure solvent, products therefrom is a light yellow solid, with the dissolving of 40 mL methylene dichloride, becomes stock solution;
Other gets 10 mL anhydrous ethylenediamines and is well-dispersed in the 40 mL methylene dichloride, under the ice bath above-mentioned stock solution is slowly splashed in this quadrol/methylene dichloride mixing solutions; Drip and finish, continue ice bath 30 min, recession removes ice bath, room temperature reaction 8 h; Using mass concentration is that 5% hydrochloric acid, zero(ppm) water, saturated sodium-chloride wash organic layer successively, until the organic layer clarification and be neutral, and the SODIUM SULPHATE ANHYDROUS 99PCT that adds capacity in the organic layer 1 h after-filtration that dewaters, the filtrate decompression distillation obtains compound 3;
C: get 3 g compounds 3 and be dissolved in fully in the mixing solutions of THF and methyl alcohol, both volume ratios are 70 mL:90 mL; The 5 mol/L aqueous sodium hydroxide solutions that add 10 mL, stirred overnight reaction under the room temperature; Remove solvent under reduced pressure, add 200 mL redistilled waters, abundant stir about 0.5 h under the room temperature, decompress filter, filter cake to neutral, removes solvent with the second distillation water washing under reduced pressure, gets compound 4.
D: take by weighing 40 g PEG4000, be dissolved in 80 mL trichloromethanes fully, add 1 g succinyl oxide and 0.04 g tosic acid, more than back flow reaction 48 h; Add 10 mL redistilled waters, continue 0.5 h that refluxes, backflow finishes, and reaction solution naturally cools to room temperature, standing demix, and organic phase is extremely neutral with the second distillation water washing, again through the saturated common salt water washing; Organic phase concentrates with SODIUM SULPHATE ANHYDROUS 99PCT 4 h that dewater, and adds anhydrous diethyl ether in the liquid after concentrating rapidly and is settled out product, and product obtains compound 6 with anhydrous diethyl ether crystallization 2 times;
E: get 8 g compounds 6 and be dissolved in fully in the 50 mL methylene dichloride, slowly drip 1 mL oxalyl chloride under the condition of ice bath, dropwise continued and keep condition of ice bath and stir 0.5 h, the back is in continuing under the room temperature more than reaction 24 h; Reaction finishes, and with above-mentioned solution decompression distillation, gets faint yellow gluey thing; Add the methylene dichloride dissolving, and the evaporated under reduced pressure solvent, be cooled to room temperature, obtain compound 7;
F: the compound 7 that step e is obtained is dissolved in the 40 mL methylene dichloride fully, becomes reserve liquid; Getting 1 g compound 3 and be dissolved in fully in the methylene dichloride, is acid binding agent with 1 mL triethylamine, under 0 ℃ of condition, reserve liquid is slowly splashed into wherein, and under room temperature, reacts 16 h; Steaming desolventizes, and the dissolving of resistates adding methylene dichloride slowly splashes in the ice-cold anhydrous diethyl ether, and the gained deposition with the methylene dichloride dissolving, is used ether sedimentation more afterwards again, with this step repetition of methylene dichloride dissolving 2 ~ 3 times, gets compound 8;
A:12 g ursolic acid dissolves with 40 mL pyridines, under condition of ice bath, slowly drips 30 mL diacetyl oxides, drips reaction 6 h under the complete room temperature; Stopped reaction removes pyridine under reduced pressure, and resistates dissolves with methylene dichloride; And to use mass concentration successively be 5% hydrochloric acid, zero(ppm) water, saturated nacl aqueous solution washing organic phase; Organic phase with the SODIUM SULPHATE ANHYDROUS 99PCT 3 h after-filtration that dewater, is filtrated and behind 40 ℃ of following concentrating under reduced pressure, is dried to constant weight again, bullion; Bullion is used the absolute ethyl alcohol recrystallization, gets compound 2;
B: get 6 g compounds 2 and be dissolved in fully in the 30 mL methylene dichloride, slowly splash into 7 mL oxalyl chlorides under the condition of ice bath, dropwise continued and keep ice bath and stir 2 h, reaction 36 h are continued in the back under room temperature; Reaction finishes, and with above-mentioned solution decompression distillation, gets white foam shape solid; Add a small amount of 60 mL methylene dichloride and evaporated under reduced pressure solvent, products therefrom is a light yellow solid, with the dissolving of 60 mL methylene dichloride, becomes stock solution;
Other gets 30 mL anhydrous ethylenediamines and is well-dispersed in the 60 mL methylene dichloride, under the ice bath above-mentioned stock solution is slowly splashed in this quadrol/methylene dichloride mixing solutions; Drip and finish, continue ice bath 30 min, recession removes ice bath, room temperature reaction 14 h; Using mass concentration is that 5% hydrochloric acid, zero(ppm) water, saturated sodium-chloride wash organic layer successively, until the organic layer clarification and be neutral, and the SODIUM SULPHATE ANHYDROUS 99PCT that adds capacity in the organic layer 3 h after-filtration that dewater, the filtrate decompression distillation obtains compound 3;
C: get 5 g compounds and be dissolved in fully in the mixing solutions of THF and methyl alcohol, both volume ratios are 90 mL:70 mL; The 3 mol/L aqueous sodium hydroxide solutions that add 30 mL, stirred overnight reaction under the room temperature; Remove solvent under reduced pressure, add 300 mL redistilled waters, abundant stir about 2 h under the room temperature, decompress filter, filter cake to neutral, removes solvent with the second distillation water washing under reduced pressure, gets compound 4.
D: take by weighing 100 g PEG10000, be dissolved in 120 mL trichloromethanes fully, add 4 g succinyl oxides and 0.08 g tosic acid, more than back flow reaction 48 h; Add 30 mL redistilled waters, continue 3 h that reflux, backflow finishes, and reaction solution naturally cools to room temperature, standing demix, and organic phase is extremely neutral with the second distillation water washing, again through the saturated common salt water washing; Organic phase concentrates with SODIUM SULPHATE ANHYDROUS 99PCT 1 h that dewaters, and adds anhydrous diethyl ether in the liquid after concentrating rapidly and is settled out product, and product obtains compound 6 with anhydrous diethyl ether crystallization 2 times;
E: get 10 g compounds 6 and be dissolved in fully in the 80 mL methylene dichloride, slowly drip 3 mL oxalyl chlorides under the condition of ice bath, dropwise continued and keep condition of ice bath and stir 2 h, the back is in continuing under the room temperature more than reaction 24 h; Reaction finishes, and with above-mentioned solution decompression distillation, gets faint yellow gluey thing; Add the methylene dichloride dissolving, and the evaporated under reduced pressure solvent, be cooled to room temperature, obtain compound 7c;
F: the compound 7 that step e is obtained is dissolved in the 60 mL methylene dichloride fully, becomes reserve liquid; Getting 3 g compounds 3 and be dissolved in fully in the methylene dichloride, is acid binding agent with 3 mL triethylamines, under 5 ℃ of conditions, reserve liquid is slowly splashed into wherein, and under room temperature, reacts 8 h; Steaming desolventizes, and the dissolving of resistates adding methylene dichloride slowly splashes in the ice-cold anhydrous diethyl ether, and the gained deposition with the methylene dichloride dissolving, is used ether sedimentation more afterwards again, from beginning repetition 2 ~ 3 times with methylene dichloride this step of dissolving, gets compound 8;
The above is merely preferred embodiment of the present invention, and all equalizations of doing according to claim of the present invention change and modify, and all should belong to covering scope of the present invention.
Claims (9)
1. ursolic acid verivate through the modification of polyoxyethylene glycol chemistry, it is characterized in that: the structural formula of said ursolic acid verivate is:
(I), wherein: R
1Be hydroxyl, acetoxyl group, R
2Be structure shown in the formula (II):
(II).
2. the ursolic acid verivate through the modification of polyoxyethylene glycol chemistry according to claim 1 is characterized in that: said R
2Polyoxyethylene glycol, Succinic Acid and quadrol condensation by different polymerization degree form, and the molecular-weight average of used polyoxyethylene glycol is between 200 ~ 60000.
3. the preparation method of the ursolic acid verivate through the modification of polyoxyethylene glycol chemistry as claimed in claim 1, it is characterized in that: said preparing method's flow process is:
1）
2）
4. the preparation method of the ursolic acid verivate through the modification of polyoxyethylene glycol chemistry according to claim 3, it is characterized in that: said preparing method's concrete steps are:
1) ursolic acid and acetic anhydride generate compound 2; After the compound 2 process oxalyl chloride activation, generate compound 3 with reacting ethylenediamine; Compound 3 obtains compound 4 through alkaline hydrolysis, acidifying;
2) get the polyoxyethylene glycol PEG (OH) of different polymerization degree
2Being compound 5, is catalyzer with the tosic acid, carries out condensation reaction with succinyl oxide and prepares Compound P EG (OOCCH
2CH
2COOH)
2Be compound 6; Compound 6 prepares PEG (OOCCH with the oxalyl chloride effect
2CH
2COCl)
2Be compound 7; Compound 7 reacts with compound 3 or 4 respectively, obtains corresponding compounds 8 or 9; Wherein, when 3 of ursolic acid were acetoxyl group, structure was a compound 8 shown in the formula (I); When 3 of ursolic acid were hydroxyl, structure was a compound 9 shown in the formula (I).
5. the preparation method of the ursolic acid verivate through the modification of polyoxyethylene glycol chemistry according to claim 4, it is characterized in that: the concrete preparation process of said step 1) is:
A:8-12 g ursolic acid slowly drips 20-30 mL diacetyl oxide with the dissolving of 40-50 mL pyridine under condition of ice bath, drip under the complete room temperature and react 6-9h; Stopped reaction removes pyridine under reduced pressure, and resistates dissolves with methylene dichloride; And to use mass concentration successively be 5% hydrochloric acid, zero(ppm) water, saturated nacl aqueous solution washing organic phase, and organic phase with the SODIUM SULPHATE ANHYDROUS 99PCT 1-3 h after-filtration that dewaters, is filtrated and behind 40-50 ℃ of following concentrating under reduced pressure, dried to constant weight again; Bake out temperature is 50-70 ℃; Get bullion, bullion is used the absolute ethyl alcohol recrystallization, gets compound 2;
B: get 4-6 g compound 2 and be dissolved in fully in the 30-50 mL methylene dichloride, slowly splash into 4-7 mL oxalyl chloride under the condition of ice bath, dropwise continued and keep ice bath stirring 0.5-2 h, reaction 12-36 h is continued in the back under room temperature; Reaction finishes, and with above-mentioned solution decompression distillation, gets white foam shape solid; In the white foam shape solid that obtains, add 40-60 mL methylene dichloride and evaporated under reduced pressure solvent, products therefrom is a light yellow solid, with the dissolving of 40-60 mL methylene dichloride, becomes stock solution;
Other gets 10-30 mL anhydrous ethylenediamine and is well-dispersed in the 40-60 mL methylene dichloride, under the ice bath stock solution is slowly splashed into this quadrol/dichloromethane solution; Drip and finish, continue ice bath 30 min, recession removes ice bath, room temperature reaction 8-14 h; Using mass concentration is that 5% hydrochloric acid, zero(ppm) water, saturated sodium-chloride wash organic layer successively, until the organic layer clarification and be neutral, and the SODIUM SULPHATE ANHYDROUS 99PCT that adds capacity in the organic layer 1-3 h after-filtration that dewaters, the filtrate decompression distillation obtains compound 3;
C: get 3-5 g compound 3 and be dissolved in fully in the mixing solutions of THF and methyl alcohol, both volumes are 70-90 mL; The 3-5 mol/L aqueous sodium hydroxide solution that adds 10-30 mL, stirred overnight reaction under the room temperature; Remove solvent under reduced pressure, adding 200-300 mL redistilled water fully stirs 0.5-2 h under the room temperature, decompress filter, and filter cake to neutral, removes solvent with the second distillation water washing under reduced pressure, gets compound 4.
6. the preparation method of the ursolic acid verivate through the modification of polyoxyethylene glycol chemistry according to claim 4, it is characterized in that: concrete preparation process said step 2) is:
D: take by weighing 8-12 mmol PEG, be dissolved in fully in the 80-120 mL trichloromethane, add 1-4 g succinyl oxide and 0.04-0.08 g tosic acid, more than back flow reaction 48 h; Add 10-30 mL redistilled water, continue backflow 0.5-3 h, backflow finishes, and reaction solution naturally cools to room temperature, standing demix, and organic phase is extremely neutral with the second distillation water washing, again through the saturated common salt water washing; Organic phase concentrates with the SODIUM SULPHATE ANHYDROUS 99PCT 1-4 h that dewaters, and adds anhydrous diethyl ether in the liquid after concentrating rapidly and is settled out product, and product obtains compound 6 with anhydrous diethyl ether crystallization 2 times;
E: get 8-12 mmol compound 6 and be dissolved in fully in the 50-80mL methylene dichloride, slowly drip 1-3 mL oxalyl chloride under the condition of ice bath, dropwise continued and keep condition of ice bath stirring 0.5-2 h, the back is in continuing under the room temperature more than reaction 24 h; Reaction finishes, and with above-mentioned solution decompression distillation, gets faint yellow gluey thing; Add the methylene dichloride dissolving, and the evaporated under reduced pressure solvent, be cooled to room temperature, obtain compound 7;
F: the compound 7 that step e is obtained is dissolved in the 40-60 mL methylene dichloride fully, becomes reserve liquid 1; Getting 1-3 g compound 3 and be dissolved in fully in the methylene dichloride, is acid binding agent with 1-3 mL triethylamine, under 0 ~ 5 ℃ of condition, reserve liquid 1 is slowly splashed into wherein, and under room temperature, reacts 8-16 h; Steaming desolventizes, and resistates adds the methylene dichloride dissolving, slowly splashes in the ice-cold anhydrous diethyl ether, and the gained deposition with the methylene dichloride dissolving, is used ether sedimentation more afterwards again, and methylene dichloride dissolved procedure 2 ~ 3 times are used in the deposition repetition that obtains for the first time, get compound 8;
G: compound 3 is replaced with compound 4, and the remaining reaction step is identical with f, makes compound 9.
7. the preparation method of the ursolic acid verivate through the modification of polyoxyethylene glycol chemistry according to claim 6, it is characterized in that: the compound 8 that obtains among the said step f is for when 3 of ursolic acid are acetoxyl group, suc as formula structure shown in (I).
8. the preparation method of the ursolic acid verivate through the modification of polyoxyethylene glycol chemistry according to claim 6, it is characterized in that: the compound 9 that obtains among the said step f is for when 3 of ursolic acid are hydroxyl, suc as formula structure shown in (I).
9. the ursolic acid verivate through the modification of polyoxyethylene glycol chemistry according to claim 1, it is characterized in that: described ursolic acid verivate has antitumor action, can be used for treating tumor disease.
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| CN102516351A (en) * | 2011-11-22 | 2012-06-27 | 福州大学 | Ursolic acid derivative with anti-cancer activity and preparation method thereof |
| CN106749486A (en) * | 2016-11-30 | 2017-05-31 | 沈阳化工大学 | A kind of oleanolic acid derivate and its application with ethylenediamine as linking arm |
| CN106750250A (en) * | 2016-12-21 | 2017-05-31 | 沈阳化工大学 | Using amino acid as polyethylene glycol oleanolic acid derivate of linking arm and its preparation method and application |
| CN111764165A (en) * | 2020-07-06 | 2020-10-13 | 温州大学 | Preparation method of antibacterial drug-loaded gauze and foot cover for diabetic foot patient |
| CN112225775A (en) * | 2020-10-28 | 2021-01-15 | 籍建亚 | Antibacterial and anti-inflammatory ursolic acid derivative and preparation method thereof |
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Cited By (7)
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| CN102516351A (en) * | 2011-11-22 | 2012-06-27 | 福州大学 | Ursolic acid derivative with anti-cancer activity and preparation method thereof |
| CN106749486A (en) * | 2016-11-30 | 2017-05-31 | 沈阳化工大学 | A kind of oleanolic acid derivate and its application with ethylenediamine as linking arm |
| CN106750250A (en) * | 2016-12-21 | 2017-05-31 | 沈阳化工大学 | Using amino acid as polyethylene glycol oleanolic acid derivate of linking arm and its preparation method and application |
| CN106750250B (en) * | 2016-12-21 | 2019-04-23 | 沈阳化工大学 | Polyethylene glycol oleanolic acid derivate using amino acid as linking arm and its preparation method and application |
| CN111764165A (en) * | 2020-07-06 | 2020-10-13 | 温州大学 | Preparation method of antibacterial drug-loaded gauze and foot cover for diabetic foot patient |
| CN111764165B (en) * | 2020-07-06 | 2022-11-18 | 温州大学 | Preparation method of antibacterial drug-loaded gauze and foot cover for diabetic foot patient |
| CN112225775A (en) * | 2020-10-28 | 2021-01-15 | 籍建亚 | Antibacterial and anti-inflammatory ursolic acid derivative and preparation method thereof |
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