CN102516350B - Glycyrrhetinic acid modifier with antitumor activity and preparation method thereof - Google Patents
Glycyrrhetinic acid modifier with antitumor activity and preparation method thereof Download PDFInfo
- Publication number
- CN102516350B CN102516350B CN201110354326.0A CN201110354326A CN102516350B CN 102516350 B CN102516350 B CN 102516350B CN 201110354326 A CN201110354326 A CN 201110354326A CN 102516350 B CN102516350 B CN 102516350B
- Authority
- CN
- China
- Prior art keywords
- glycyrrhetinic acid
- ethyl ester
- carboxylic acid
- acid
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Abstract
The invention relates to a glycyrrhetinic acid modifier with antitumor activity and a preparation method thereof, which relate to structural modification technology of glycyrrhetinic acid. The method comprises the following step that: after carrying out esterification on 30-bit carboxyl and alkyl chloride of the glycyrrhetinic acid, modifying an A loop to realize structural modification of the glycyrrhetinic acid so as to obtain a series of glycyrrhetinic acid derivatives (I 1-5, I I1-5, III 1-5, IV 1-5 and V1-5). Through a test, the glycyrrhetinic acid modifier has a certain inhibiting effect for human body cervical carcinoma HeLa cells, hepatocelular carcinoma HepG2 cells and gastric cancer BGC-823 cells. The structure of the glycyrrhetinic acid derivatives is shown in the description.
Description
Technical field
The present invention relates to a kind of natural product glycyrrhetinic acid structure of modification method, especially relate to glycyrrhetinic acid modifier of a class anti-tumor activity and preparation method thereof.
Background technology
Glycyrrhetinic acid (Glycyrrhetinic acid, GA) belongs to pentacyclic triterpenoid, has another name called glycyrrhetinic acid, chemistry 3 beta-hydroxies-11-oxo-olea type-12-alkene-30-acid by name, and molecular formula is C
30h
46o
4, white crystal, 289 ~ 291 DEG C of fusing points.GA is the aglycon of Potenlini, and it is distributed widely in vegitabilia, exists with free form or the many and sugared form that is combined into glycosides.Studies have shown that, GA has the biological activity of thyroliberin (ACTH) sample, anti-CCl
4to the acute poisoning of liver, anti-immune anti-inflammatory etc., propagation, the invasion and attack of going back inhibition tumor cell, energy cell death inducing simultaneously, tumour cell is shown to stronger cytotoxic activity, and glycyrrhetinic acid all has restraining effect to Several Kinds of Malignancies such as cancer of the stomach, liver cancer, mammary cancer, malignant melanomas.
The chemical structural formula of glycyrrhetinic acid:
Research shows, GA is except suppressing 11 β-HSD2(11 beta-hydroxysteroid dehydrogenase) activity of isozyme improves the anti-colon-cancer cell proliferation function of hydrocortisone, raise Cytoplasmic Ca 2+ level and suppress human breast cancer cell (MCF-7) increment and apoptosis-induced outside, can also block the cell cycle G0 ∕ G1 phase, raise P21, P27 protein expression inhibition BGC823 cell proliferation,, be potential cancer chemoprevention product, there is good prospect in medicine and exploitation value.
Summary of the invention
The object of the present invention is to provide a kind of glycyrrhetinic acid with anti-tumor activity as lead compound, design the derivative of a series of glycyrrhetinic acid acid.
The object of the invention is to be achieved through the following technical solutions:
Have a glycyrrhetinic acid modifier for anti-tumor activity, the glycyrrhetinic acid modifier described in it comprises:
The Radix Glycyrrhizae time derivative that one class formation formula is following
,
Wherein, R
1for
or
or
or
; R
2for being carbonyl or hydrogen; R
2for methanoyl ethyl ester, methanoyl benzyl ester, methanoyl ethyl acetate, methanoyl isopropyl ester, the positive butyl ester of methanoyl, wherein:
R
1for
, R
2during for hydrogen, be chemical compounds I:
,
Wherein, R
3expression-COOC
2h
5,-COOBn ,-COOCH
2cOOC
2h
5,-COOCH (CH
3)
2,-COO (CH
2)
3cH
3;
R
1for
, R
2during for carbonyl, be compound ii:
,
Wherein, R
3expression-COOC
2h
5,-COOBn ,-COOCH
2cOOC
2h
5,-COOCH (CH
3)
2,-COO (CH
2)
3cH
3;
R
1for
, R
2during for carbonyl, be compound III:
,
Wherein, R
3expression-COOC
2h
5,-COOBn ,-COOCH
2cOOC
2h
5,-COOCH (CH
3)
2,-COO (CH
2)
3cH
3;
R
1for
, R
2during for carbonyl, be compounds Ⅳ:
,
Wherein, R
3expression-COOC
2h
5,-COOBn ,-COOCH
2cOOC
2h
5,-COOCH (CH
3)
2,-COO (CH
2)
3cH
3;
R
1for
, R
2during for carbonyl, be compound V:
,
Wherein, R
3expression-COOC
2h
5,-COOBn ,-COOCH
2cOOC
2h
5,-COOCH (CH
3)
2,-COO (CH
2)
3cH
3.
Described a kind of glycyrrhetinic acid modifier with anti-tumor activity, the glycyrrhetinic acid modifier described in it has anti-tumor activity, can be used for treating tumor disease.
Have a preparation method for the glycyrrhetinic acid modifier of anti-tumor activity, this preparation method comprises the following steps:
(1) glycyrrhetinic acid and zinc amalgam reagent react obtain 11-deoxidation glycyrrhetinic acid;
(2) 11-deoxidation glycyrrhetinic acid and glycyrrhetinic acid carry out esterification with halohydrocarbon respectively and obtain 11-deoxidation glycyrrhetinic acid carboxylic acid ester compound and glycyrrhetinic acid ester compound;
(3) 11-deoxidation glycyrrhetinic acid carboxylic acid ester compound reacts with 0 DEG C of Methanesulfonyl chloride and obtains 3 Beta-methyl sulphur oxygen base-oleanane type-12-alkene-30 carboxylic acid ester compounds;
(4) 3 Beta-methyl sulphur oxygen base-oleanane type-12-alkene-30 carboxylic acid ester compounds and 168 DEG C of backflow oleanane type-2 of Quilonum Retard, 12-alkene-30 carboxylic acid ester compound obtains compound
i 1-5 ;
(5) glycyrrhetinic acid carboxylic acid ester compound reacts with 0 DEG C of Methanesulfonyl chloride and obtains 3 Beta-methyl sulphur Oxy-1 1-carbonyl oleanane type-12-alkene-30 carboxylic acid ester compounds;
(6) 3 Beta-methyl sulphur Oxy-1 1-carbonyl oleanane type-12-alkene-30 carboxylic acid ester compounds and 168 DEG C of backflows of Quilonum Retard obtain 11-carbonyl oleanane type-2,12-diene-30 carboxylic acid ester compound
iI 1-5 ;
(7) glycyrrhetinic acid carboxylic acid ester compound in chloroform with anhydrous CH
3cOONa and PCl
5reaction, and use NaHCO
3solution-treated obtain A ring be rearranged to pentacyclic derivative 11-oxo-A-new-olea type-3,12-diene-30-carboxylic acid ester compound
iII 1-5 ;
(8) glycyrrhetinic acid carboxylic acid ester compound makes 3-oxo glycyrrhetinic acid carboxylicesters through Jone ' s reagent oxidation, then generation 3-oximido-11-oxo-olea type-12-alkene-30-carboxylic acid ester compound that refluxes in pyridine with oxammonium hydrochloride
iV 1-5 ;
(9) 3-oximido-11-oxo-olea type-12-alkene-30-carboxylic acid ester compound and SOCl
2reaction, generates A ring p-Coumaric acid 3-cyano group-11-oxo-3 by Beckmann rearrangement, and 4-splits olea type-4,12-diene-30-carboxylic acid ester compound
v 1-5 .
Embodiment
The present invention is described in detail below:
1. glycyrrhetinic acid and zinc amalgam reagent react obtain 11-deoxidation glycyrrhetinic acid, carry out esterification with halohydrocarbon, react, then obtain compound with 168 DEG C of backflows of Quilonum Retard with 0 DEG C of Methanesulfonyl chloride in DMAC
i 1-5 .
Wherein: R
1for
, R
2for hydrogen, R
3expression-COOC
2h
5,-COOBn ,-COOCH
2cOOC
2h
5,-COOCH (CH
3)
2,-COO (CH
2)
3cH
3.
2. glycyrrhetinic acid and halohydrocarbon carry out esterification, react with 0 DEG C of Methanesulfonyl chloride, obtain compound afterwards in DMAC with 168 DEG C of backflows of Quilonum Retard
iI 1-5 .
Wherein: R
1for
, R
2for carbonyl, R
3expression-COOC
2h
5,-COOBn ,-COOCH
2cOOC
2h
5,-COOCH (CH
3)
2,-COO (CH
2)
3cH
3.
3. glycyrrhetinic acid and halohydrocarbon carry out after esterification in chloroform and anhydrous CH3COONa and PCl
5reaction, and use NaHCO
3solution-treated obtains A ring and is rearranged to pentacyclic derivative
iII 1-5 .
Wherein: R
1for
, R
2for carbonyl, R
3expression-COOC
2h
5,-COOBn ,-COOCH
2cOOC
2h
5,-COOCH (CH
3)
2,-COO (CH
2)
3cH
3.
4. glycyrrhetinic acid and halohydrocarbon carry out using Jone ' s reagent oxidation after esterification, then reflux and obtain compound in pyridine with oxammonium hydrochloride
iV 1-5 .
Wherein: R
1for
, R
2for carbonyl, R
3expression-COOC
2h
5,-COOBn ,-COOCH
2cOOC
2h
5,-COOCH (CH
3)
2,-COO (CH
2)
3cH
3.
5. compound
iV 1-5 with SOCl
2reaction, generates A ring p-Coumaric acid by Beckmann rearrangement
v 1-5 .
Wherein: R
1for
, R
2for carbonyl, R
3expression-COOC
2h
5,-COOBn ,-COOCH
2cOOC
2h
5,-COOCH (CH
3)
2,-COO (CH
2)
3cH
3.
With Gefitinib and the positive contrast of VP-16, adopt mtt assay to carry out preliminary anti tumor activity in vitro test to the compound of ursolic acid and synthesized.Research shows that the compound of synthesized has obvious restraining effect to Human Cervical (HeLa) cell, human liver cancer cell (HepG2) and cancer of the stomach (BGC-823) cell, and compound structure and in vitro tests result are as shown in table 1 ~ table 3.
The anti tumor activity in vitro of table 1 target compound to HeLa cell
Compound | R 1 | R 2 | R 3 | Inhibition (%) a | IC 50 b(μmol/L) |
Ⅰ 1 | H | COOC 2H 5 | 24.4 | >10 | |
Ⅱ 1 | =O | COOC 2H 5 | 42.0 | 8.24 | |
Ⅲ 1 | =O | COOC 2H 5 | 41.9 | 7.6 | |
Ⅳ 1 | =O | COOC 2H 5 | 41.9 | 17.68 | |
Ⅴ 4 | =O | COOCH(CH 3) 2 | 47.5 | 16.3 | |
Gefitinib | 36.66 | 25.02 | |||
VP-16 | 66.17 | 3.36 |
Note: a. compound concentration is 10
-5the inhibiting rate recording when mol/L; B. IC
50represent half effective inhibition concentration.
The anti tumor activity in vitro of table 2 target compound to HepG2 cell
Compound | R 1 | R 2 | R 3 | Inhibition (%) a | IC 50 b(μmol/L) |
Ⅰ 1 | H | COOC 2H 5 | 25.0 | >10 | |
Ⅱ 1 | =O | COOC 2H 5 | 44.0 | 30.34 | |
Ⅲ 1 | =O | COOC 2H 5 | 21 | >10 | |
Ⅳ 1 | =O | COOC 2H 5 | 52.63 | 18.02 | |
Ⅴ 4 | =O | COOCH(CH 3) 2 | 55.52 | 37.27 | |
Gefitinib | 38.27 | 37.09 | |||
VP-16 | 52.73 | 7.73 |
Note: a. compound concentration is 10
-5the inhibiting rate recording when mol/L; B. IC
50represent half effective inhibition concentration.
The anti tumor activity in vitro of table 3 target compound to BGC-823 cell
Compound | R 1 | R 2 | R 3 | Inhibition (%) a | IC 50 b(μmol/L) |
Ⅰ 1 | H | COOC 2H 5 | 23.3 | >10 | |
Ⅱ 1 | =O | COOC 2H 5 | 13.9 | >10 | |
Ⅲ 1 | =O | COOC 2H 5 | 18.8 | 7.6 | |
Ⅳ 1 | =O | COOC 2H 5 | 53.2 | 13.42 | |
Ⅴ 4 | =O | COOCH(CH 3) 2 | 39.3 | 56.17 | |
Gefitinib | 33.46 | 33.8 | |||
VP-16 | 53.65 | 7.86 |
Note: a. compound concentration is 10
-5the inhibiting rate recording when mol/L; B. IC
50represent half effective inhibition concentration.
Below in conjunction with example, the present invention is further described:
Embodiment 1
The preparation of 11-deoxidation glycyrrhetinic acid
By HgCl
2(0.2g) be dissolved in 20mL3% dilute hydrochloric acid, add zinc powder (20g), after shake well is even, remove liquid, solid fully washs with dioxane, is prepared into zinc amalgam reagent.Glycyrrhetinic acid (110mg, 0.23mmol) is dissolved in 8mL dioxane, adds the above-mentioned zinc amalgam making of 1g to it, under room temperature, stir after 30 minutes and drip concentrated hydrochloric acid.Occur adding dioxane until solution becomes clarification, TLC detection reaction terminal after a large amount of white foams.After completion of the reaction, suction filtration, obtains white solid 11-deoxidation glycyrrhetinic acid (100mg, 0.22mmol).IR(KBr): 3438, 2945, 2855, 1707, 1465, 1384, 1228, 1176, 1027, 996 cm-1。
The preparation of 11-deoxidation glycyrrhetinic acid ethyl ester and glycyrrhetinic acid ethyl ester
By 11-deoxidation glycyrrhetinic acid or glycyrrhetinic acid (100mg, 0.21mmol) be dissolved in 4 mL N, dinethylformamide (DMF), add Anhydrous potassium carbonate (0.06g), slowly drip 3 of monobromethanes (0.88mmol), room temperature reaction, TLC detection reaction terminal, decompression steams after remaining monobromethane, and with saturated salt and ethyl acetate extraction three times, merging organic phase is washed to after neutrality, concentrated, vacuum-drying, obtains 11-deoxidation glycyrrhetinic acid ethyl ester or glycyrrhetinic acid ethyl ester 90.6mg, productive rate 89%.
Embodiment 2
The preparation of 3 Beta-methyl sulfonyloxy-olea type-12-diene-30-carboxylic acid, ethyl esters
11-deoxidation glycyrrhetinic acid ethyl ester (100mg, 0.21mmol) is dissolved in 5mL methylene dichloride and 1.5mL triethylamine, under ice bath, in this mixed solution, drips 1mL Methanesulfonyl chloride (MSCl), control temperature of reaction 0 DEG C of left and right.After dropwising, compound of reaction stirs 3 hours, TLC detection reaction terminal.Suction filtration, filtrate is washed to subacidity with 1mol/L hydrochloric acid soln, then is washed to neutrality, and anhydrous magnesium sulfate drying filters, and revolves steaming, obtains compound 3 Beta-methyl sulfonyloxy-volatile oils-12-alkene-30-carboxylic acid, ethyl ester.IR(KBr): 3429, 2954, 1726, 1463, 1355, 1332, 1217, 1173, 1159, 1088, 942 cm-1。
Olea type-2,12-diene-30-carboxylic acid, ethyl ester (compound
i 1 ) preparation
Add 6mL N,N-dimethylacetamide (DMAC) that it is dissolved completely 3 Beta-methyl sulfonyloxy-olea type-12-diene-30-carboxylic acid, ethyl esters, add Quilonum Retard (70mg, 0.94mmol).168 DEG C of reaction mixtures reflux half an hour.After reaction solution is cooling, filter filtrate water and ethyl acetate extraction 3 times.Merge organic phase, 1mol/L hydrochloric acid soln washs to subacidity, then is washed to neutrality.Anhydrous magnesium sulfate drying, filters, and underpressure distillation obtains olea type-2,12-diene-30-carboxylic acid, ethyl ester.Crude product is through silica gel chromatography, and eluent is petrol ether/ethyl acetate=65/1(V/V), vacuum-drying obtains white powder 33.3mg, productive rate 34%.mp:128.6-133.2℃. IR(KBr):3430, 2956, 1727, 1465, 1381, 1212, 1174, 1152, 1089, 1018, 727 cm
-1; ESI-MS m/z: 467.4 (M+H)
+,490.9[M+23]
+。
Embodiment 3
3 beta-hydroxies-11-oxo-olea type-12-alkene-30-carboxylic acid, ethyl ester
In the 25 mL eggplant-shape bottles that magnetic agitation is housed by glycyrrhetinic acid (100mg, 0.21mmol) be dissolved in 4mL N, dinethylformamide (DMF), add Anhydrous potassium carbonate (0.06g), slowly drip 3 of monobromethanes (0.88mmol), room temperature reaction, TLC detection reaction terminal, decompression steams after remaining monobromethane, add appropriate saturated salt solution 2mL, with the each 4mL extraction of ethyl acetate 3 times, merging organic phase is washed to after neutrality, concentrated, anhydrous magnesium sulfate drying, can carry out next step reaction without further processing, obtain 3 beta-hydroxies-11-carbonyl-olea type-12-alkene-30-carboxylic acid, ethyl ester white solid 95.4mg, productive rate 91%.
The preparation of 3 Beta-methyl sulfonyloxy-11-carbonyl-olea type-12-alkene-30-carboxylic acid, ethyl esters
3 beta-hydroxies-11-carbonyl-olea type-12-alkene-30-carboxylic acid, ethyl ester (100mg, 0.20mmol) is dissolved in 5mL methylene dichloride and 1.5mL triethylamine, under ice bath, in this mixed solution, drips 1mL Methanesulfonyl chloride (M
scl).Control temperature of reaction 0 DEG C of left and right.After dropwising, compound of reaction stirs 3 hours, through TLC detection reaction terminal.Filter, filtrate is washed to subacidity with 1mol/L hydrochloric acid soln, then is washed to neutrality, and anhydrous magnesium sulfate drying filters, and revolves steaming, obtains compound 3 Beta-methyl sulfonyloxy-11-carbonyl volatile oil-12-alkene-30-carboxylic acid, ethyl esters.IR(KBr): 3429, 2954, 1726, 1463, 1355, 1332, 1217, 1173, 1159, 1088, 942 cm-1。
11-carbonyl olea type-2,12-diene-30-carboxylic acid, ethyl ester (compound
iI 1 ) preparation
By upper 3 Beta-methyl sulfonyloxy-11-carbonyl volatile oil-12-alkene-30-carboxylic acid, ethyl ester (100mg, 0.20 mmol) be dissolved in 5mL methylene dichloride and 1.5mL triethylamine, under ice bath, in this mixed solution, drip 1mL Methanesulfonyl chloride (MSCl).Control temperature of reaction 0 DEG C of left and right.After dropwising, compound of reaction stirs 3 hours, through TLC detection reaction terminal.Filter, filtrate is washed to subacidity with 1mol/L hydrochloric acid soln, then is washed to neutrality, and anhydrous magnesium sulfate drying filters, and revolves steaming, obtains compound 3 Beta-methyl sulfonyloxy-11-carbonyl volatile oil-12-alkene-30-carboxylic acid, ethyl esters.IR(KBr):3417, 2957, 2927, 1717, 1651, 1359, 1175, 913cm
-1;
1H-NMR (300MHz, CDCl
3): 5.65 (s, 1H, H-12), 4.35~4.41 (dd, 1H, H-3), 4.13~4.18 (m, 2H, O
CH 2 CH
3), 3.02 (s, 3H, CH
3S), 2.85~2.90 (dd, 1H, H-1), 2.34 (s, 1H, H-9), 1.24~1.36 (s, 9H, 3×CH
3), 1.16 (s, 3H, CH
3), 1.14 (s, 3H, CH
3), 1.12 (s, 3H, CH
3), 0.89 (s, 3H, CH
3), 0.80(s, 3H, CH
3)。
Embodiment 4
11-oxo-A-is new-olea type-3, and 12-diene-30-carboxylic acid, ethyl ester (compound
iII 1 ) preparation glycyrrhetinic acid ethyl ester is dissolved in 6mL chloroform, control temperature of reaction 4 DEG C of left and right, add (63mg, 0.77mmol) sodium acetate, anhydrous stirs 15 minutes, add afterwards (62mg, 0.3mmol) phosphorus pentachloride, TLC detection reaction terminal.Process and stir 3 hours with the sodium hydrogen carbonate solution of 5mL 3.3%, separate chloroform layer, be washed to neutrality, anhydrous magnesium sulfate drying.Filter, underpressure distillation obtain 11-oxo-A-new-olea type-3,12-diene-30-carboxylic acid, ethyl ester.Crude product is through silica gel chromatography, and eluent is petrol ether/ethyl acetate=20/1 (V/V), obtains white amorphous solid 32.15mg, productive rate 31.8%.mp: 209.3-210.7℃,IR (KBr): 3420, 2872, 1721, 1650, 1456, 1386, 1217, 1156cm
-1;
1H-NMR (300MHz, CDCl
3): δ7.27 (s, 2H, OCH
2), δ5.71 (s, 1H, 12-H), 4.13~4.20 (m, 2H, OCH
2CH
3), δ2.78 (t, 1H, 1β-H), δ2.36(s, 1H, 9α-H), δ2.20 (t, 1H, 18β-H), δ1.76 (s, 3H, =CCH
3),δ1.61 (s, 3H, =CCH
3), δ1.16 (s, 3H, CH
3), δ1.15 (s, 3H, CH
3), δ1.13 (s, 3H, CH
3), δ0.89 (s, 3H, CH
3), δ0.82 (s, 3H, CH
3). ESI-MS: 481.5[M+1]
+。
Embodiment 5
3-oximido-11-oxo-olea type-12-alkene-30-carboxylic acid, ethyl ester (compound
iV 1 ) preparation
Glycyrrhetinic acid ethyl ester is dissolved in 4mL acetone, under ice bath, dropwise adds 0.4mL new system Jone ' s reagent, TLC detection reaction terminal, add 4mL Virahol to stir 30 minutes, filtration residue, concentrated saturated aqueous common salt and the ethyl acetate used of filtrate extracts 3 times, merge organic phase, anhydrous magnesium sulfate drying.Filter, underpressure distillation, vacuum-drying obtains crude product.Be dissolved in 4mL pyridine, add (200mg, 2.88mmol) oxammonium hydrochloride refluxes 3 hours, be cooled to room temperature and add cold water that it is fully precipitated, suction filtration, washing filter cake is to neutral, and vacuum-drying obtains white powder (3-oximido-11-oxo-olea type-12-alkene-30-carboxylic acid, ethyl ester).Crude product is through silica gel chromatography, and eluent is petrol ether/ethyl acetate=8/1 (V/V), obtains white solid 45.43mg, productive rate 42.3%.mp:226.9-231.5℃,IR(KBr): 445, 2927, 2858, 1727, 1657, 1458, 1386, 1216, 1153, 1088, 922cm
-1; ESI-MS:534.0 [M+23]
+。
Embodiment 6
3-itrile group-11-oxo-3, break-olea type-4 of 4-, 12-diene-30-carboxylic acid, ethyl ester (compound
v 1 ) preparation
3-oximido-11-oxo-olea type-12-alkene-30-carboxylic acid, ethyl ester is dissolved in to 8mL dioxane, drip 0.8mL sulfur oxychloride, control temperature of reaction 10 DEG C of left and right, stir after 20 minutes, add cold 1%KOH that it is precipitated completely, suction filtration, washing filter cake is to neutral, vacuum-drying obtains buff powder (3-itrile group-11-oxo-3, break-olea type-4 of 4-, 12-diene-30-carboxylic acid, ethyl ester).Crude product is through silica gel chromatography, and eluent is petrol ether/ethyl acetate=10/1 (V/V), obtains white solid 54mg, productive rate 25.1%.mp: 180.7-182.7℃,IR (KBr): 3433, 2960, 2927, 2869, 2245, 1725, 1649, 1455, 1387, 1217, 1174, 1088, 1031, 898cm
-1;
1H-NMR(300MHz, CDCl
3): 0.82 (s, 3H, CH
3-28), 1.15 (s, 3H, CH
3-28), 1.27 (s, 3H, CH
3-26), 1.40 (s, 3H, CH
3-25), 1.76, 1.58 (CH
3-29, CH
3-23), 1.97~2.18 (m, CH, CH
2), 4.13~4.19 (m, 2H, COO
CH 2 CH
3), 4.93 (s, 1H, H-12), 5.70 (s, 2H, =CH
2-24). ESI-MS:516.0[M+23]
+。
Claims (1)
1. a preparation method with the glycyrrhetinic acid modifier of anti-tumor activity, is characterized in that, this preparation method's step is:
(1) prepare 11-deoxidation glycyrrhetinic acid:
Take 0.2g HgCl
2be dissolved in 20mL, in 3% dilute hydrochloric acid, add 20g zinc powder, after shake well is even, remove liquid, solid fully washs with dioxane, is prepared into zinc amalgam reagent; 110mg glycyrrhetinic acid is dissolved in 8mL dioxane, adds the above-mentioned zinc amalgam making of 1g to it, under room temperature, stir after 30 minutes and drip concentrated hydrochloric acid, occur adding dioxane until solution becomes clarification, TLC detection reaction terminal after a large amount of white foams; After completion of the reaction, suction filtration, obtains 100mg white solid 11-deoxidation glycyrrhetinic acid;
(2) prepare 11-deoxidation glycyrrhetinic acid ethyl ester:
100mg 11-deoxidation glycyrrhetinic acid is dissolved in to 4mL DMF, adds 0.06g Anhydrous potassium carbonate, slowly drip 3 0.88mmol monobromethanes, room temperature reaction, TLC detection reaction terminal, decompression steams after remaining monobromethane, with saturated aqueous common salt and ethyl acetate extraction three times, merge organic phase, be washed to after neutrality, concentrated, vacuum-drying, obtains 90.6mg 11-deoxidation glycyrrhetinic acid ethyl ester, productive rate 89%;
(3) prepare 3 Beta-methyl sulfonyloxy-oleanane types-12-alkene-30-carboxylic acid, ethyl ester:
100mg 11-deoxidation glycyrrhetinic acid ethyl ester is dissolved in 5mL methylene dichloride and 1.5mL triethylamine, under ice bath, in this mixed solution, drip 1mL Methanesulfonyl chloride, control temperature of reaction at 0 DEG C, after dropwising, compound of reaction stirs 3 hours, TLC detection reaction terminal; Suction filtration, filtrate is washed to subacidity with 1mol/L hydrochloric acid soln, then is washed to neutrality, and anhydrous magnesium sulfate drying filters, and revolves steaming, obtains compound 3 Beta-methyl sulfonyloxy-oleanane types-12-alkene-30-carboxylic acid, ethyl ester;
(4) prepare oleanane type-2,12-diene-30-carboxylic acid, ethyl ester:
3 Beta-methyl sulfonyloxy-oleanane types-12-alkene-30-carboxylic acid, ethyl ester is added to 6mL N, N-N,N-DIMETHYLACETAMIDE dissolves it completely, add 70mg Quilonum Retard, 168 DEG C of reaction mixtures reflux half an hour, after reaction solution is cooling, filter, filtrate water and ethyl acetate extraction 3 times, merge organic phase, 1mol/L hydrochloric acid soln washs to subacidity, be washed to again neutrality, anhydrous magnesium sulfate drying, filter, underpressure distillation obtains oleanane type-2, 12-diene-30-carboxylic acid, ethyl ester, crude product is through silica gel chromatography, eluent is the sherwood oil of volume ratio 65:1: ethyl acetate, vacuum-drying obtains white powder 33.3mg, productive rate 34%,
Described glycyrrhetinic acid modifier is oleanane type-2,12-diene-30-carboxylic acid, ethyl ester, and its structure is:
, wherein, R
1for
, R
2for H, R
3for COOC
2h
5.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201110354326.0A CN102516350B (en) | 2011-11-10 | 2011-11-10 | Glycyrrhetinic acid modifier with antitumor activity and preparation method thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201110354326.0A CN102516350B (en) | 2011-11-10 | 2011-11-10 | Glycyrrhetinic acid modifier with antitumor activity and preparation method thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
CN102516350A CN102516350A (en) | 2012-06-27 |
CN102516350B true CN102516350B (en) | 2014-12-10 |
Family
ID=46287466
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201110354326.0A Active CN102516350B (en) | 2011-11-10 | 2011-11-10 | Glycyrrhetinic acid modifier with antitumor activity and preparation method thereof |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN102516350B (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107375314A (en) * | 2017-07-14 | 2017-11-24 | 广东食品药品职业学院 | A kind of Ypsilandra steroid saponin YB16 and enoxolone compound medicament composition and application thereof |
CN113651867B (en) * | 2021-09-17 | 2022-09-16 | 山东大学 | Sulfonamide 18 beta-glycyrrhetinic acid derivative and preparation method and application thereof |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3311613A (en) * | 1964-03-24 | 1967-03-28 | Biorex Laboratories Ltd | Derivatives of glycyrrhetinic acid and process for the preparation thereof |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101200488A (en) * | 2007-12-07 | 2008-06-18 | 北京润德康医药技术有限公司 | Novel biogastrone acid derivatives, preparation method and medical uses thereof |
CN101775059B (en) * | 2010-02-04 | 2013-02-13 | 中国药科大学 | Novel glycyrrhetinic acid derivative, and preparation method and medicinal uses thereof |
-
2011
- 2011-11-10 CN CN201110354326.0A patent/CN102516350B/en active Active
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3311613A (en) * | 1964-03-24 | 1967-03-28 | Biorex Laboratories Ltd | Derivatives of glycyrrhetinic acid and process for the preparation thereof |
Non-Patent Citations (6)
Title |
---|
John S. Baran, et al..Synthesis and Biological Activities of Substituted Glycyrrhetic Acids.《Journal of Medicinal Chemistry》.1974,第17卷(第2期),第184-186页. * |
René Csuk, et al..Synthesis and antitumor activity of ring A modified glycyrrhetinic acid derivatives.《European Journal of Medicinal Chemistry》.2011,第46卷第5356-5363页. * |
Synthesis and antitumor activity of ring A modified glycyrrhetinic acid derivatives;René Csuk, et al.;《European Journal of Medicinal Chemistry》;20110831;第46卷;第5356-5363页 * |
Synthesis and Biological Activities of Substituted Glycyrrhetic Acids;John S. Baran, et al.;《Journal of Medicinal Chemistry》;19741231;第17卷(第2期);第184-186页 * |
甘草次酸衍生物的合成及其抗癌活性;金健民等;《应用化学》;20011130;第18卷(第11期);第869-870页 * |
金健民等.甘草次酸衍生物的合成及其抗癌活性.《应用化学》.2001,第18卷(第11期),第869-870页. * |
Also Published As
Publication number | Publication date |
---|---|
CN102516350A (en) | 2012-06-27 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN105418721A (en) | Oleanolic acid chemical modifier with antitumor activity and preparation method thereof | |
IL258359B1 (en) | Farnesoid x receptor modulators | |
CN101245090A (en) | 3,6-di-substituted sterides oximes compound as antineoplastic medicament | |
CN101157715B (en) | Ursolic acid chemical modified compound amino alcohol having antitumor activity | |
CN102180939B (en) | Ursolic acid chemical modifier with antitumor activity and preparation method thereof | |
CN102516350B (en) | Glycyrrhetinic acid modifier with antitumor activity and preparation method thereof | |
CN103214542A (en) | B-nor-6-(4'-alkyl) aminothizone cholestane compound, and preparation method and application thereof in anticancer drugs | |
CN103626828A (en) | Anti-tumor active ursolic acid chemical modifier and preparation method thereof | |
CN103450310A (en) | Stigmasterol derivative and application thereof in preparation of anti-cancer drug | |
CN114409725B (en) | Oleanolic acid A ring derivative with anti-tumor activity and preparation method thereof | |
CN103772277B (en) | Oxychloroquine linolenate and synthetic method thereof | |
US9296774B2 (en) | Halogenated dideoxy sugar derivates, preparation method and application thereof | |
CN102391351B (en) | Asiatic acid modifier with anti-tumor activity and preparation method of the same | |
Zhou et al. | Design, synthesis and anti-tumor activities of carbamate derivatives of cinobufagin | |
CN113292554A (en) | Dihydronaphtho [2,1-d ] isoxazole amide derivatives and application thereof in antitumor drugs | |
CN113121613A (en) | Tetravalent platinum complex for targeted inhibition of AKR1C3 and reversal of tumor drug resistance and preparation method thereof | |
CN107382872B (en) | Branched 2-nitroimidazole compound and application thereof in drug delivery system | |
CN104672294B (en) | Synthesis method of compound 3-O-(2-(5-fluorouracil-1-)acetyl)-ursolic acid methyl ester and application of compound as antitumor drug | |
CN113372375A (en) | Preparation method of temsirolimus intermediate | |
CN104497086B (en) | Androstane-3 β, 5 α, 6 β, 19-tetrol and preparation method and application | |
CN103204892A (en) | Beta-norcholest-6-(4'-phenyl)-aminothizone compound and synthesis method and application thereof in preparing antitumor drug | |
Zhang et al. | Synthesis of oleandrin derivatives and their cytotoxic activity | |
CN113171467B (en) | Chimeric molecule based on NQO1 regulation and control and application thereof | |
CN110804084B (en) | Quaternary phosphonium salt diosgenin derivative and synthesis method and application thereof | |
CN109053841A (en) | The bis- sulphur of 6- replace -2 '-deoxyguanosine class compounds and its preparation method and application |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant |