CN104151391A - Oleanolic acid derivative having antineoplastic effect, preparation method and purpose thereof - Google Patents
Oleanolic acid derivative having antineoplastic effect, preparation method and purpose thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of medicines, and provides an oleanolic acid derivative having a structure shown in a general formula in a specification, and the definition of R in the general formula is shown in the specification. The invention also relates to a preparation method of the compounds, and a latent application of the compound as antitumor drugs.
Description
Technical field
The invention belongs to medical technical field, relate to a kind of oleanolic acid derivate that contains triazole group and preparation method thereof and medicinal use, be specifically related to novel 1-substituted-phenyl-1H-1,2,3-triazole-4-yl-Oleanolic Acid methyl compound and preparation method thereof and the inhibited proliferation to tumour cell have potential application aspect antitumor drug.
Background technology
Oleanolic Acid (oleanolic acid) is a kind of pentacyclic triterpene natural product, very abundant at the content of occurring in nature, in the plant such as Glossy Privet Fruit, Mile Swertia Herb.Oleanolic Acid has multiple important biological activity, as protect the liver, anti-inflammatory, antitumor, reducing blood-fat, antiulcer agent etc., again because its toxicity is low, side effect is little, thereby is widely used in clinical.
At anti-tumor aspect, Kim etc. have investigated the inhibition ability of Oleanolic Acid to multiple tumor lines, its ED to nonsmall-cell lung cancer (A549) cell, ovarian cancer (SK-OV-3) cell, melanoma (SK-MEL-3) cell, colorectal carcinoma (HCT15) cell
50value (μ g/mL) is respectively 16.4,12.4,18.5,12.1, and ED to central nerve neuroma (XF498) cell
50>30 μ g/mL (Planta Med 2000,66:485 – 486).The IC of Oleanolic Acid to human lymphoma cell P3HR1
50be 26.74 μ g/mL (Am J Chin Med 2003,31:37 – 46); In experiment, Oleanolic Acid can suppress mouse ascites cancer cell multiplication in vitro, and can reduce the damage of radiotherapy to hemopoietic tissue, recovers postradiation hemopoietic function (Cancer Lett 1997,111:7 – 13).In addition, Oleanolic Acid can also be induced mouse breast epithelial cell differentiation (Pharmacal Research1998,21:398 – 405), inducing mouse granulocyte leukemia (M1) cell and Human acute promyelocytic leukemia (HL-60) cytodifferentiation (Chem Pharm Bull 1992,40:401 – 405), and there is the effect (lung cancer in China magazine 2003,6:254 – 257) of induction human lung carcinoma cell (PGCL3) apoptosis.The discovery Oleanolic Acids such as Fernandes can suppress K562 leukemia cell's growth and promote its apoptosis, the more important thing is, still have and suppress proliferation function (Cancer Lett2003,190:165 – 169) for the K562 cell multidrug resistance strain (MDR) of tolerance vincristine(VCR).
Calendar year 2001, the Americanized scholar Sharpless of Nobel chemistry Prize winner proposes " Click reaction " this concept (Angew Chem Int Edit 2001,40:2004 – 2021).In current reported Click reaction, with Huisge 1,3-Dipolar Cycloaddition is main, and, under catalyst action, end-group alkyne and azido-effect generate 1,2,3-triazoles compound.Because its raw materials is easy to get, reaction conditions gentleness, product yield is high, selectivity good and be easy to the features such as separating-purifying, Click reaction is the new synthesis technology that brings again significant innovation continue combinatorial chemistry after to traditional Synthetic Organic Chemistry.In addition, react and in target molecule, introduce 1 by Click, 2,3-triazole ring usually can be improved solvability, pharmacodynamics and the pharmacokinetic property of original drug molecule, and can be by forming hydrogen bond, dipole and dipole, the pi-pi accumulation interaction raising action effect of compound and the specificity of effect, so Click reaction more and more demonstrates vital role at drug discovery.
The present invention is based on the constitutional features of Oleanolic Acid and the activity at anti-tumor aspect, reacted on its 28 carboxylic acids and introduced substituted triazole structure by Click, the novel oleanolic acid derivate of a class has been synthesized in design, performance antitumor action.
Summary of the invention
The object of the invention is to the design 1-substituted-phenyl-1H-1 novel with a synthetic class, 2,3-triazole-4-yl-Oleanolic Acid methyl compound, has the medicine initiative research for the treatment of cancer.
In order to complete the present invention's object, can adopt following technical scheme:
The novel oleanolic acid derivate of (I) structure that the present invention relates to have general formula, and optically active body, diastereomer.
Wherein,
R is any one group in following groups: (1) hydrogen atom, (2) hydroxyl, (3) halogen atom, (4) cyano group, (5) nitro, (6) do not replace or the following group of various replacements: C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl group, C1-6 alkoxyl group, C2-6 alkenyloxy, C2-6 chain oxy-acetylene, substituting group is halogen atom, hydroxyl, cyano group, nitro, one or more in carboxyl and amino, (7) do not replace or the carbonyl of various replacements, and it is selected from hydroxyl arbitrarily, C1-6 alkyl, C1-6 alkoxyl group, C1-6 alkylamino, C3-8 cycloalkyl, halogen atom, cyano group, one or more substituting groups in nitro and amino replace, and (8) do not replace or the amino of various replacements, and it is selected from hydroxyl arbitrarily, carbonyl, one or more substituting groups in C1-6 alkyl replace, and (8) do not replace or the following group of various replacements: phenyl, benzyl, benzoyl, pyridyl, pyrazolyl, pyrryl, pyrimidyl, quinolyl, imidazolyl, morpholinyl, piperazinyl, pyridazinyl, pyrazinyl, piperidyl, thienyl, pyranyl, indyl, furyl, substituting group is selected from hydroxyl, methylol, sulfydryl, amino, sulfonyl amido, carboxyl, ester group, cyano group, nitro, halogen atom, C1-6 alkyl, C1-6 alkoxyl group, C1-6 alkylamino, C3-7 cycloalkyl, C1-6 alkoxyl group, carbobenzoxy-(Cbz), one or more in trihalogenmethyl,
R is preferably any one group in following groups: (1) hydrogen atom (2) halogen atom, (3) cyano group, (4) nitro, (5) do not replace or the following group of various replacements: C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl group, C1-6 alkoxyl group, C2-6 alkenyloxy, C2-6 chain oxy-acetylene, substituting group is halogen atom, hydroxyl, cyano group, nitro, one or more in carboxyl and amino, (6) do not replace or the carbonyl of various replacements, it is selected from hydroxyl arbitrarily, C1-6 alkyl, C1-6 alkoxyl group, C1-6 alkylamino, C3-8 cycloalkyl, halogen atom, cyano group, one or more substituting groups in nitro and amino replace, (7) hydroxyl,
R is preferably (1) hydrogen atom; (2) C1-6 alkyl, C1-6 alkoxyl group (3) hydroxyl, (4) halogen atom (5) ethanoyl, (6) cyano group; (7) nitro, (8) benzyl.
R is particularly preferably hydrogen atom, methyl, hydroxyl, methoxyl group, bromine, cyano group, ethanoyl, phenyl, benzyl.
The preferred compound of the present invention is:
In order to prepare the described compound of general formula of the present invention (I), and optically active body, adopt following route to synthesize this compounds: under the aqueous solution of salt of wormwood and the catalysis of Tetrabutyl amonium bromide, Oleanolic Acid 1 and propargyl bromide reaction obtain intermediate 2, intermediate 2 again with the aryl azide compound of various replacements in tertiary butanol and water mixing solutions, by Cu (I) catalysis, occur 1,3 Dipolar Cycloaddition, obtain the compound of general formula (I).
Reaction formula is as follows:
Wherein,
R is any one group in following groups: (1) hydrogen atom, (2) hydroxyl, (3) halogen atom, (4) cyano group, (5) nitro, (6) do not replace or the following group of various replacements: C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl group, C1-6 alkoxyl group, C2-6 alkenyloxy, C2-6 chain oxy-acetylene, substituting group is halogen atom, hydroxyl, cyano group, nitro, one or more in carboxyl and amino, (7) do not replace or the carbonyl of various replacements, and it is selected from hydroxyl arbitrarily, C1-6 alkyl, C1-6 alkoxyl group, C1-6 alkylamino, C3-8 cycloalkyl, halogen atom, cyano group, one or more substituting groups in nitro and amino replace, and (8) do not replace or the amino of various replacements, and it is selected from hydroxyl arbitrarily, carbonyl, one or more substituting groups in C1-6 alkyl replace, and (8) do not replace or the following group of various replacements: phenyl, benzyl, benzoyl, pyridyl, pyrazolyl, pyrryl, pyrimidyl, quinolyl, imidazolyl, morpholinyl, piperazinyl, pyridazinyl, pyrazinyl, piperidyl, thienyl, pyranyl, indyl, furyl, substituting group is selected from hydroxyl, methylol, sulfydryl, amino, sulfonyl amido, carboxyl, ester group, cyano group, nitro, halogen atom, C1-6 alkyl, C1-6 alkoxyl group, C1-6 alkylamino, C3-7 cycloalkyl, C1-6 alkoxyl group, carbobenzoxy-(Cbz), one or more in trihalogenmethyl.
Specific embodiments
Contact following embodiment, will understand better compound of the present invention and their preparation, these embodiment are intended to set forth instead of limit the scope of the invention.
Embodiment 1: Oleanolic Acid-[1-phenyl-1H-1,2,3-triazole-4-yl] methyl esters (C1)
Oleanolic Acid (0.44mmol, 200.0mg) is dissolved in 20mL methylene dichloride, adds successively wet chemical, Tetrabutyl amonium bromide and propargyl bromide, reflux 2h at 50 DEG C, stopped reaction, washing, saturated NaCl washes, anhydrous Na SO
4dry, filter, concentrated, column chromatography (sherwood oil: ethyl acetate=9:1), obtains 193.7mg white solid 2;
193.7mg compound 2 is dissolved in to 15mL t-BuOH-H
2in O (2:1), add successively sodium ascorbate (0.20equi, 15.5mg), cupric sulfate pentahydrate (0.15equi, 14.7mg) and aziminobenzene (2.0equi, 98.2mg), 60 DEG C of reaction 1h, concentrated, methylene dichloride dilution, washing, saturated NaCl washes, anhydrous Na SO
4dry filter, concentrated, column chromatography (sherwood oil: ethyl acetate=12:1), obtains 211.3mg white solid C1, yield 83.03%.
ESI-MS(m/z):1249.40[2M+Na]
+；
1H?NMR(600MHz,CDCl
3)δ8.03(s,1H),7.72(d,J＝8.0Hz,2H),7.53(t,J＝7.7Hz,2H),7.45(t,J＝7.4Hz,1H),5.38–5.09(m,3H),3.19(d,J＝11.2Hz,1H),2.94–2.77(m,1H),1.10(s,3H),0.96(s,3H),0.91(s,3H),0.89(s,3H),0.77(s,3H),0.74(s,3H),0.46(s,3H)；
13C?NMR(150MHz,CDCl3)δ177.68,143.71,143.27,133.83,133.13,131.80,128.90,126.11,122.49,79.01,57.38,55.23,47.63,46.81,45.92,41.75,41.27,39.36,38.76,38.46,37.04,33.86,33.04,32.70,32.30,30.66,28.11,27.71,27.21,26.93,25.83,23.58,23.41,23.05,18.31,17.06,15.58,15.32。
Embodiment 2: Oleanolic Acid-[1-(3-aminomethyl phenyl)-1H-1,2,3-triazole-4-yl] methyl esters (C2)
The compounds process for production thereof of embodiment 2 is with embodiment 1, and between just using, aminomethyl phenyl nitrine replaces aziminobenzene, obtains 198.75mg white solid C2, yield 80.92%.
ESI-MS(m/z):1277.52[2M+Na]
+；
1H?NMR(600MHz,CDCl
3)δ8.01(s,1H),7.54(s,1H),7.48(d,J＝7.9Hz,1H),7.39(t,J＝7.7Hz,1H),7.25(d,J＝10.5Hz,1H),5.26(q,J＝12.2Hz,3H),3.19(d,J＝9.7Hz,1H),2.86(d,J＝11.3Hz,1H),2.44(s,3H),1.09(s,3H),0.96(s,3H),0.91(s,3H),0.88(s,3H),0.77(s,3H),0.74(s,3H),0.44(s,3H)；
13C?NMR(150MHz,CDCl
3)δ177.83,143.63,143.59,139.96,136.87,129.57,129.50,124.19,122.75,122.46,121.22,117.61,78.94,77.26,77.05,76.84,57.33,55.14,47.51,46.74,45.85,41.66,41.36,39.25,38.71,38.40,36.97,33.82,33.05,32.62,32.42,32.39,30.66,28.08,27.60,27.13,25.75,23.60,23.33,22.95,21.38,18.23,16.75,15.54,15.16。
Embodiment 3: Oleanolic Acid-[1-(4-hydroxy phenyl)-1H-1,2,3-triazole-4-yl] methyl esters (C3)
The compounds process for production thereof of embodiment 3, with embodiment 1, just uses p-hydroxybenzene nitrine to replace aziminobenzene, obtains 198.75mg white solid C3, yield 75.23%.
ESI-MS(m/z):1281.84[2M+Na]
+；
1H?NMR(600MHz,CDCl
3)δ7.78(s,1H),7.45–7.40(m,1H),7.38(d,J＝7.5Hz,1H),7.33(d,J＝4.0Hz,1H),5.29(q,J＝12.8Hz,3H),3.20(dd,J＝11.4,3.9Hz,1H),2.87(dd,J＝13.6,3.9Hz,1H),1.12(s,3H),0.98(s,3H),0.91(s,3H),0.89(s,3H),0.84(s,3H),0.77(s,3H),0.59(s,3H)；
13C?NMR(150MHz,CDCl
3)δ177.87,155.79,143.65,143.05,136.34,133.49,131.57,129.93,129.62,126.85,125.92,125.61,122.50,120.57,115.34,79.08,77.24,77.03,76.82,57.48,55.19,47.57,46.82,45.88,41.72,41.33,39.33,38.75,38.44,37.02,33.84,33.06,32.69,32.43,30.67,28.11,27.68,27.16,25.81,23.60,23.38,22.99,18.29,17.90,17.00,15.58,15.27。
Embodiment 4: Oleanolic Acid-[1-(2-p-methoxy-phenyl)-1H-1,2,3-triazole-4-yl] methyl esters (C4)
The compounds process for production thereof of embodiment 4, with embodiment 1, just uses o-methoxyphenyl nitrine to replace aziminobenzene, obtains 198.75mg white solid C4, yield 86.92%.
ESI-MS(m/z):1309.48[2M+Na]
+；
1H?NMR(600MHz,CDCl
3)δ8.15(s,1H),7.78(d,J＝7.8Hz,1H),7.42(t,J＝7.9Hz,1H),7.13–7.07(m,2H),5.33–5.22(m,3H),3.89(s,3H),3.21–3.16(m,1H),2.87(d,J＝10.5Hz,1H),1.10(s,3H),0.97(s,3H),0.91(s,3H),0.88(s,3H),0.80(s,3H),0.76(s,3H),0.51(s,3H)；
13C?NMR(150MHz,CDCl
3)δ177.69,150.98,143.67,142.57,130.09,126.28,126.23,125.42,122.44,121.19,112.23,78.96,57.53,55.96,55.18,47.56,46.73,45.87,41.68,41.35,39.27,38.74,38.43,37.00,33.85,33.07,32.67,32.39,30.68,28.10,27.64,27.18,25.81,23.63,23.36,22.96,18.28,16.76,15.57,15.23。
Embodiment 5: Oleanolic Acid-[1-(3-p-methoxy-phenyl)-1H-1,2,3-triazole-4-yl] methyl esters (C5)
The compounds process for production thereof of embodiment 5, with embodiment 1, just uses m-methoxyphenyl nitrine to replace aziminobenzene, obtains 198.75mg white solid C5, yield 80.92%.
ESI-MS(m/z):1309.49[2M+Na]
+；
1H?NMR(600MHz,CDCl
3)δ8.01(s,1H),7.40(t,J＝8.2Hz,1H),7.32(t,J＝2.1Hz,1H),7.24(dd,J＝7.9,1.7Hz,1H),6.97(dd,J＝8.3,2.3Hz,1H),5.31–5.21(m,3H),3.88(s,3H),3.18(dd,J＝11.6,3.8Hz,1H),2.86(dd,J＝13.8,4.1Hz,1H),1.09(s,3H),0.96(s,3H),0.91(s,3H),0.88(s,3H),0.77(s,3H),0.74(s,3H),0.45(s,3H)；
13C?NMR(150MHz,CDCl
3)δ177.81,160.65,143.76,143.62,137.97,130.51,122.67,122.49,114.64,112.36,106.40,78.97,57.34,55.64,55.17,47.54,46.75,45.87,41.68,41.38,39.27,38.73,38.41,36.99,33.83,33.06,32.64,32.42,30.67,28.09,27.63,27.18,25.76,23.61,23.35,22.97,18.25,16.78,15.53,15.16。
Embodiment 6: Oleanolic Acid-[1-(4-p-methoxy-phenyl)-1H-1,2,3-triazole-4-yl] methyl esters (C6)
The compounds process for production thereof of embodiment 6, with embodiment 1, just uses p-methoxyphenyl nitrine to replace aziminobenzene, obtains 201.15mg white solid C6, yield 81.90%.
ESI-MS(m/z):1308.76[2M+Na]
+；
1H?NMR(600MHz,CDCl
3)δ7.94(s,1H),7.61(d,J＝8.8Hz,2H),7.02(d,J＝8.8Hz,2H),5.31–5.21(m,3H),3.87(s,3H),3.19(s,1H),2.87(d,J＝10.7Hz,1H),1.10(s,3H),0.97(s,3H),0.91(s,3H),0.89(s,3H),0.79(s,3H),0.75(s,3H),0.47(s,3H)；
13C?NMR(150MHz,CDCl
3)δ177.53,160.04,143.61,130.92,128.84,122.65,122.46,122.13,114.99,114.75,110.71,78.96,61.61,57.41,55.65,55.16,47.53,46.74,45.86,41.67,41.37,39.27,38.73,38.41,36.99,33.82,33.06,32.64,32.41,30.67,28.09,27.63,25.77,23.61,22.97,18.26,16.79,15.55,15.20,14.11。
Embodiment 7: Oleanolic Acid-[1-(2-bromophenyl)-1H-1,2,3-triazole-4-yl] methyl esters (C7)
The compounds process for production thereof of embodiment 7, with embodiment 1, just uses 2-bromophenyl nitrine to replace aziminobenzene, obtains 221.12mg white solid C7, yield 89.45%.
ESI-MS(m/z):1406.53[2M+Na]
+；
1H?NMR(600MHz,CDCl
3)δ8.00(s,1H),7.76(dd,J＝8.0,0.9Hz,1H),7.56(dd,J＝7.9,1.4Hz,1H),7.49(dd,J＝11.0,4.3Hz,1H),7.40(td,J＝7.9,1.5Hz,1H),5.35–5.24(m,1H),3.20(dd,J＝11.4,4.3Hz,1H),2.87(dd,J＝13.7,4.1Hz,1H),1.12(s,3H),0.98(s,3H),0.90(s,3H),0.89(s,3H),0.85(s,3H),0.77(s,3H),0.59(s,3H)；
13C?NMR(150MHz,CDCl
3)δ177.70,143.66,142.97,136.45,134.01,131.19,128.46,128.16,126.13,122.49,118.37,78.98,57.42,55.20,47.58,46.79,45.88,41.71,41.32,39.34,38.75,38.44,37.03,33.85,33.06,32.70,32.42,30.67,28.11,27.68,27.19,25.82,23.61,23.39,23.00,18.31,16.98,15.59,15.30。
Embodiment 8: Oleanolic Acid-[1-(3-bromophenyl)-1H-1,2,3-triazole-4-yl] methyl esters (C8)
The compounds process for production thereof of embodiment 8, with embodiment 1, just uses 3-bromophenyl nitrine to replace aziminobenzene, obtains 187.23mg white solid C8, yield 75.74%.
ESI-MS(m/z):1406.54[2M+Na]
+；
1H?NMR(600MHz,CDCl
3)δ8.02(s,1H),7.92(t,J＝1.8Hz,1H),7.67(dd,J＝8.1,1.2Hz,1H),7.58(d,J＝8.0Hz,1H),7.40(t,J＝8.1Hz,1H),5.31–5.20(m,3H),3.18(dd,J＝11.5,4.1Hz,1H),2.86(dd,J＝13.7,4.1Hz,1H),1.10(s,3H),0.96(s,3H),0.91(s,3H),0.89(s,3H),0.78(s,3H),0.75(s,3H),0.42(s,3H)；
13C?NMR(150MHz,CDCl
3)δ177.86,144.07,143.57,137.86,131.85,131.06,123.69,123.35,122.71,122.51,118.97,78.98,57.21,55.17,47.51,46.77,45.86,41.68,41.39,39.28,38.73,38.42,36.99,33.83,33.05,32.64,32.44,30.67,28.09,27.61,27.18,26.93,25.74,23.60,23.34,22.97,18.24,16.78,15.55,15.23,14.12。
Embodiment 9: Oleanolic Acid-[1-(4-bromophenyl)-1H-1,2,3-triazole-4-yl] methyl esters (C9)
The compounds process for production thereof of embodiment 9, with embodiment 1, just uses 4-bromophenyl nitrine to replace aziminobenzene, obtains 213.69mg white solid C9, yield 86.44%.
ESI-MS(m/z):1406.49[2M+Na]
+；
1H?NMR(600MHz,CDCl
3)δ8.01(s,1H),7.66(d,J＝8.8Hz,2H),7.61(d,J＝8.8Hz,2H),5.32–5.20(m,1H),3.19(d,J＝10.9Hz,1H),2.86(dd,J＝13.8,4.0Hz,1H),1.10(s,3H),0.97(s,3H),0.91(s,3H),0.89(s,3H),0.77(s,3H),0.75(s,3H),0.44(s,3H)；
13C?NMR(150MHz,CDCl
3)δ177.85,144.10,143.58,135.93,132.91,122.51,122.45,121.87,78.97,57.27,55.16,47.51,46.77,45.84,41.68,41.38,39.28,38.73,38.41,36.99,33.81,33.05,32.63,32.42,30.67,28.09,27.62,27.18,25.76,23.60,23.35,22.97,18.25,16.78,15.55,15.17。
Embodiment 10: Oleanolic Acid-[1-(2-cyano-phenyl)-1H-1,2,3-triazole-4-yl] methyl esters (C10)
The compounds process for production thereof of embodiment 10, with embodiment 1, just uses 2-cyano-phenyl nitrine to replace aziminobenzene, obtains 207.83mg white solid C10, yield 83.47%.
ESI-MS(m/z):1298.71[2M+Na]
+；
1H?NMR(600MHz,CDCl
3)δ8.26(s,1H),7.87(d,J＝8.2Hz,2H),7.80(t,J＝7.8Hz,1H),7.61(t,J＝7.8Hz,1H),5.34–5.26(m,3H),3.20(d,J＝11.2Hz,1H),2.87(dd,J＝13.7,4.1Hz,1H),1.11(s,3H),0.98(s,3H),0.91(s,3H),0.89(s,3H),0.81(s,3H),0.76(s,3H),0.53(s,3H)；
13C?NMR(150MHz,CDCl
3)δ177.66,144.15,143.59,138.44,134.40,134.23,129.59,125.38,124.56,122.53,115.51,106.68,78.97,57.22,55.17,47.56,46.80,45.86,41.69,41.35,39.32,38.74,38.42,37.01,33.81,33.07,32.65,32.39,30.67,28.10,27.66,27.18,25.81,23.62,23.36,22.98,18.30,16.82,15.58,15.25,13.70。
Embodiment 11: Oleanolic Acid-[1-(3-cyano-phenyl)-1H-1,2,3-triazole-4-yl] methyl esters (C11)
The compounds process for production thereof of embodiment 11, with embodiment 1, just uses 3-cyano-phenyl nitrine to replace aziminobenzene, obtains 197.33mg white solid C11, yield 79.26%.
ESI-MS(m/z):1298.79[2M+Na]
+；
1H?NMR(600MHz,CDCl
3)δ8.08(s,1H),8.05(s,1H),8.00(d,J＝8.1Hz,1H),7.74(d,J＝7.7Hz,1H),7.67(t,J＝8.0Hz,1H),5.30–5.22(m,3H),3.18(dd,J＝11.3,3.6Hz,1H),2.86(dd,J＝13.7,4.0Hz,1H),1.10(s,3H),0.96(s,3H),0.91(s,3H),0.89(s,3H),0.77(s,3H),0.74(s,3H),0.43(s,3H)；
13C?NMR(150MHz,CDCl
3)δ177.86,144.50,143.52,137.47,132.11,130.90,124.36,123.62,122.54,122.50,117.25,114.27,78.93,57.14,55.15,47.48,46.79,45.81,41.68,41.39,39.29,38.72,38.40,36.98,33.80,33.04,32.63,32.43,30.66,28.08,27.61,27.16,25.75,23.60,23.34,22.97,18.24,16.79,15.55,15.20。
Embodiment 12: Oleanolic Acid-[1-(4-cyano-phenyl)-1H-1,2,3-triazole-4-yl] methyl esters (C12)
The compounds process for production thereof of embodiment 12, with embodiment 1, just uses 4-cyano-phenyl nitrine to replace aziminobenzene, obtains 189.35mg white solid C12, yield 76.05%.
ESI-MS(m/z):1298.57[2M+Na]
+；
1H?NMR(600MHz,CDCl
3)δ8.10(s,1H),7.90(d,J＝8.7Hz,2H),7.84(d,J＝8.7Hz,2H),5.31–5.23(m,3H),3.22–3.15(m,1H),2.89–2.82(m,1H),1.10(s,3H),0.97(s,3H),0.91(s,3H),0.89(s,3H),0.76(s,3H),0.75(s,3H),0.43(s,3H)；
13C?NMR(150MHz,CDCl
3)δ177.91,144.57,143.52,139.72,133.92,122.54,122.40,120.55,117.61,112.57,78.94,57.12,55.14,47.49,46.80,45.80,41.69,41.40,39.28,38.72,38.41,36.98,33.79,33.04,32.62,32.43,30.66,28.08,27.62,27.16,25.76,23.59,23.34,22.97,18.24,16.74,15.56,15.17。
Embodiment 13: Oleanolic Acid-[1-(2-acetyl phenyl)-1H-1,2,3-triazole-4-yl] methyl esters (C13)
The compounds process for production thereof of embodiment 13, with embodiment 1, just uses 2-acetyl aziminobenzene to replace aziminobenzene, obtains 183.89mg white solid C13, yield 71.94%.
ESI-MS(m/z):1332.56[2M+Na]
+；
1H?NMR(600MHz,CDCl
3)δ7.90(s,1H),7.71(dd,J＝7.5,1.6Hz,1H),7.64–7.58(m,2H),7.45(dd,J＝7.7,1.3Hz,1H),5.29–5.25(m,3H),3.19(dd,J＝11.4,4.4Hz,1H),2.85(dd,J＝13.6,4.5Hz,1H),2.17(s,3H),1.11(s,3H),0.96(s,3H),0.89(s,3H),0.88(s,3H),0.84(s,3H),0.75(s,3H),0.59(s,3H)；
13C?NMR(150MHz,CDCl
3)δ199.19,177.64,143.74,143.55,136.15,134.22,131.79,129.90,129.00,125.52,125.47,122.40,78.88,60.32,57.25,55.08,47.47,46.68,45.75,41.61,41.23,39.22,38.65,38.33,36.92,33.72,32.96,32.55,30.57,29.08,28.00,27.57,27.07,25.72,23.51,23.28,22.88,18.19,16.86,15.49,15.18。
Embodiment 14: Oleanolic Acid-[1-(3-acetyl phenyl)-1H-1,2,3-triazole-4-yl] methyl esters (C14)
The compounds process for production thereof of embodiment 14, with embodiment 1, just uses 3-acetyl aziminobenzene to replace aziminobenzene, obtains 203.55mg white solid C14, yield 79.63%.
ESI-MS(m/z):1332.75[2M+Na]
+；
1H?NMR(600MHz,CDCl
3)δ8.28(s,1H),8.11(s,1H),8.04–7.97(m,2H),7.65(t,J＝7.9Hz,1H),5.32–5.21(m,3H),3.18(dd,J＝11.4,3.8Hz,1H),2.87(dd,J＝13.7,4.0Hz,1H),2.67(s,3H),1.10(s,3H),0.95(s,3H),0.91(s,3H),0.89(s,3H),0.74(s,3H),0.72(s,3H),0.45(s,3H)；
13CNMR(150MHz,CDCl
3)δ196.43,177.79,144.14,143.52,138.56,137.34,130.20,128.45,124.65,122.59,122.52,119.71,78.92,57.25,55.14,47.50,46.76,45.83,41.67,41.38,39.27,38.71,38.39,36.97,33.81,33.05,32.63,32.42,30.66,28.08,27.62,27.16,26.72,25.75,23.61,23.33,22.97,18.23,16.75,15.53,15.15。
Embodiment 15: Oleanolic Acid-[1-(4-acetyl phenyl)-1H-1,2,3-triazole-4-yl] methyl esters (C15)
The compounds process for production thereof of embodiment 15, with embodiment 1, just uses 4-acetyl aziminobenzene to replace aziminobenzene, obtains 183.34mg white solid C15, yield 71.72%.
ESI-MS(m/z):1332.76[2M+Na]
+；
1H?NMR(600MHz,CDCl
3)δ8.15–8.08(m,3H),7.86(d,J＝8.6Hz,2H),5.30–5.23(m,3H),3.18(dd,J＝11.6,4.0Hz,1H),2.86(dd,J＝13.8,4.1Hz,1H),2.65(s,3H),1.10(s,3H),0.96(s,3H),0.91(s,3H),0.89(s,3H),0.74(s,3H),0.73(s,3H),0.44(s,3H)；
13C?NMR(150MHz,CDCl
3)δ196.44,177.85,144.26,143.56,139.96,136.94,130.06,122.51,120.04,78.94,57.25,57.22,55.13,47.50,46.78,45.83,41.68,41.39,39.27,38.72,38.39,36.97,33.80,33.05,32.62,32.42,30.67,28.07,27.63,27.16,26.67,25.76,23.60,23.34,22.97,18.23,16.76,15.54,15.16。
Embodiment 16: Oleanolic Acid-[1-(2-nitrophenyl)-1H-1,2,3-triazole-4-yl] methyl esters (C16)
The compounds process for production thereof of embodiment 16, with embodiment 1, just uses 2-nitrophenyl nitrine to replace aziminobenzene, obtains 213.17mg white solid C16, yield 83.02%.
ESI-MS(m/z):1338.69[2M+Na]
+；
1H?NMR(600MHz,CDCl
3)δ8.09(d,J＝8.0Hz,1H),7.90(s,1H),7.79(t,J＝7.5Hz,1H),7.71(t,J＝7.6Hz,1H),7.62(d,J＝7.8Hz,1H),5.32–5.23(m,3H),3.20(dd,J＝11.3,4.2Hz,1H),2.86(dd,J＝13.7,3.9Hz,1H),1.12(s,3H),0.98(s,3H),0.91(s,3H),0.89(s,3H),0.85(s,3H),0.76(s,3H),0.58(s,3H)；
13C?NMR(150MHz,CDCl
3)δ177.77,144.41,143.81,143.65,133.72,130.83,130.16,127.87,125.70,125.64,122.49,78.97,57.23,55.18,47.57,46.80,45.88,41.72,41.33,39.34,38.75,38.43,37.03,33.82,33.06,32.65,32.35,30.67,28.10,27.67,27.18,25.81,23.61,23.37,23.00,18.30,16.93,15.59,15.28。
Embodiment 17: Oleanolic Acid-[1-(3-nitrophenyl)-1H-1,2,3-triazole-4-yl] methyl esters (C17)
The compounds process for production thereof of embodiment 17, with embodiment 1, just uses 3-nitrophenyl nitrine to replace aziminobenzene, obtains 202.10mg white solid C17, yield 78.70%.
ESI-MS(m/z):1338.67[2M+Na]
+；
1H?NMR(600MHz,CDCl
3)δ8.58(s,1H),8.32(d,J＝8.2Hz,1H),8.16(d,J＝9.5Hz,2H),7.76(t,J＝8.1Hz,1H),5.33–5.22(m,3H),3.18(dd,J＝11.1,3.8Hz,1H),2.87(d,J＝10.4Hz,1H),1.10(s,3H),0.96(s,3H),0.91(s,3H),0.89(s,3H),0.74(s,3H),0.72(s,3H),0.45(s,3H)；
13C?NMR(150MHz,CDCl
3)δ177.87,148.96,143.50,137.64,130.98,128.84,125.89,123.27,122.67,122.55,115.29,78.92,61.61,57.15,55.13,47.48,46.80,45.81,41.69,41.39,39.29,38.71,38.39,36.96,33.80,33.04,32.63,32.43,30.66,28.07,27.62,27.15,25.75,23.59,23.33,22.97,18.22,16.76,15.51,15.11,14.11。
Embodiment 18: Oleanolic Acid-[1-(4-nitrophenyl)-1H-1,2,3-triazole-4-yl] methyl esters (C18)
The compounds process for production thereof of embodiment 18, with embodiment 1, just uses 4-nitrophenyl nitrine to replace aziminobenzene, obtains 193.67mg white solid C18, yield 75.42%.
ESI-MS(m/z):1338.48[2M+Na]
+；
1H?NMR(600MHz,CDCl
3)δ8.42(d,J＝9.0Hz,2H),8.14(s,1H),7.96(d,J＝9.0Hz,2H),5.34–5.23(m,3H),3.18(d,J＝10.9Hz,1H),2.86(dd,J＝13.7,4.1Hz,1H),1.11(s,3H),0.96(s,3H),0.91(s,3H),0.89(s,3H),0.76(s,3H),0.73(s,3H),0.45(s,3H)；
13C?NMR(150MHz,CDCl
3)δ177.91,147.33,144.72,143.53,141.07,125.53,122.55,120.48,78.94,57.11,55.14,47.49,46.82,45.80,41.70,41.41,39.29,38.72,38.40,36.98,33.79,33.04,32.63,32.43,30.67,28.07,27.63,27.16,25.77,23.60,23.34,22.98,18.25,16.75,15.54,15.17。
Embodiment 19: Oleanolic Acid-[1-xenyl-1H-1,2,3-triazole-4-yl] methyl esters (C19)
The compounds process for production thereof of embodiment 19, with embodiment 1, just uses xenyl nitrine to replace aziminobenzene, obtains 198.75mg white solid C19, yield 80.92%.
ESI-MS(m/z):1401.92[2M+Na]
+；
1H?NMR(600MHz,CDCl
3)δ8.03(s,1H),7.72(d,J＝8.0Hz,4H),7.53(t,J＝7.7Hz,4H),7.45(t,J＝7.4Hz,1H),5.38–5.09(m,3H),3.19(d,J＝11.2Hz,1H),2.94–2.77(m,1H),1.10(s,3H),0.96(s,3H),0.91(s,3H),0.89(s,3H),0.77(s,3H),0.74(s,3H),0.46(s,3H)；
13C?NMR(150MHz,CDCl3)δ177.68,143.71,143.27,133.83,133.13,131.80,128.90,126.11,122.49,79.01,57.38,55.23,47.63,46.81,45.92,41.75,41.27,39.36,38.76,38.46,37.04,33.86,33.04,32.70,32.30,30.66,28.11,27.71,27.21,26.93,25.83,23.58,23.41,23.05,18.31,17.06,15.58,15.32。
Embodiment 20: Oleanolic Acid-[1-(4-benzyl phenyl)-1H-1,2,3-triazole-4-yl] methyl esters (C20)
The compounds process for production thereof of embodiment 20, with embodiment 1, just uses 4-benzyl phenyl base nitrine to replace aziminobenzene, obtains 198.75mg white solid C20, yield 75.23%.
ESI-MS(m/z):1429.94[2M+Na]
+；
1H?NMR(600MHz,CDCl
3)δ8.10(s,1H),7.90(d,J＝8.7Hz,4H),7.84(d,J＝8.7Hz,4H),5.31–5.23(m,4H),3.22–3.15(m,1H),2.89–2.82(m,1H),1.10(s,3H),0.97(s,3H),0.91(s,3H),0.89(s,3H),0.76(s,3H),0.75(s,3H),0.43(s,3H)；
13C?NMR(150MHz,CDCl
3)δ177.91,144.57,143.52,139.72,133.92,122.54,122.40,120.55,117.61,112.57,78.94,57.12,55.14,47.49,46.80,45.80,41.69,41.40,39.28,38.72,38.41,36.98,33.79,33.04,32.62,32.43,30.66,28.08,27.62,27.16,25.76,23.59,23.34,22.97,18.24,16.74,15.56,15.17。
The pharmacological research of product of the present invention
Human cervical carcinoma cell HeLa, human liver cancer cell HepG2, human fibrosarcoma cell HT-1080, human colon cancer cell HCT116, human melanoma cell A375-S2 is purchased from American Type Culture Collection (ATCC, Rockville, MD, USA).Cell is seeded in the RPMI-1640 nutrient solution containing 10% foetal calf serum, 2% glutamine, at 37 DEG C, and 5%CO
2in incubator, cultivate.
Select the tumour cell of logarithmic phase, with after trysinization, use containing the RPMIl640 substratum of 10% calf serum and be made into 5 × 10
4the cell suspension of/mL, is seeded in 96 well culture plates, every hole 100 μ L, 37 DEG C, 5%CO
2cultivate 24h.The nutrient solution containing different concns sample that experimental group more renews, control group is changed the nutrient solution containing equal-volume solvent, establishes 3 parallel holes, 37 DEG C, 5%CO for every group
2cultivate 48h.Abandoning supernatant, carefully washes 2 times with PBS, and every hole adds the freshly prepared substratum containing 0.5mg/mL MTT of 100 μ L, and 37 DEG C are continued to cultivate 4h.Careful supernatant discarded, and add 150 μ L DMSO, mixes after 10min with microoscillator, by microplate reader in 492nm place mensuration optical density value.
Be calculated as follows the inhibiting rate of medicine to growth of tumour cell:
Growth of tumour cell inhibiting rate (%)
=[A
492(negative control)-A
492(dosing group)]/A
492(negative control) × 100%
Therefrom obtain the half-inhibition concentration (IC of sample
50).
The restraining effect IC of compound to five kinds of human cancer cell in-vitro multiplications
50(μ M)
Claims (10)
1. the class shown in general formula (I) has the oleanolic acid derivate of antitumor action, and optically active body, diastereomer:
Wherein:
R is any one group in following groups: (1) hydrogen atom, (2) hydroxyl, (3) halogen atom, (4) cyano group, (5) nitro, (6) do not replace or the following group of various replacements: C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl group, C1-6 alkoxyl group, C2-6 alkenyloxy, C2-6 chain oxy-acetylene, substituting group is halogen atom, hydroxyl, cyano group, nitro, one or more in carboxyl and amino, (7) do not replace or the carbonyl of various replacements, and it is selected from hydroxyl arbitrarily, C1-6 alkyl, C1-6 alkoxyl group, C1-6 alkylamino, C3-8 cycloalkyl, halogen atom, cyano group, one or more substituting groups in nitro and amino replace, and (8) do not replace or the amino of various replacements, and it is selected from hydroxyl arbitrarily, carbonyl, one or more substituting groups in C1-6 alkyl replace, and (8) do not replace or the following group of various replacements: phenyl, benzyl, benzoyl, pyridyl, pyrazolyl, pyrryl, pyrimidyl, quinolyl, imidazolyl, morpholinyl, piperazinyl, pyridazinyl, pyrazinyl, piperidyl, thienyl, pyranyl, indyl, furyl, substituting group is selected from hydroxyl, methylol, sulfydryl, amino, sulfonyl amido, carboxyl, ester group, cyano group, nitro, halogen atom, C1-6 alkyl, C1-6 alkoxyl group, C1-6 alkylamino, C3-7 cycloalkyl, C1-6 alkoxyl group, carbobenzoxy-(Cbz), one or more in trihalogenmethyl.
2. derivative according to claim 1, and optically active body, diastereomer:
Wherein:
R is any one group in following groups: (1) hydrogen atom, (2) hydroxyl, (3) halogen atom, (4) cyano group, (5) nitro, (6) do not replace or the following group of various replacements: C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl group, C1-6 alkoxyl group, C2-6 alkenyloxy, C2-6 chain oxy-acetylene, substituting group is halogen atom, hydroxyl, cyano group, nitro, one or more in carboxyl and amino, (7) do not replace or the carbonyl of various replacements, it is selected from hydroxyl arbitrarily, C1-6 alkyl, C1-6 alkoxyl group, C1-6 alkylamino, C3-8 cycloalkyl, halogen atom, cyano group, one or more substituting groups in nitro and amino replace.
3. derivative according to claim 1 and 2, and optically active body, diastereomer,
Wherein:
R is (1) hydrogen atom, (2) C1-6 alkyl, (3) C1-6 alkoxyl group; (4) hydroxyl, (5) halogen atom (6) ethanoyl, (7) cyano group; (8) nitro, (9) benzyl.
4. the derivative described in any one according to claim 1-3, and optically active body, diastereomer,
Wherein:
R is hydrogen atom, methyl, methoxyl group, hydroxyl, bromine, cyano group, ethanoyl, nitro, phenyl, benzyl.
5. the compound of claim 1-4 described in any one, and optically active body,, diastereomer, is selected from:
C1: Oleanolic Acid-[1-phenyl-1H-1,2,3-triazole-4-yl] methyl esters
C2: Oleanolic Acid-[1-(3-aminomethyl phenyl)-1H-1,2,3-triazole-4-yl] methyl esters
C3: Oleanolic Acid-[1-(4-hydroxy phenyl)-1H-1,2,3-triazole-4-yl] methyl esters
C4: Oleanolic Acid-[1-(2-p-methoxy-phenyl)-1H-1,2,3-triazole-4-yl] methyl esters
C5: Oleanolic Acid-[1-(3-p-methoxy-phenyl)-1H-1,2,3-triazole-4-yl] methyl esters
C6: Oleanolic Acid-[1-(4-p-methoxy-phenyl)-1H-1,2,3-triazole-4-yl] methyl esters
C7: Oleanolic Acid-[1-(2-bromophenyl)-1H-1,2,3-triazole-4-yl] methyl esters
C8: Oleanolic Acid-[1-(3-bromophenyl)-1H-1,2,3-triazole-4-yl] methyl esters
C9: Oleanolic Acid-[1-(4-bromophenyl)-1H-1,2,3-triazole-4-yl] methyl esters
C10: Oleanolic Acid-[1-(2-cyano-phenyl)-1H-1,2,3-triazole-4-yl] methyl esters
C11: Oleanolic Acid-[1-(3-cyano-phenyl)-1H-1,2,3-triazole-4-yl] methyl esters
C12: Oleanolic Acid-[1-(4-cyano-phenyl)-1H-1,2,3-triazole-4-yl] methyl esters
C13: Oleanolic Acid-[1-(2-acetyl phenyl)-1H-1,2,3-triazole-4-yl] methyl esters
C14: Oleanolic Acid-[1-(3-acetyl phenyl)-1H-1,2,3-triazole-4-yl] methyl esters
C15: Oleanolic Acid-[1-(4-acetyl phenyl)-1H-1,2,3-triazole-4-yl] methyl esters
C16: Oleanolic Acid-[1-(2-nitrophenyl)-1H-1,2,3-triazole-4-yl] methyl esters
C17: Oleanolic Acid-[1-(3-nitrophenyl)-1H-1,2,3-triazole-4-yl] methyl esters
C18: Oleanolic Acid-[1-(4-nitrophenyl)-1H-1,2,3-triazole-4-yl] methyl esters
C19: Oleanolic Acid-[1-xenyl-1H-1,2,3-triazole-4-yl] methyl esters
C20: Oleanolic Acid-[1-(4-benzyl phenyl)-1H-1,2,3-triazole-4-yl] methyl esters
Its structure is as follows:
6. compound and optically active body thereof described in claim 1, the preparation method of diastereomer, is characterized in that:
The synthetic method of general formula (I) compound is as follows:
Under the aqueous solution of salt of wormwood and the catalysis of Tetrabutyl amonium bromide, Oleanolic Acid 1 and propargyl bromide reaction obtain intermediate 2, intermediate 2 again with the aryl azide compound of various replacements in tertiary butanol and water mixing solutions, by Cu (I) catalysis, occur 1,3 Dipolar Cycloaddition, obtain the compound of general formula (I).
Reaction formula is as follows:
Wherein, R as claimed in claim 1.
7. a pharmaceutical composition, comprises compound and optically active body thereof, diastereomer and the pharmaceutically acceptable carrier of claim 1-5 described in any one.
8. compound and the optically active body thereof of claim 1-5 described in any one, pharmaceutical composition is in the application of preparing in antitumor drug described in diastereomer or claim 7.
9. compound and the optically active body thereof of claim 1-5 described in any one, the application of pharmaceutical composition in preparation treatment cancer drug described in diastereomer or claim 7.
10. compound and the optically active body thereof of claim 1-5 described in any one, the application of pharmaceutical composition in preparation treatment cervical cancer, liver cancer, fibrosarcoma, colorectal carcinoma, skin carcinoma medicine described in diastereomer or claim 7.
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| JP6082488B1 (en) * | 2016-03-16 | 2017-02-15 | 浩 丸田 | Preparation of ester of PAK1 blocker acidified by carboxyl group and application to treatment of cancer and other PAK1-dependent diseases |
| CN106366151A (en) * | 2016-08-25 | 2017-02-01 | 沈阳药科大学 | Oleanolic acid-3-one derivative having antitumor effects, preparation method, and application thereof |
| CN106366151B (en) * | 2016-08-25 | 2018-07-03 | 沈阳药科大学 | Oleanolic acid -3- ketone derivatives with antitumor action and its preparation method and application |
| CN106967146A (en) * | 2017-05-16 | 2017-07-21 | 烟台大学 | Oleanolic acid terazole derivatives and its production and use |
| CN111961110A (en) * | 2020-09-17 | 2020-11-20 | 昆明理工大学 | Oleanolic acid C-3 sugar conjugate, preparation method thereof and application thereof in resisting influenza virus |
| CN115181156A (en) * | 2022-05-31 | 2022-10-14 | 延边大学 | Hederagenin derivative and application thereof in preparation of anti-tumor drugs |
| CN115181156B (en) * | 2022-05-31 | 2023-11-10 | 延边大学 | Hederagenin derivative and application thereof in preparation of antitumor drugs |
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