CN102241726B - Glycyrrhetinic acid derivative and application thereof as antitumor medicament - Google Patents

Glycyrrhetinic acid derivative and application thereof as antitumor medicament Download PDF

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CN102241726B
CN102241726B CN 201110139249 CN201110139249A CN102241726B CN 102241726 B CN102241726 B CN 102241726B CN 201110139249 CN201110139249 CN 201110139249 CN 201110139249 A CN201110139249 A CN 201110139249A CN 102241726 B CN102241726 B CN 102241726B
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glycyrrhetinic acid
compound
structural formula
preparation
derivative
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CN102241726A (en
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敖桂珍
乔春华
候丙波
曹毅
楚小晶
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Suzhou University
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Suzhou University
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Abstract

The invention relates to the field of medicaments, in particular to glycyrrhetinic acid derivatives capable of releasing gas signaling molecule hydrogen sulfide, pharmaceutically acceptable salts thereof, preparation methods thereof, a medicinal composition containing the derivatives and antitumor functions thereof, in particular to application thereof to the preparation of antitumor medicaments. The glycyrrhetinic acid derivatives are obtained by coupling glycyrrhetinic acid, a glycyrrhetinic acid derivative and a hydrogen sulfide donor through an ester bond or an amide bond. The invention initially provides the glycyrrhetinic acid derivatives capable of releasing gas signaling molecule H2S. The antitumor medicaments with higher activity are obtained by modifying the glycyrrhetinic acid.

Description

Enoxolone derivative and as the application of antitumor drug
Technical field
The present invention relates to pharmaceutical field, be specifically related to a class and can discharge Enoxolone derivative and pharmacy acceptable salt, their preparation method, the medicinal compositions that contains these derivatives and their antitumor action of gaseous signal molecule hydrogen sulfide, particularly in the application of the medicine of preparation anti-tumor disease.
Background technology
Radix Glycyrrhizae belongs to leguminous plants, mainly is distributed in the areas such as China western part, is one of China's herbal medicine commonly used.Potenlini and aglycon glycyrrhetinic acid thereof (glycyrrhetinic acid is called for short GA) are the main pharmacological active substances of Radix Glycyrrhizae.Modern study shows, GA have anti-inflammatory, antiulcer agent, antiviral, anti-arrhythmia, reducing blood-fat, promotion absorption of insulin, the multiple pharmacologically active such as antitumor (Gong Xuelong, Strait Pharmaceutical Journal, 20 08,20(9), 4-7).GA particularly at anti-inflammatory, protect the liver, antiviral and anti-tumor aspect has good effect, and is and little to human normal cell's toxicity.At anti-tumor aspect, GA can suppress the propagation of the kinds of tumor cells such as leukemia, liver cancer, colorectal carcinoma, cancer of the stomach, mammary cancer, cervical cancer.Yet natural GA anti-tumor activity relatively a little less than, in order further to improve the anti-tumor activity of GA, people have carried out structural modification and transformation to it, have obtained the higher GA derivative (as WO2008000070, CN200910256534 etc.) of some activity.
Application number is that 201010105386.4 Chinese invention patent discloses a kind of Enoxolone derivative, and described Enoxolone derivative is to carry out by ester bond or amido linkage the compound that coupling obtains by furazan oxynitride class nitric oxide donors and glycyrrhetinic acid.Pharmacological testing proves that such Enoxolone derivative has stronger antitumor action, can be used for preparing antitumor drug.
Current research is found, Endogenous Hydrogen Sulfide (H 2S) wide participation the physiological function of the systems such as neural, cardiovascular, digestion regulate, be considered to the 3rd kind of gaseous signal molecule after NO and CO.Exogenous H 2S donor NaHS can suppress the propagation of T lymphocyte, HEK-293 cell etc. and stimulate the apoptosis of lymphocyte etc.A kind of release H 2The compound that the S ability is stronger is 5-p-hydroxybenzene-D3T (being called for short ADT-OH).
But, have no H in prior art 2Any report of S donator type Enoxolone derivative and pharmaceutically-acceptable salts thereof also has no any about the report to this compounds bioactivity research.
Summary of the invention
Goal of the invention of the present invention is to provide a kind of Enoxolone derivative, and glycyrrhetinic acid is carried out structural modification, improves the anti-tumor activity of Enoxolone derivative.
To achieve the above object of the invention, the technical solution used in the present invention is: a kind of Enoxolone derivative, described Enoxolone derivative is made of by ester bond or amido linkage coupling glycyrrhetinic acid group and hydrogen sulfide donor.
In technique scheme, the structural formula of described Enoxolone derivative is selected from:
Structural formula one
Figure 313606DEST_PATH_IMAGE001
, structural formula two , structural formula three
Figure 589659DEST_PATH_IMAGE003
Or structural formula four
Figure 110902DEST_PATH_IMAGE004
In formula, R 1Be selected from: H, CH 3CO, C 2H 5CO, C 3H 7CO or COCH 2COOH; R 2Be selected from:
Figure 78333DEST_PATH_IMAGE005
,
Figure 419447DEST_PATH_IMAGE006
,
Figure 881259DEST_PATH_IMAGE007
, , (CH 3) 2N-or Et 2N-; X is selected from: NH or O; Y is (CH 2) n, CH (CH 3) (CH 2) 2, CH 2CH=CHCH 2Or CH 2C ≡ CCH 2, wherein, n=2 ~ 6; Z is selected from: O or NH.
In preferred technical scheme, described Enoxolone derivative is selected from: structural formula one or the represented compound of structural formula three.
In further preferred technical scheme, described Enoxolone derivative is:
Figure 864182DEST_PATH_IMAGE009
, in formula, R 1Be selected from: H or CH 3CO; X is O; Y is (CH 2) n, n=2 ~ 4; Z represents O.
The present invention is the acceptable salt of medical science of claimed above-mentioned Enoxolone derivative simultaneously.
The present invention is claimed a kind of mixture simultaneously, and described mixture comprises above-mentioned Enoxolone derivative or the acceptable salt of its medical science.
In technique scheme, the preparation method of structural formula one described Enoxolone derivative comprises the following steps: with a kind of in the esterified derivative of glycyrrhetinic acid or glycyrrhetinic acid and
Figure 66493DEST_PATH_IMAGE010
Or
Figure 193980DEST_PATH_IMAGE011
Be reactant, the carboxyl in the esterified derivative of glycyrrhetinic acid or glycyrrhetinic acid and
Figure 14781DEST_PATH_IMAGE012
In amino generation condensation reaction or
Figure 546519DEST_PATH_IMAGE013
Bromine generation substitution reaction, prepare the described Enoxolone derivative of structural formula one;
Wherein, the structural formula of the esterified derivative of glycyrrhetinic acid is: , in formula, R 1Be selected from: CH 3CO, C 2H 5CO, C 3H 7CO or COCH 2COOH; The esterified derivative of described glycyrrhetinic acid is to be prepared by esterification by glycyrrhetinic acid;
Described
Figure 492271DEST_PATH_IMAGE015
Be by
Figure 170508DEST_PATH_IMAGE016
With bromo alkylamine BrYNH 2The generation substitution reaction prepares; Described Be by
Figure 821291DEST_PATH_IMAGE018
Prepare with two bromoalkane generation substitution reactions.
In technique scheme, the preparation method of structural formula two described Enoxolone derivatives is similar to the method for preparing structural formula one described Enoxolone derivative, and difference is, at first the glycyrrhetinic acid reduction is obtained compound 1, then prepare its esterified derivative compound 2, with compound 1Or compound 2In a kind of and
Figure 22071DEST_PATH_IMAGE019
Or
Figure 961340DEST_PATH_IMAGE020
Be reactant, prepare the described Enoxolone derivative of structural formula two;
The structural formula of described compound 1 is
Figure 284480DEST_PATH_IMAGE021
The structural formula of described compound 2 is
Figure 574778DEST_PATH_IMAGE022
In technique scheme, the preparation method of structural formula three described Enoxolone derivatives is: glycyrrhetinic acid and halo Acetyl Chloride 98Min. generate compound 3, compound 3With piperidines
Figure 703884DEST_PATH_IMAGE023
, piperazine
Figure 871560DEST_PATH_IMAGE024
, the pyrroles
Figure 165269DEST_PATH_IMAGE025
, morpholine
Figure 284142DEST_PATH_IMAGE026
, dimethylamine (CH 3) 2NH or diethylamine Et 2A kind of reaction in NH prepares compound 4With compound 4 Hes
Figure 95234DEST_PATH_IMAGE027
Or
Figure 865219DEST_PATH_IMAGE028
Be reactant, compound 4In carboxyl and
Figure 579097DEST_PATH_IMAGE029
Amino condensation or
Figure 703042DEST_PATH_IMAGE030
In bromine replace, prepare the described Enoxolone derivative of structural formula three;
Described compound 3Structural formula be
Figure 924683DEST_PATH_IMAGE031
, A is Br, Cl; Described compound 4Structural formula be
Figure 286525DEST_PATH_IMAGE032
In technique scheme, the preparation method of structural formula four described Enoxolone derivatives is similar with the preparation method of structural formula three described Enoxolone derivatives, and difference is, at first the glycyrrhetinic acid reduction is obtained compound 1, then according to the preparation method who prepares structural formula three described Enoxolone derivatives, with compound 1Replacing glycyrrhetinic acid is that initial reactant prepares the described Enoxolone derivative of structural formula four.
The pharmacological results shows, above-mentioned Enoxolone derivative is inhibited to human tumor cell's propagation, and the activity of preferred Enoxolone derivative obviously is better than glycyrrhetinic acid; Therefore, the present invention's claimed above-mentioned Enoxolone derivative or the application of its medically acceptable salt in the preparation antitumor drug simultaneously.
The present invention is claimed a kind of antitumor drug simultaneously, and described antitumor drug is above-mentioned Enoxolone derivative or its medically acceptable salt.
The present invention is claimed a kind of antineoplastic pharmaceutical compositions simultaneously, and the main component of described antitumor drug is above-mentioned Enoxolone derivative or its medically acceptable salt, also comprises pharmaceutically receptible carrier or auxiliary material.
Enoxolone derivative of the present invention or its medically acceptable salt can be made the preparation administration separately or with more than one acceptable carrier composition.For example, solvent, thinner etc.Can the oral dosage form administration, but as tablet, capsule dispersed powders, granule etc.The various formulations of pharmaceutical composition of the present invention can be prepared according to the method for knowing in pharmaceutical field.Can contain for example 0.05% ~ 90% weight activeconstituents with carrier combinations in these medicinal preparationss, the more common approximately activeconstituents between 15% ~ 60%.The compounds of this invention dosage can make 0.005 ~ 5000mg/kg/ days, also can exceed this dosage range according to the different using dosages of disease severity or formulation.
Enoxolone derivative of the present invention or its medically acceptable salt can with other antitumor drugs, for example alkylating agent, antimetabolite, topoisomerase enzyme inhibitor, mitotic division enzyme inhibitors, DNA intercalating agent combined utilization, in addition can also with the radiotherapy combined utilization.These other antitumour drugs or radiotherapy can or give at different time with the compounds of this invention while.Thereby these combination therapys can produce synergy to help to improve result for the treatment of.
In preferred technical scheme, described tumour comprises: liver cancer, prostate cancer and mammary cancer.
Because technique scheme is used, the present invention compared with prior art has following advantages:
The present invention openly provides a kind of gaseous signal molecule H that discharges first 2The Enoxolone derivative of S has obtained active higher antitumor drug by modifying glycyrrhetinic acid.
Embodiment
The invention will be further described below in conjunction with drawings and Examples:
Embodiment one:
5-[4-(2-bromine oxethyl) phenyl]-D3T ( 5a) preparation
ADT-OH (0.325g, 1.4mmol), glycol dibromide (0.50mL, 5.8mmol), anhydrous K 2CO 3(0.396g, 2.8mmol) is dissolved in the DMF of 10mL drying, 120 ℃ of reaction 2h.Add the dilution of 20mL ethyl acetate after cooling, and washing (3 * 20mL), anhydrous Na 2SO 4Dry.Filter, evaporated under reduced pressure, the acetone-water recrystallization gets chocolate product 0.388g, productive rate 81.5%, mp:126.0 ~ 127.0 ℃. 1H NMR (400MHz, CDCl 3), δ(ppm): 7.59(d, 2H, J=8.9Hz, ArH), 7.36(s, 1H, =CH), 6.96 (d, 2H, J=8.9Hz, ArH), 4.33(t, 2H, J=6.1Hz, CH 2), 3.65(t, 2H, J = 6.1 Hz, CH 2)； 13C NMR (400MHz, CDCl 3), δ(ppm): 212.554, 170.180, 158.775, 132.260, 126.120, 122.226, 113.014, 65.455, 26.026。
Above-mentioned appraising datum proof gained compound is 5-[4-(2-bromine oxethyl) phenyl]-D3T ( 5a), its structural formula is:
Figure 591211DEST_PATH_IMAGE033
Compound I 1Preparation
With GA (0.47g, 1.0mmol is available from Sichuan superman's plant company limited, content〉98%), 5a(0.33g, 1.0mmol), anhydrous K 2CO 3(0.138g, 1.0mmol) and catalytic amount KI add in the 15mL dry DMF room temperature reaction 16h.The dilution of 50mL water, and ethyl acetate extraction (3 * 30ml), merge organic layer, anhydrous Na 2SO 4Dry.Filter, evaporate to dryness, column chromatography [sherwood oil (60-90): ethyl acetate=3:1 (v/v)] gets red solid 0.62g, yield 86.2%, mp:220.5 ~ 221.5 ℃. 1H NMR (400MHz, CDCl 3), δ(ppm): 7.62 (d, 2H, J=8.8Hz, ArH), 7.39(s, 1H, =CH), 7.01(d, 2H, J=8.8Hz, ArH), 5.60(s, 1H, C 12-H), 4.50(m, 2H, OCH 2), 4.27(t, 2H,OCH 2), 3.23(m, 1H, C 3-H), 2.78(brs, 1H, OH), 2.32(s, 1H, C 9-H), 1.35(s, 3H, CH 3), 1.16(s, 3H, CH 3), 1.12(s, 3H, CH 3), 1.09(s, 3H, CH 3), 1.00 (s, 3H, CH 3), 0.81 (s, 3H, CH 3), 0.74 (s, 3H, CH 3)； 13CNMR (400MHz,CDCl 3), δ(ppm): 215.533, 200.554, 176.753, 173.349, 169.535, 169.518, 162.089, 135.186, 129.113, 128.886, 124.996, 115.961, 79.140, 66.660, 62.727, 62.232, 55.308, 48.714, 45.785, 44.558, 43.551, 41.437, 39.538, 39.514, 38.079, 37.471, 33.101, 32.188, 31.551, 28.983, 28.687, 28.497, 27.708, 26.832, 26.794, 23.842, 19.030, 17.863, 16.796, 16.002；IR(KBr, cm -1): 3442.0 (OH), 1725.9(C=O), 1653.1(C=O), 1635.0, 1602.8, 1575.8, 1489.6 (C=C), 1172.0 (C=S)；HR-MS: Calcd. For C 41H 54O 5S 3 [M+H] +: 723.3206, Found: 723.3191。Above-mentioned appraising datum proof gained compound is Compound I 1, its structural formula is:
Figure 920561DEST_PATH_IMAGE034
。
Embodiment two:
5-[4-(3-bromine propoxy-) phenyl]-3H-1,2-dithiole-3-thioketones ( 5b) preparation
Be raw material with 1,3-dibromopropane, reference 5aMethod preparation, productive rate 83.2%, mp:79.0 ~ 80.0 ℃. 1H NMR(400MHz,CDCl 3), δ(ppm): 7.62(d, 2H, J= 8.8Hz, ArH), 7.40(s, 1H, =CH), 7.00(d, 2H, J= 8.7Hz, ArH), 4.19(t, 2H, J = 5.8 Hz, CH 2), 3.62(t, 2H, J = 6.3Hz, CH 2), 2.36(p, 2H, J =6.0 Hz, CH 2)； 13C NMR (400MHz, CDCl 3), δ(ppm): 212.460, 170.437, 159.454, 132.073, 126.065, 121.751, 112.886, 63.118, 29.453, 27.178。Above-mentioned appraising datum proof gained compound is 5-[4-(3-bromine propoxy-) phenyl]-3H-1,2-two sulphur-3-thioketones ( 5b), its structural formula is:
Figure 198090DEST_PATH_IMAGE035
Compound I 2Preparation
With GA and 5bBe raw material, with reference to I 1Synthetic method preparation, red solid, yield 86.6%, mp:79.1 ~ 80.7 ℃. 1H NMR (400MHz, CDCl 3), δ(ppm): 7.54 (d, 2H, J=8.8 Hz, ArH), 7.31 (s, 1H, =CH), 6.91 (d, 2H, J=8.8 Hz, ArH), 5.54 (s, 1H, C 12-H), 4.24 (t, 2H, OCH 2), 4.06 (t, 2H, OCH 2), 3.16 (dd, 1H, C 3-H), 2.72 (brs, 1H, OH), 2.26 (s, 1H, C 9-H), 2.10 (p, 2H, CH 2), 1.29 (s, 3H, CH 3), 1.08 (s, 3H, CH 3), 1.07 (s, 3H, CH 3), 1.03 (s, 3H, CH 3), 0.93 (s, 3H, CH 3), 0.74 (s, 3H, CH 3), 0.69 (s, 3H, CH 3)； 13C NMR (400MHz,CDCl 3), δ(ppm): 215.213, 200.442, 176.583, 173.337, 169.515, 162.304, 134.798, 128.899, 128.658, 124.447, 115.692, 78.889, 72.011, 65.004, 62.039, 61.222, 55.101, 48.673, 45.620, 44.286, 43.420, 41.251, 39.342, 37.923, 37.288, 32.918, 32.038, 31.292, 28.757, 28.717, 28.642, 28.320, 27.919, 27.467, 26.632, 26.566, 23.641, 21.307, 19.397, 18.850, 16.618, 15.853；IR(KBr, cm -1): 3567.4 (OH), 1732.1 (C=O), 1652.4 (C=O), 1599.4, 1522.6, 1492.6 (C=C), 1179.7 (C=S)；HR-MS: Calcd. For C 42H 56O 5S 3 [M+H] +: 737.3383, Found: 737.3387。Above-mentioned appraising datum proof gained compound is Compound I 2, its structural formula is:
Figure 592204DEST_PATH_IMAGE036
。
Embodiment three:
5-[4-(4-bromine butoxy) phenyl]-D3T ( 5c) preparation
Take Isosorbide-5-Nitrae-dibromobutane as raw material, reference 5aMethod preparation, productive rate 79.4%, mp:70.0 ~ 71.0 ℃. 1H NMR(400MHz,CDCl 3), δ(ppm): 7.60(d, 2H, J= 8.7Hz, ArH), 7.38(s, 1H, =CH), 6.96(d, 2H, J=8.7Hz, ArH), 4.07(t, 2H, J=5.9Hz, CH 2), 3.50(t, 2H, J=6.4Hz, CH 2), 2.08(m, 2H, CH 2), 1.99(m, 2H, CH 2)； 13C NMR (400MHz,CDCl 3), δ(ppm): 212.439, 170.554, 159.670, 132.006, 126.057, 121.553, 112.834, 64.759, 30.795, 26.729, 25.133。Above-mentioned appraising datum proof gained compound is 5-[4-(4-bromine butoxy) phenyl]-D3T ( 5c), its structural formula is:
Figure 552944DEST_PATH_IMAGE037
Compound I 3Preparation
With GA and 5cBe raw material, with reference to I 1Synthetic method preparation, red solid, yield 89.2%, mp:138.2 ~ 139.2 ℃. 1H NMR (400MHz, CDCl 3), δ(ppm): 7.60 (d, 2H, J= 8.8Hz,), 7.39 (s, 1H, =CH), 6.98(d, 2H, J=8.8 Hz, ArH), 5.64(s, 1H, C 12-H), 4.20 (t, 2H,CH 2), 4.08 (t, 2H, CH 2), 3.23 (m, 1H, C 3-H), 2.78 (brs, 1H, OH), 2.34 (s, 1H, C 9-H), 1.37 (s, 3H, CH 3), 1.16 (s, 3H, CH 3), 1.13 (s, 3H, CH 3), 1.12 (s, 3H, CH 3), 1.01 (s, 3H, CH 3), 0.81 (s, 6H, CH 3)； 13C NMR (400MHz, CDCl 3), δ(ppm): 215.234, 200.481, 176.668, 173.396, 169.582, 162.512, 134.737, 128.810, 128.690, 124.261, 115.706, 78.893, 67.907, 64.179, 62.053, 55.122, 48.687, 45.619, 44.250, 43.434, 41.266, 39.349, 37.950, 37.299, 32.951, 32.068, 31.309, 28.794, 28.668, 28.328, 27.492, 26.671, 26.602, 26.027, 25.743, 23.630, 18.884, 17.691, 16.604, 15.844；IR(KBr, cm -1): 3446.9(OH), 1722.7(C=O), 1653.4 (C=O), 1647.7, 1602.3, 1489.6 (C=C), 1177.1 (C=S)；HR-MS: Calcd. For C 43H 58O 5S 3 [M+H] + 751.3519, Found: 751.3477。Above-mentioned appraising datum proof gained compound is Compound I 3, its structural formula is:
Figure 55076DEST_PATH_IMAGE038
。
Embodiment four:
3-O-ethanoyl glycyrrhetinic acid ( 6a) preparation:
GA (1.88g, 4.0mmol) is dissolved in the 10mL pyridine, drips diacetyl oxide (3.78mL, 40.0mmol) under stirring at room.Then reaction 12h pours in frozen water, filters, and the acetone-water recrystallization gets white solid 1.90g, productive rate 92.7%, mp:312.0 ~ 313.0 ℃. 1H NMR(400MHz, CDCl 3), δ(ppm): 5.72(s, 1H, C 12-H), 4.52(dd, 1H, J=11.13, 4.51Hz, C 3-H), 2.37(s, 1H, C 9-H), 2.06(s, 3H, CH 3), 1.37(s, 3H, CH 3), 1.23(s, 3H, CH 3), 1.17(s, 3H, CH 3), 1.13(s, 3H, CH 3), 0.88(s, 6H, CH 3), 0.84(s, 3H, CH 3)。Above-mentioned appraising datum proof gained compound be 3-O-ethanoyl glycyrrhetinic acid ( 6a), its structural formula is:
Figure 605138DEST_PATH_IMAGE039
。
Compound I 4Preparation
With 6aWith 5aBe raw material, with reference to I 1Synthetic method preparation, red solid, productive rate 86.0%.96.0 ~ 97.0 ℃ of fusing points. 1H NMR(400MHz, CDCl 3), δ(ppm): 7.63 (d, 2H, J= 8.8Hz, ArH), 7.40 (s, 1H, =CH), 7.01 (d, 2H, J=8.8Hz, ArH), 5.60 (s, 1H, C 12-H), 4.50(m, 2H, OCH 2), 4.27 (t, 2H,OCH 2), 3.23 (m, 1H, C 3-H), 2.78 (brs, 1H, OH), 2.32 (s, 1H, C 9-H), 2.05(s, 3H, CH 3), 1.35 (s, 3H, CH 3), 1.16 (s, 3H, CH 3), 1.12 (s, 3H, CH 3), 1.09 (s, 3H, CH 3), 1.00 (m, 4H, CH 3 & CH 2), 0.80 (s, 3H, CH 3), 0.72 (s, 3H, CH 3)；IR(KBr, cm -1): 1732.1(C=O), 1692.4(C=O), 1602.6, 1575.6, 1491.4, 1464.5 (C=C), 1178.9(C=S)；HR-MS: Calcd. For C 43H 57O 6S 3 [M+H] +: 765.3312 , Found: 765.3314。Above-mentioned appraising datum proof gained compound is Compound I 4, its structural formula is:
Figure 954954DEST_PATH_IMAGE040
Embodiment five:
Compound I 5Preparation
With 6aWith 5bBe raw material, with reference to I 1Synthetic method make, red solid, yield 89.5%, mp:253.2 ~ 254.2 ℃. 1H NMR(400MHz, CDCl 3), δ(ppm): 7.62 (d, 2H, J=8.8Hz, ArH), 7.40(s, 1H,CH=CH), 6.98(d, 2H, J=8.8Hz, ArH), 5.61(s, 1H, C 12-H), 4.52 (m, 1H, C 3-H), 4.31(t, 2H, J=6.2Hz, OCH 2), 4.12(t, 2H, J=6.1Hz, OCH 2), 2.35(s, 1H, C 9-H), 2.18(m, 2H, CH 2), 2.06(s, 3H, CH 3), 1.35(s, 3H, CH 3), 1.16(s, 3H, CH 3), 1.15(s, 3H, CH 3), 1.10 (s, 3H, CH 3), 0.88 (s, 6H, CH 3), 0.75 (s, 3H, CH 3)； 13C NMR (400MHz, CDCl 3), δ(ppm): 215.341, 200.253, 176.574, 173.274, 171.275, 169.441, 162.292, 134.889, 128.901, 128.681, 124.528, 115.698, 80.797, 64.973, 61.972, 61.199, 55.220, 48.704, 45.631, 44.299, 43.431, 41.246, 39.024, 38.261, 37.930, 37.161, 32.884, 32.048, 31.314, 28.750, 28.650, 28.258, 26.595, 23.787, 23.582, 21.567, 18.865, 17.580, 16.908, 16.659；IR(KBr, cm -1): 1732.1 (C=O), 1651.9 (C=O), 1596.7 1577.3, 1520.7, 1489.9 (C=C), 1180.4 (C=S)；HR-MS: Calcd. For C 44H 59O 6S 3 [M+H] + 779.3468, Found: 779.3468。Above-mentioned appraising datum proof gained compound is Compound I 5, its structural formula is:
Figure 463427DEST_PATH_IMAGE041
。
Embodiment six:
Compound I 6Preparation
With 6aWith 5cBe raw material, with reference to I 1Synthetic method make, red solid, yield 89.6%, mp:253.8 ~ 254.8 ℃. 1H NMR (400MHz, CDCl 3), δ(ppm): 7.61 (d, 2H, J = 8.7 Hz, ArH), 7.40 (s, 1H, CH=CH), 6.98 (d, 2H, J= 8.7Hz, ArH), 5.64 (s, 1H, C 12-H), 4.23-4.16 (m, 2H, OCH 2), 4.08 (t, 2H, OCH 2), 2.36 (s, 1H, C 9-H), 2.06 (s, 3H, CH 3), 1.36 (s, 3H, CH 3), 1.16 (s, 6H, CH 3), 1.12 (s, 3H, CH 3), 0.88 (s, 6H, CH 3), 0.80 (s, 3H, CH 3)；IR(KBr, cm -1): 1729.1 (C=O), 1705.8 (C=O), 1654.0 (C=O), 1601.0, 1576.6, 1491.2 (CH=CH), 1178.8 (C=S)；HR-MS: Calcd. For C 45H 61O 6S 3 [M+H] + 793.3625, Found: 793.3635。Above-mentioned appraising datum proof gained compound is Compound I 6, its structural formula is:
Figure 390538DEST_PATH_IMAGE042
。
Embodiment seven:
11-deoxidation glycyrrhetinic acid ( 1) preparation
In the 20mL dioxane, add the 20g zinc powder (to use HgCl 2The activation), GA (2.0g, 4.26mmol), room temperature reaction drips the 1.20mL concentrated hydrochloric acid simultaneously, filter after 2h, concentrated, column chromatography [sherwood oil (60-90): ethyl acetate=7:1 (v/v)], obtain white solid 1.48g, productive rate 74.0%, mp:330.1 ~ 331.0 ℃.IR(KBr, cm -1): 3437.7(-COOH), 1707.4(-COOH)；HR-MS: Calcd. For C 30H 47O 3 [M-H] - 455.3531, Found: 455.3524。Above-mentioned appraising datum proof gained compound be 11-deoxidation glycyrrhetinic acid ( 1), its structural formula is:
Figure 259137DEST_PATH_IMAGE043
。
Compound I 7Preparation
With compound 1With 5bBe raw material, with reference to chemical compounds I in embodiment one 1Synthetic method make, red solid, yield 92.2%, mp:141.0 ~ 142.0 ℃. 1H NMR (400MHz, CDCl 3), δ(ppm): 7.62 (d, 2H, J = 8.6 Hz, ArH), 7.40 (s, 1H, =CH), 6.98 (d, 2H, J = 8.6Hz, ArH), 5.13 (m, 1H, C 12-H), 4.30 (t, 2H, J= 6.5Hz, CH 2), 4.14 (t, 2H, J = 6.1 Hz, CH 2), 3.22 (m, 1H, C 3-H), 2.18(p, 2H, J = 6.1 Hz, CH 2), 1.14(s, 3H, CH 3), 1.12 (s, 3H, CH 3), 0.99 (s, 3H, CH 3), 0.92 (s, 3H, CH 3), 0.91 (s, 3H, CH 3), 0.78 (s, 3H, CH 3), 0.74(s, 3H, CH 3)； 13C NMR (400MHz, CDCl 3), δ(ppm): 177.314, 173.157, 162.385, 144.711, 134.857, 131.169, 129.067, 128.816, 122.712, 115.689, 79.213, 65.822, 65.072, 60.765, 55.362, 48.610, 47.787, 44.539, 43.068, 41.728, 39.963, 38.984, 38.535, 37.120, 32.801, 32.179, 31.472, 28.861, 28.781, 28.444, 28.307, 27.431, 27.102, 26.328, 26.197, 23.685, 18.549, 16.956, 15.825, 15.715；IR(KBr, cm -1): 1725.0(C=O), 1669.6, 1653.4, 1635.9, 1601.7(CH=CH), 1178.9(C=S)；HR-MS: Calcd. For C 42H 59O 4S 3 [M+H] + 723.3570, Found: 723.3570。Above-mentioned appraising datum proof gained compound is Compound I 7, its structural formula is:
Figure 184499DEST_PATH_IMAGE044
。
Embodiment eight:
3-O-(2-chloracetyl) glycyrrhetinic acid ( 3a)
GA (1.41g, 3.0mmol), pyridine (0.36mL, 4.5mmol) add in the 10mL tetrahydrofuran (THF), drip chloroacetyl chloride (0.29mL, 3.9mmol) under stirring at room.After reaction 4h, pour in 40mL water, filter, drying gets white solid 1.54g, productive rate 96.2%, mp:279.8 ~ 280.9 ℃. 1H NMR (400MHz, CDCl 3), δ(ppm): 5.72(s, 1H, C 12-H), 4.62(m, 1H, C 3-H), 4.07(s, 2H, CH 2), 2.37(s, 1H, C 9- H), 1.38(s, 3H, CH 3), 1.25(s, 3H, CH 3), 1.20(s, 3H, CH 3), 1.13(s, 3H, CH 3), 0.90 (s, 6H, CH 3), 0.84 (s, 3H, CH 3)。Above-mentioned appraising datum proof gained compound be 3-O-(2-chloracetyl) glycyrrhetinic acid ( 3a), its structural formula is:
Figure 159146DEST_PATH_IMAGE045
3-O-(2-piperidyl-ethanoyl) glycyrrhetinic acid ( 4a)
3a(1.066g, 1.95mmol), triethylamine (0.28mL, 1.95mmol) and piperidines (0.252mL, 2.54mmol) add in the 15mL tetrahydrofuran (THF), backflow 10h.Cooling, concentrated, then add water 20mL, filter.Filter residue acetone-water recrystallization gets white solid 1.03g, productive rate 89.2%, mp:305.6 ~ 307.2 ℃. 1H NMR (400MHz, CDCl 3), δ(ppm): 5.71(s, 1H, C 12-H), 4.57(m, 1H, C 3-H), 3.19(s, 2H, NCH 2), 2.32(s, 1H, C 9-H), 1.32(s, 3H, CH 3), 1.01(s, 3H, CH 3), 0.86(s, 6H, CH 3), 0.72(s, 3H, CH 3), 1.10(s, 3H, CH 3), 1.07(s, 3H, CH 3)。Above-mentioned appraising datum proof gained compound be 3-O-(2-piperidyl-ethanoyl) glycyrrhetinic acid ( 4a), its structural formula is:
Figure 26083DEST_PATH_IMAGE046
Compound I I 8Preparation
With 4aWith 5bBe raw material, with reference to I 1Method preparation, red solid, yield 81.6%, mp:142.4 ~ 143.4 ℃. 1H NMR (400MHz, CDCl 3), δ(ppm): 7.62 (d, 2H, J = 8.7 Hz, ArH), 7.39 (s, 1H, CH=CH), 6.99 (d, 2H, J = 8.7 Hz, ArH), 5.61 (s, 1H, C 12-H), 4.61 (m, 1H, C 3-H), 4.31 (t, 2H, OCH 2), 4.13 (t, 2H, OCH 2), 3.50 (s, 2H, NCH 2), 2.35 (s, 1H, C 9-H), 2.18(m, 2H, CH 2), 1.36 (s, 3H, CH 3), 1.15 (s, 6H, CH 3), 1.10 (s, 3H, CH 3), 0.87 (s, 6H, CH 3), 0.75 (s, 3H, CH 3)；IR(KBr, cm -1): 1727.2 (C=O), 1655.2 (C=O), 1601.0, 1576.5, 1504.5, 1490.5 (CH=CH), 1173.4 (C=S)；HR-MS: Calcd. For C 49H 68NO 6S 3 [M+H] + 862.4203, Found: 862.4203。Above-mentioned appraising datum proof gained compound is compound III 8, its structural formula is:
Figure 934259DEST_PATH_IMAGE047
。
Embodiment nine:
With 4aWith 5cBe raw material, with reference to I 1Method preparation, red solid, yield 86.4%, mp:107.3 ~ 108.3 ℃. 1H NMR (400MHz, CDCl 3), δ(ppm): 7.60 (d, 2H, J = 8.8 Hz, ArH), 7.39 (s, 1H, CH=CH), 6.98 (d, 2H, J = 8.7 Hz, ArH), 5.64 (s, 1H, C 12-H), 4.59 (m, 1H, C 3-H), 4.19 (m, 2H, OCH 2), 4.08 (m, 2H, OCH 2), 3.58 (s, 2H, NCH 2), 2.35 (s, 1H, C 9-H), 1.37 (s, 3H, CH 3), 1.16 (s, 6H, CH 3), 1.12 (s, 3H, CH 3), 0.87 (s, 6H, CH 3), 0.80 (s, 3H, CH 3)； 13C NMR(400MHz,CDCl 3), δ(ppm): 210.109, 195.042, 171.467, 164.505, 157.326, 129.635, 123.656, 123.496, 123.109, 119.144, 110.535, 110.288, 76.990, 62.732, 58.993, 56.740, 50.033, 48.404, 43.540, 40.450, 39.094, 38.282, 36.091, 33.777, 33.107, 32.770, 31.961, 27.676, 26.914, 24.280, 23.628, 23.599, 23.502, 23.186, 21.498, 21.413, 21.380, 21.302, 20.857, 20.592, 18.674, 18.438, 13.717, 12.398, 11.782, 11.469；IR(KBr, cm -1): 1724.9 (C=O), 1655. 5(C=O), 1601.9, 1576.0, 1504.5, 1490. 3(CH=CH), 1177.7 (C=S).
HR-MS: Calcd. For C 49H 70NO 6S 3 [M+H] + 876.4360, Found: 876.4360。Above-mentioned appraising datum proof gained compound is compound III 9, its structural formula is:
Figure 914460DEST_PATH_IMAGE048
。
Adopt routinely the blue colorimetry of tetramethyl-nitrogen azoles (MTT) to estimate above-claimed cpd to human cancer cell strain liver cancer cell Hep G-2, the antiproliferative activity of prostate cancer cell DU-145 and mammary cancer MDA-MB-435S.
Experimental technique is as follows: the vegetative period of taking the logarithm, cell in good condition was one bottle, added 0.25% tryptic digestion, and attached cell is come off, and made every milliliter and contained 5 * 10 6~ 6 * 10 6The suspension of individual cell.The obtained cell suspension kind is on 96 orifice plates, and every hole 50 μ L put constant temperature CO 2Cultivated 24 hours in incubator.Change liquid, add test-compound (compound is rear with the substratum dilution with the DMSO dissolving, and test-compound concentration is respectively 5,10,20,40,80,160 μ mol/L), every hole 50 μ L cultivated 48 hours.MTT is added in 96 orifice plates, every hole 20 μ L, in incubator, reaction is 4 hours.Add SDS, every hole 50 μ L.With the optical density of enzyme linked immunological tester in the every hole of mensuration, wavelength 570nm place, calculate cell inhibitory rate.Experimental result is as shown in table 3.
Cell inhibitory rate=(negative control group OD value-tested material group OD value)/(negative control group OD value-blank group OD value) * 100%
Anti-tumour cell proliferative activity (the IC of table 2 part of compounds 50, μ mol/L)
Compd. HepG-2 DU-145 MDA-MB-435S
GA 74.35 69.40 -
I 1 NA 21.59 -
I 3 NA NA NA
I 4 10.01 11.96 17.80
I 6 36.37 NA 40.65
I 7 NA NA NA
I 8 NA NA NA
Annotate: this compound of-expression is not done; NA represents without anti-tumour cell proliferative activity.
The pharmacological results shows, Compound I 4And I 6Propagation to the HepG-2 cell has obvious inhibition activity, and obviously is better than GA; Compound I 1And I 4Propagation to the DU-145 cell has very strong restraining effect, and activity obviously is better than GA; I 4And I 6The propagation of MDA-MB-435S cell had better restraining effect and activity obviously is better than GA.Wherein, Compound I 4Restraining effect to three-type-person's tumour cell is all very strong.

Claims (5)

1. an Enoxolone derivative, is characterized in that, the structural formula of described Enoxolone derivative is:
Figure 2011101392497100001DEST_PATH_IMAGE001
，
In formula, work as R 1During=H, Y is (CH 2) 2Work as R 1=CH 3During CO, Y is (CH 2) 2Or (CH 2) 4
2. a mixture, is characterized in that, described mixture comprises the described Enoxolone derivative of claim 1.
3. the application of the described Enoxolone derivative of claim 1 in the preparation antitumor drug.
4. an antitumor drug, is characterized in that, described antitumor drug is the described Enoxolone derivative of claim 1.
5. an antineoplastic pharmaceutical compositions, is characterized in that, the main active ingredient of described antitumor drug is the described Enoxolone derivative of claim 1, also comprises pharmaceutically receptible carrier or auxiliary material.
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