CN101891794A - Ursolic acid piperazine derivative having antitumor activity and preparation method thereof - Google Patents
Ursolic acid piperazine derivative having antitumor activity and preparation method thereof Download PDFInfo
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Abstract
The invention provides an ursolic acid piperazine derivative having antitumor activity and a preparation method thereof. The ursolic acid piperazine derivative is N-[3beta-acetoxyl-ursa-12-ene-28-acyl]-(1-hydroxyethylethyoxyl) piperazine (a compound I). In the method, ursolic acid is reacted with acetic anhydride to form 3-O-acetylursolic acid, the 3-O-acetylursolic acid is reacted with oxalyl chloride, and the product of the reaction is reacted with 1-hydroxyethylethyoxylpiperazine to form the compound I. The prepared ursolic acid piperazine derivative is used in the preparation of antitumor medicaments and has a better antitumor cell proliferation effect than the ursolic acid and lower human pulmonary fibroblasts HELF toxic effect than the ursolic acid.
Description
Technical field
The present invention relates to a kind of ursolic acid piperazine derivative and preparation method thereof, is a kind of ursolic acid piperazine derivative with anti-tumor activity and preparation method thereof specifically.
Background technology
Ursolic acid (Ursolic acid UA), has another name called ursonic acid, urson, belongs to pentacyclic triterpenoid, chemical name (3 β)-3-Hydroxyurs-12-en-28-oic acid, and its relative molecular weight is 456.68, molecular formula is C
30H
48O
3, it is distributed widely in occurring in nature with the form of free or glucosides.Pharmaceutical research is found, ursolic acid has biological effect widely, ursolic acid has the various biological activity, antibacterial etc. as anticancer, anti-HIV, anti-liver injury, antimalarial, anti-inflammatory, wherein remarkable with antitumour activity especially, its anticancer spectrum is wide, not only multiple carcinogenic, short cancer thing is had resistant function, and to the kinds of tumor cells body is inside and outside restraining effect is arranged all.Its side effect is little, and toxicity is low, demonstrates bigger clinical application potentiality.
The chemical structural formula of ursolic acid is:
III。
At present, the research of ursolic acid is reported for work focuses mostly on aspect the separation-extraction technology and pharmaceutical research of ursolic acid both at home and abroad, and less to the structural modification aspect research of ursolic acid.Because the remarkable antitumous effect of ursolic acid makes that this research on the one hand is comparatively deep.As Wang Tao etc. " ursolic acid antitumor action and Mechanism Study progress thereof " (" medicine biotechnology ", 2008,15[2]); " antitumor action of ursolic acid " of Liu Xunhua etc. (" Jiangsu medicine ", 2007,33[2]); " the ursolic acid antitumor action progress " of Xia Guohao etc. (" foreign medical oncology credit volume ", 2002,29[6]); Or the like.Most investigators think that ursolic acid can wait generation, invasion and the transfer that suppresses tumour by chemoprophylaxis, anti-mutation, cytotoxicity, antineoplastic vascular generation and inducing tumor cell differentiation, apoptosis.
The oxygen that contains of domestic increase ursolic acid A such as Bai Yujun ring replaces, and carries out structural modification, synthetic 6 kinds of parent nucleus modifiers (West China Journal of Pharmaceutical Sciences, 2003,18[2]); Vertical big grade is utilized beta-cyclodextrin, adopts saturated water solution method inclusion ursolic acid, has solved the problem (" ursolic acid-Benexate Hydrochloride Study on Preparation ", 2008,29[1]) of ursolic acid poorly water-soluble; Meng Yanqiu etc. have developed ursolic acid and have modified multinomial patents such as series derivates such as containing aminocompound.Foothold of the present invention is to research and develop a kind of ursolic acid piperazine derivative N-[3 β-acetoxyl group-black bearberry alkane-12-alkene-28-acyl with antitumour activity]-(1-ethoxylated hydroxyethylcellulose) piperazine, do not see its report both at home and abroad.
Summary of the invention
The objective of the invention is with the ursolic acid is lead compound, synthetic ursolic acid piperazine derivative with antitumour activity.
Ursolic acid piperazine derivative of the present invention is N-[3 β-acetoxyl group-black bearberry alkane-12-alkene-28-acyl]-(1-ethoxylated hydroxyethylcellulose) piperazine, structural formula is suc as formula shown in the I:
The preparation method is as follows:
(1) ursolic acid and acetic anhydride reaction generates 3-O-ethanoyl ursolic acid; The structural formula of 3-O-ethanoyl ursolic acid is suc as formula shown in the II;
II。
(2) 3-O-ethanoyl ursolic acid and oxalyl chloride the reaction, again with 1-ethoxylated hydroxyethylcellulose piperazine react N-[3 β-acetoxyl group-black bearberry alkane-12-alkene-28-acyl]-(1-ethoxylated hydroxyethylcellulose) piperazine, structural formula is suc as formula shown in the I.
Described preparation method's concrete steps are as follows:
The ursolic acid stirring and dissolving of (1) 1 weight part is added dropwise to the acetic anhydride of 2-3 weight part in the pyridine of 40-50 weight part, add the DMAP of 0.001-0.02 weight part, stir 16-18 h under the room temperature, after reaction finishes, regulate pH 3-4 with 2 N HCl, steaming desolventizes, suction filtration, and the washing filter cake is to neutral, dry, sample on the dried product dry method, column chromatography purification, dehydrated alcohol thermosol, cool off recrystallization, get the 3-O-ethanoyl ursolic acid of white powder;
(2) 1 weight part 3-O-ethanoyl ursolic acid are dissolved in 30-35 weight part CH
2Cl
2In, dropwise add the oxalyl chloride of 1-2 weight part, stirring reaction 36-48h under the room temperature steams the gas that desolventizes and react generation, the crude product of 3-O-ethanoyl UA acyl chlorides intermediate, directly enter next step reaction; The CH that in the crude product of above-mentioned intermediate, adds the 20-30 weight part
2Cl
2, triethylamine regulator solution pH 8-9, the 1-ethoxylated hydroxyethylcellulose piperazine of adding 2-3 weight part, stirring reaction 3-5h under the room temperature, after reaction finishes, add the water of 5-10 weight part in the reaction solution, regulate pH3-4 with 2N HCl, filter, the washing filter cake is neutral to filtrate pH, drying; Sample on the dried product dry method, column chromatography purification, the dehydrated alcohol thermosol, the cooling recrystallization gets white powder N-[3 β-acetoxyl group-black bearberry alkane-12-alkene-28-acyl]-(1-ethoxylated hydroxyethylcellulose) piperazine.
In addition, N-[3 β-acetoxyl group-black bearberry alkane-12-alkene-28-acyl]-hydrolysis reaction also can take place with NaOH in (1-ethoxylated hydroxyethylcellulose) piperazine, further generates derivative, and structural formula is suc as formula shown in the IV:
Concrete steps are as follows:
Take by weighing the N-[3 β-acetoxyl group-black bearberry alkane-12-alkene-28-acyl of 1 weight part]-(1-ethoxylated hydroxyethylcellulose) piperazine, be dissolved in the CH of 20-30 weight part
3OH-THF(1:1.5 v:v) in, add the 4N NaOH of 1-1.5 weight part, stirring reaction 3.5-4h reacts completely under the room temperature, the water that in mixture, adds the 5-10 weight part, 2 N HCl transfer pH 3-4, remove solvent under reduced pressure, and water washing and precipitating is to neutral, column chromatography purification, the dehydrated alcohol thermosol, the cooling recrystallization gets derivative I V.
Can make a series of ursolic acid piperazine derivatives according to aforesaid method, the preparation method is as follows, and concrete steps are the same:
(1) ursolic acid and acetic anhydride reaction generates 3-O-ethanoyl ursolic acid;
(2) 3-O-ethanoyl ursolic acid and oxalyl chloride the reaction, again with the N-2-hydroxyethyl piperazine react the derivative V.
(3) hydrolysis reaction takes place in derivative V and NaOH, further generates the derivative VI.
Wherein said derivative V, VI structural formula are as follows:
The a series of ursolic acid piperazine derivatives of above-mentioned institute's synthetic can be used for preparing anti-tumor medicine.
The invention has the advantages that, the present invention carries out structure of modification to the natural product ursolic acid, obtain N-[3 β-acetoxyl group-black bearberry alkane-12-alkene-28-acyl]-(1-ethoxylated hydroxyethylcellulose) piperazine (I) and serial piperazine compounds (IV, V, VI) thereof, body outer cell proliferation suppresses experiment and shows, Compound I, IV and V are better than ursolic acid to the inhibited proliferation of survey tumor cell line HepG2, BGC823, SH-SY5Y, Hela, and the toxic action of human embryonic lung fibroblast HELF then is lower than ursolic acid.Wherein the effect of Compound I is best.
Description of drawings
Fig. 1 is N-[3 β-acetoxyl group-black bearberry alkane-12-alkene-28-acyl among the present invention]-(1-ethoxylated hydroxyethylcellulose) piperazine (Compound I) and N-[3 beta-hydroxy-black bearberry alkane-12-alkene-28-acyl]-synthetic route of (1-ethoxylated hydroxyethylcellulose) piperazine (compound IV);
N-[3 β-acetoxyl group among Fig. 2 the present invention-black bearberry alkane-12-alkene-28-acyl]-(N-2 hydroxyethyl) piperazine (compound V) and N-[3 beta-hydroxy-black bearberry alkane-12-alkene-28-acyl]-synthetic route of (N-2 hydroxyethyl) piperazine (compound VI).
Specific embodiment
Below for specific embodiments of the invention and comparative example can further be well understood to the present invention, but they are not limitation of the invention:
Embodiment 1
The preparation of 3-O ethanoyl ursolic acid (Compound I I):
Take by weighing 0.7062 g ursolic acid, add 30 ml pyridines, be added dropwise to 1.8 ml acetic anhydride after the stirring and dissolving; add a spot of DMAP, stir 16 h under the room temperature, after reaction finishes; transfer pH 3-4 with 2 N HCl, steaming desolventizes, suction filtration; the washing filter cake is to neutrality, 100 ℃ of dryings of normal pressure, sample on the dried product dry method; column chromatography purification (sherwood oil (60-90 ℃): ethyl acetate=3:1); the dehydrated alcohol thermosol, the cooling recrystallization gets 3-O ethanoyl ursolic acid.
Proterties: white powder; Productive rate: 86.17%; Mp:286-288 ℃.
IRData (KBr, cm
-1) and ownership: υ: the 3293(O-H stretching vibration), 2927 (C-H stretching vibrations), 1736(s, C=O stretching vibration), 1370(UA A district characteristic absorbance) and, 1245 (s, C-O-C asymmetrical stretching vibration) cm
-1
?ESI-MS：m/z?497.5?[M-H]
+，521.5[M+Na]
?+。
1H?NMR（400MHz，CDCl
3）δ：5.23（t，1H，H-12，
J=2.8Hz），4.49（t，1H，H-3，
J=7.2Hz），2.17（d，1H，H-18，
J=10.8Hz），2.04（s，3?H，CH
3COO），1.06（s，3?H，CH
3），0.97（s，3H,?CH
3），0.94（s，3?H，CH
3），0.92（s，3H，CH
3），0.82（d,?3?H，CH
3，
J=6.4Hz），0.78（s，3?H，CH
3），0.76（s，3?H，CH
3）。
Embodiment 2
N-[3 β-acetoxyl group-black bearberry alkane-12-alkene-28-acyl]-preparation of (1-ethoxylated hydroxyethylcellulose) piperazine (Compound I):
Take by weighing 0.2837 g 3-O ethanoyl ursolic acid and be dissolved in 20 ml CH
2Cl
2In, in batches, dropwise adding oxalyl chloride 0.53 ml, stirring reaction 36 h under the room temperature steam the gas that desolventizes and react generation, get the crude product of 3-O-ethanoyl UA acyl chlorides intermediate, directly enter next step reaction.In above-mentioned intermediate, add 20 ml CH
2Cl
2, triethylamine regulator solution pH 8-9 adds 1-ethoxylated hydroxyethylcellulose piperazine 0.5703g, and stirring reaction 4 h under the room temperature after reaction finishes, add 10 ml distilled water in the reaction solution, transfer pH3-4 with 2N HCl, filter, and the washing filter cake is neutral to filtrate pH, drying.Column chromatography purification (chloroform: acetone=3:1), the dehydrated alcohol thermosol, the cooling recrystallization gets N-[3 β-acetoxyl group-black bearberry alkane-12-alkene-28-acyl]-(1-ethoxylated hydroxyethylcellulose) piperazine.
Proterties: white powder; Productive rate: 37.87%; Mp:105-107 ℃.
IR data (KBr, cm
-1) and ownership: υ: the 3446(O-H stretching vibration), the 2945(C-H stretching vibration), 1734(s, the C=O stretching vibration), 1633(s, C=O stretching vibration, acid amides I peak), 1370(UA A district characteristic absorbance), the 1246(C-O-C asymmetrical stretching vibration) and cm
-1
?LC-MS：m/z?656.1[M+H]
+，677.6[M+Na]
?+。
?1H?NMR（400MHz，CDCl
3）δ：5.21（s，1H，H-12），4.48?(t，1H，
J?=4.0Hz，H-3)，3.71~3.61（m，8H，4×C
H 2），2.58（t，2H，
J=5.2Hz，-N(C
H 2)
2），2.48（br，4H，-N(CH
2C
H 2)
2），2.04（s,?3?H,?C
H 3CO），1.06（s，3H，CH
3），0.93（d,?3?H，CH
3，
J=6.0Hz），0.86~0.84（m,?9H，3×CH
3），0.84（s,?3?H,?CH
3），0.73（s,?3?H,?CH
3）。
Embodiment 3
N-[3 beta-hydroxy-black bearberry alkane-12-alkene-28-acyl]-preparation of (1-ethoxylated hydroxyethylcellulose) piperazine (compound VI):
Take by weighing I 0.3128g, be dissolved in 20ml CH
3OH-THF(1:1.5 v:v) in, add 2.0ml 4N NaOH, stirring reaction 3.5 h react completely under the room temperature, in mixture, add an amount of water, 2 N HCl transfer pH 3-4, remove solvent under reduced pressure, and water washing and precipitating is to neutral, column chromatography purification (chloroform: acetone=1:1), the ethanol thermosol, the cooling recrystallization gets N-[3 beta-hydroxy-black bearberry alkane-12-alkene-28-acyl]-(1-ethoxylated hydroxyethylcellulose) piperazine (VI).
Proterties: white powder; Productive rate: 87.26%; Mp:111-113 ℃.
IR data (KBr, cm
-1) and ownership: υ: the 3414(O-H stretching vibration), the 2925(C-H stretching vibration), 1616(s, C=O stretching vibration, acid amides I peak) and, 1376(UA A district characteristic absorbance), 1227(UA B district characteristic absorbance) and, cm
-1
?LC-MS：m/z?613.6[M+H]
+，635.6[M+Na]
?+。
?1H?NMR（400MHz，CDCl
3）δ：5.21（s，1H，H-12），3.71（t，2H，
J=4.4Hz，C
H 2CH
2OH），3.71~3.61（m，8H，4×C
H 2），2.58（t，4H，
J=5.2Hz，-N(C
H 2)
2），2.49（br，4H，-N(CH
2C
H 2)
2），1.05（s，3H，CH
3），0.94~0.93（m，6?H，2×CH
3），0.88~0.85（m,?9H，3×CH
3），0.76（s,?3?H,?CH
3）。
Embodiment 4
N-[3 β-acetoxyl group-black bearberry alkane-12-alkene-28-acyl]-preparation of (N-2 hydroxyethyl) piperazine (V):
Take by weighing 0.5014 g I and be dissolved in 20 ml CH
2Cl
2In, in batches, dropwise adding oxalyl chloride 0.61 ml, stirring reaction 36 h under the room temperature steam the gas that desolventizes and react generation, get the crude product of 3-O-ethanoyl UA acyl chlorides intermediate, directly enter next step reaction.In above-mentioned intermediate, add 20 ml CH
2Cl
2, triethylamine regulator solution pH 8-9 adds N-2-hydroxyethyl piperazine 0.19g, and stirring reaction 3 h under the room temperature after reaction finishes, add 10 ml distilled water in the reaction solution, transfer pH3-4 with 2N HCl, filter, and the washing filter cake is neutral to filtrate pH, drying.Column chromatography purification (chloroform: acetone=3:1), the ethanol thermosol, the cooling recrystallization gets N-[3 β-acetoxyl group-black bearberry alkane-12-alkene-28-acyl]-(N-2 hydroxyethyl) piperazine (V).
Proterties: white powder; Yield: 46.81%; Mp:196-198 ℃.
IR data (KBr, cm
-1) and ownership: υ: the 3417(O-H stretching vibration), the 2943(C-H stretching vibration), 1724(s, the C=O stretching vibration), 1595(s, C=O stretching vibration, acid amides I peak), 1368(UA A district characteristic absorbance), the 1251(C-O-C asymmetrical stretching vibration) and cm
-1
?LC-MS：m/z?611.6[M+H]
+，633.6[M+Na]
?+。
?1H?NMR（400MHz，CDCl
3）δ：5.22（s，1H，H-12），4.48?(t，1H，
J?=6.0Hz，H-3)，3.63（t，2H，
J=5.2Hz，C
H 2OH），3.22（t，1H，
J=3.2Hz，H-3），2.55（t，2H，
J=5.2Hz，-N(C
H 2)
2），2.47（br，4H，-N(CH
2C
H 2)
2），2.04（s,?3?H,?C
H 3CO），1.07（s，3?H，CH
3），0.95（s，3H,?CH
3），0.93（d,?3?H，
J=6.4Hz，CH
3），0.91（s,?3H,?CH
3），0.86（d,?3H，
J=6.4Hz，CH
3），0.85（s,?3?H,?CH
3），0.75（s,?3?H,?CH
3）。
Embodiment 5
The preparation of derivative (VI):
Take by weighing V 0.6128g, be dissolved in 25ml CH
3OH-THF(1:1.5 v:v) in, add 4.0ml 4N NaOH, stirring reaction 4 h react completely under the room temperature, in mixture, add an amount of water, 2 N HCl transfer pH3-4, remove solvent under reduced pressure, and water washing and precipitating is to neutral, column chromatography purification (chloroform: acetone=1:1), the ethanol thermosol, the cooling recrystallization gets N-[3 beta-hydroxy-black bearberry alkane-12-alkene-28-acyl]-(N-2 hydroxyethyl) piperazine (VI).
Proterties: white powder; Productive rate: 81.38%; Mp:208-210 ℃.
IR data (KBr, cm
-1) and ownership: υ: the 3380(O-H stretching vibration), the 2926(C-H stretching vibration), 1635(s, C=O stretching vibration, acid amides I peak) and, 1368(UA A district characteristic absorbance) cm
-1
?LC-MS：：m/z?570.0[M+H]
+，591.5[M+Na]
?+。
?1H?NMR（400MHz，CDCl
3）δ：5.22（s，1H，H-12），3.63（t，2H，
J=6.0Hz，C
H 2OH），3.22（t，1H，
J=3.2Hz，H-3），2.55（t，2H，
J=5.2Hz，-N(C
H 2)
2），2.47（br，4H，-N(CH
2C
H 2)
2），2.17（t，1H，
J=3.6Hz?，H-18），1.07（s，3H，CH
3），0.98（s，3H，CH
3），0.94（d,?3?H，CH
3，
J=6.0Hz），0.91（s，3H，CH
3），0.87（d,?3?H，CH
3，
J=6.4Hz），0.77（s，3H，CH
3），0.75（s，3H，CH
3）。
Embodiment 6
The external antitumour activity of ursolic acid (UA, III) and derivative (Compound I, II, IV, V, VI) thereof--the inhibited proliferation of mtt assay detection of drugs pair cell
(1) get and be in one bottle in logarithmic phase cell in good condition, tryptic digestion makes 5 * 10
4The cell suspension of individual/ml.
(2) cell suspension moves into 96 orifice plates, and every hole 100ul makes a circle and fills with PBS in week, puts 37 ℃, 5% CO
2Cultivate 24 h in the incubator.
(3) remove old substratum, adding is tried derivative, and (will be tried derivative storage liquid with substratum dilutes, set different activities), every hole 100ul, other establishes blank group, UA control group (UA 60umol/L or 20umol/L) and taxol control group (60 umol/L or 20umol/L), establishes 6 multiple holes for every group.Behind drug effect 24 h, inhale and abandon the pastille substratum, in every hole, add serum-free, no phenol red 1640 substratum 100ul, add MTT solution 10ul again, continue to hatch 4 h, stop cultivating.
(4) the careful suction abandoned supernatant liquor in 96 orifice bores, every hole adds 150ul DMSO, 10 min vibrate, be in mensuration each hole absorbance value (OD value) on the microplate reader in 490 nm wavelength, calculate the proliferation inhibition rate of cell: inhibiting rate (%)=(the average OD value of the average OD value of 1-medication group ÷ blank group) * 100%, use the half-inhibition concentration (IC that SPSS16.0 software carries out data processing and calculates cancer cell multiplication
50), the results are shown in Table 1.
Table 1 ursolic acid piperazine derivative is to the increment restraining effect of different tumour cells
IC
50The result shows, institute's synthetic UA piperazine derivative all has certain inhibited proliferation to different tumour cells, the restraining effect of Compound I, IV, V is better than UA, and it to Normocellular toxic side effect a little less than UA, illustrate that Compound I, IV, V have the active potentiality of good anticancer, can be used as anticancer drug candidate and further study.
Claims (4)
1. ursolic acid piperazine derivative, it is characterized in that: described ursolic acid derivative is N-[3 β-acetoxyl group-black bearberry alkane-12-alkene-28-acyl]-(1-ethoxylated hydroxyethylcellulose) piperazine, structural formula is suc as formula shown in the I:
2. the preparation method of a ursolic acid piperazine derivative as claimed in claim 1 is characterized in that:
(1) ursolic acid and acetic anhydride reaction generates 3-O-ethanoyl ursolic acid; The structural formula of 3-O-ethanoyl ursolic acid is suc as formula shown in the II:
II；
(2) 3-O-ethanoyl ursolic acid and oxalyl chloride the reaction, again with 1-ethoxylated hydroxyethylcellulose piperazine react N-[3 β-acetoxyl group-black bearberry alkane-12-alkene-28-acyl]-(1-ethoxylated hydroxyethylcellulose) piperazine, structural formula is suc as formula shown in the I.
3. the preparation method of ursolic acid derivative according to claim 2 is characterized in that: described preparation method's concrete steps are as follows:
The ursolic acid stirring and dissolving of (1) 1 weight part drips the acetic anhydride of 2-3 weight part in the pyridine of 40-50 weight part, add the DMAP of 0.001-0.02 weight part again, stir 16-18 h under the room temperature, after reaction finishes, regulate pH 3-4 with 2 N HCl, steaming desolventizes, suction filtration, and the washing filter cake is to neutral, dry, sample on the dried product dry method, column chromatography purification, dehydrated alcohol thermosol, cool off recrystallization, get the 3-O-ethanoyl ursolic acid of white powder;
(2) 1 weight part 3-O-ethanoyl ursolic acid are dissolved in 30-35 weight part CH
2Cl
2In, dropwise add the oxalyl chloride of 1-2 weight part, stirring reaction 36-48h under the room temperature steams the gas that desolventizes and react generation, the crude product of 3-O-ethanoyl UA acyl chlorides intermediate, directly enter next step reaction; The CH that in the crude product of above-mentioned intermediate, adds the 20-30 weight part
2Cl
2, triethylamine regulator solution pH 8-9 adds the 1-ethoxylated hydroxyethylcellulose piperazine of 2-3 weight part, stirring reaction 3-5h under the room temperature again, after reaction finishes, add the water of 5-10 weight part in the reaction solution, regulate pH3-4 with 2N HCl, filter, the washing filter cake is neutral to filtrate pH, drying; Sample on the dried product dry method, column chromatography purification, the dehydrated alcohol thermosol, the cooling recrystallization gets white powder N-[3 β-acetoxyl group-black bearberry alkane-12-alkene-28-acyl]-(1-ethoxylated hydroxyethylcellulose) piperazine.
4. a ursolic acid piperazine derivative as claimed in claim 1 or by the ursolic acid piperazine derivative of claim 2 or 3 described preparation methods' preparations is used for preparing anti-tumor medicine.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102675405A (en) * | 2012-05-24 | 2012-09-19 | 贵州大学 | Piperazinoamide ursolate compounds, and preparation method and application 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 |
| CN112321667A (en) * | 2020-10-28 | 2021-02-05 | 桂林医学院 | Ursolic acid piperazine dithioformic acid-pyridine ruthenium complex and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102675405A (en) * | 2012-05-24 | 2012-09-19 | 贵州大学 | Piperazinoamide ursolate compounds, and preparation method and application 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 |
| CN112321667A (en) * | 2020-10-28 | 2021-02-05 | 桂林医学院 | Ursolic acid piperazine dithioformic acid-pyridine ruthenium complex and preparation method and application thereof |
| CN112321667B (en) * | 2020-10-28 | 2021-08-10 | 桂林医学院 | Ursolic acid piperazine dithioformic acid-pyridine ruthenium complex and preparation method and application thereof |
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| CN101891794B (en) | 2012-04-25 |
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