CN101891794B - 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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- CN101891794B CN101891794B CN201010240154XA CN201010240154A CN101891794B CN 101891794 B CN101891794 B CN 101891794B CN 201010240154X A CN201010240154X A CN 201010240154XA CN 201010240154 A CN201010240154 A CN 201010240154A CN 101891794 B CN101891794 B CN 101891794B
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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, and ursolic acid has the various biological activity, and is antibacterial etc. like 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 spinoff 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." ursolic acid antitumor action and Mechanism Study progress thereof " (" medicine biotechnology ", 2008,15 [2]) like Wang Tao etc.; " 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 through chemoprophylaxis, mutation, CDCC, 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]-(1-ethoxylated hydroxyethylcellulose) piperazine with antitumour activity, does 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, and structural formula is suc as formula shown in the I:
The preparation method is following:
(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.
Said preparing method's concrete steps are following:
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, stirs 16-18 h under the room temperature; After reaction finishes, regulate pH 3-4 with 2 N HCl, steaming desolventizes, suction filtration; The washing filter cake is extremely neutral, drying, appearance on the dried product dry method, column chromatography purification; The absolute ethyl alcohol thermosol cools off recrystallization, gets 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 bullion of 3-O-ethanoyl UA acyl chlorides midbody, directly get into next step reaction; The CH that in the bullion of above-mentioned midbody, 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 the pH that filtrates, drying; Appearance on the dried product dry method, column chromatography purification, the absolute ethyl 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]-(1-ethoxylated hydroxyethylcellulose) piperazine also can with the NaOH hydrolytic reactions, further generate verivate, structural formula is suc as formula shown in the IV:
Concrete steps are following:
Take by weighing N-[3 β-acetoxyl group-black bearberry alkane-12-alkene-28-acyl]-(1-ethoxylated hydroxyethylcellulose) piperazine of 1 weight part, be dissolved in the CH of 20-30 weight part
3Among the OH-THF (1:1.5 v:v), add the 4N NaOH of 1-1.5 weight part, stirring reaction 3.5-4h under the room temperature; React completely, in mixture, add the water of 5-10 weight part, 2 N HCl transfer pH 3-4; Remove solvent under reduced pressure, water washing and precipitating is to neutrality, column chromatography purification; The absolute ethyl 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 following, 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 verivate V.
(3) verivate V and NaOH hydrolytic reactions further generate the verivate VI.
Wherein said verivate V, VI structural formula are following:
?Ⅴ
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 superior to ursolic acid to the inhibited proliferation of survey tumor cell line HepG2, BGC823, SH-SY5Y, Hela, and the toxic action of HELF HELF then is lower than ursolic acid.Wherein the effect of compound I is best.
Description of drawings
Fig. 1 is the synthetic route of N-[3 β-acetoxyl group-black bearberry alkane-12-alkene-28-acyl]-(1-ethoxylated hydroxyethylcellulose) piperazine (compound I) among the present invention and N-[3 beta-hydroxies-black bearberry alkane-12-alkene-28-acyl]-(1-ethoxylated hydroxyethylcellulose) piperazine (compound IV);
The synthetic route of N-among Fig. 2 the present invention [3 β-acetoxyl group-black bearberry alkane-12-alkene-28-acyl]-(N-2 hydroxyethyl) piperazine (compound V) and N-[3 beta-hydroxies-black bearberry alkane-12-alkene-28-acyl]-(N-2 hydroxyethyl) piperazine (compound VI).
Specific embodiment
Below for practical implementation example of the present invention and comparative example can further be well understood to the present invention, but they are not to qualification of the present 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 extremely neutral, 100 ℃ of dryings of normal pressure, appearance on the dried product dry method; Column chromatography purification (sherwood oil (60-90 ℃): ETHYLE ACETATE=3:1), and the absolute ethyl 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: 3293 (O-H stretching vibrations), 2927 (C-H stretching vibrations), 1736 (s, C=O stretching vibrations), 1370 (UA A district characteristic absorbance), 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
The preparation of N-[3 β-acetoxyl group-black bearberry alkane-12-alkene-28-acyl]-(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 bullion of 3-O-ethanoyl UA acyl chlorides midbody, directly get into next step reaction.In above-mentioned midbody, 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 the reaction end, add 10 ml zero(ppm) water in the reaction solution, transfer pH3-4 with 2N HCl, filter, and the washing filter cake is neutral to the pH that filtrates, drying.Column chromatography purification (chloroform: acetone=3:1), and the absolute ethyl 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: 3446 (O-H stretching vibrations), 2945 (C-H stretching vibrations), 1734 (s; The C=O stretching vibration), 1633 (s, C=O stretching vibrations; Acid amides I peak), 1370 (UA A district characteristic absorbance), 1246 (C-O-C asymmetrical stretching vibration) 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
The preparation of N-[3 beta-hydroxies-black bearberry alkane-12-alkene-28-acyl]-(1-ethoxylated hydroxyethylcellulose) piperazine (compound VI):
Take by weighing I 0.3128g, be dissolved in 20ml CH
3Among the OH-THF (1:1.5 v:v), add 2.0ml 4N NaOH, stirring reaction 3.5 h under the room temperature; React completely, in mixture, add an amount of water, 2 N HCl transfer pH 3-4; Remove solvent under reduced pressure, water washing and precipitating is extremely neutral, and column chromatography purification (chloroform: acetone=1:1); The ethanol thermosol, the cooling recrystallization gets N-[3 beta-hydroxies-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: 3414 (O-H stretching vibrations), 2925 (C-H stretching vibrations), 1616 (s, C=O stretching vibration, acid amides I peaks), 1376 (UA A district characteristic absorbance), 1227 (UA B district characteristic absorbance), 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
The preparation of N-[3 β-acetoxyl group-black bearberry alkane-12-alkene-28-acyl]-(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 bullion of 3-O-ethanoyl UA acyl chlorides midbody, directly get into next step reaction.In above-mentioned midbody, 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 the reaction end, add 10 ml zero(ppm) water in the reaction solution, transfer pH3-4 with 2N HCl, filter, and the washing filter cake is neutral to the pH that filtrates, drying.Column chromatography purification (chloroform: acetone=3:1), and 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: 3417 (O-H stretching vibrations), 2943 (C-H stretching vibrations), 1724 (s; The C=O stretching vibration), 1595 (s, C=O stretching vibrations; Acid amides I peak), 1368 (UA A district characteristic absorbance), 1251 (C-O-C asymmetrical stretching vibration) 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 verivate (VI):
Take by weighing V 0.6128g, be dissolved in 25ml CH
3Among the OH-THF (1:1.5 v:v), add 4.0ml 4N NaOH, stirring reaction 4 h under the room temperature; React completely, in mixture, add an amount of water, 2 N HCl transfer pH3-4; Remove solvent under reduced pressure, water washing and precipitating is extremely neutral, and column chromatography purification (chloroform: acetone=1:1); The ethanol thermosol, the cooling recrystallization gets N-[3 beta-hydroxies-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: 3380 (O-H stretching vibrations), 2926 (C-H stretching vibrations), 1635 (s, C=O stretching vibration, acid amides I peaks), 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 verivate (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 processes 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 verivate, and (will be tried verivate storage liquid with substratum dilutes; Set different effects concentration); 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 in 96 orifice bores; Every hole adds 150ul DMSO; 10 min vibrate; On ELIASA, measure each hole absorbance value (OD value) 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 result sees 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, explain that compound I, IV, V have the active potentiality of good anticancer, can be used as anticancer drug candidate and further study.
Claims (1)
1. ursolic acid piperazine derivative is characterized in that: said ursolic acid verivate, and structural formula is suc as formula shown in the I:
2.The application of a kind of ursolic acid piperazine derivative as claimed in claim 1 on preparing anti-tumor medicine.
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| 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 |
| 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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