CN101402667A - Glycosylation modified nitric oxide donor type oleaolic acid compounds, preparation and uses thereof - Google Patents
Glycosylation modified nitric oxide donor type oleaolic acid compounds, preparation and uses thereof Download PDFInfo
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- CN101402667A CN101402667A CNA2008101960436A CN200810196043A CN101402667A CN 101402667 A CN101402667 A CN 101402667A CN A2008101960436 A CNA2008101960436 A CN A2008101960436A CN 200810196043 A CN200810196043 A CN 200810196043A CN 101402667 A CN101402667 A CN 101402667A
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- Prior art keywords
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- nitric oxide
- zcvi4
- acid compounds
- oleanolic acid
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- 239000012453 solvate Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- QTENRWWVYAAPBI-YCRXJPFRSA-N streptomycin sulfate Chemical compound OS(O)(=O)=O.OS(O)(=O)=O.OS(O)(=O)=O.CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](N=C(N)N)[C@H](O)[C@@H](N=C(N)N)[C@H](O)[C@H]1O.CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](N=C(N)N)[C@H](O)[C@@H](N=C(N)N)[C@H](O)[C@H]1O QTENRWWVYAAPBI-YCRXJPFRSA-N 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000005748 tumor development Effects 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 230000004218 vascular function Effects 0.000 description 1
- 229960003487 xylose Drugs 0.000 description 1
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Abstract
本发明涉及药物领域，具体涉及一类糖基化修饰的一氧化氮供体型齐墩果酸类化合物(I)，还公开了它们的制备方法、含有这些化合物或其药学上可接受的盐或酯的药用组合物，以及在制备抗肿瘤药物中的用途。其中R的定义见说明书。
The present invention relates to the field of medicine, in particular to a class of glycosylated nitric oxide donor type oleanolic acid compounds (I), and also discloses their preparation methods, containing these compounds or their pharmaceutically acceptable salts or A pharmaceutical composition of the ester, and its application in the preparation of antitumor drugs. Wherein, the definition of R is shown in the description.
Description
Technical field
The present invention relates to pharmaceutical field, be specifically related to the glycosylation modified nitric oxide donator type Oleanolic Acid compounds (I) of a class, also disclose they the preparation method, contain the medicinal compositions of these compounds or its pharmacy acceptable salt or ester, and the purposes in the preparation antitumor drug.
Background technology
Tumour is a kind of common major disease, the serious threat mankind's healthy and life security.Though multiple antitumor drug is arranged clinically, owing to the complicacy of tumour pathological factor, the resistance of tumour and the reasons such as toxic side effect of antitumor drug, existing medicine still can not meet clinical needs.Therefore, the searching curative effect is outstanding, effect is lasting and new type antineoplastic medicine that toxic side effect is low is significant.
Nitrogen protoxide (being called for short NO, down together) as courier's material or effector molecule important in the body, participates in multiple physiology and pathologic reaction.Experimental results demonstrate that NO has dual regulation in tumour generation, tumor-blood-vessel growth, vascular function, tumor development and transfer process.This short knurl and anti-knurl dual function depend on expression, activity of nitricoxide synthase (be called for short NOS, down with) hypotype and distribute, and the concentration and the time length of NO release, cell is to the susceptibility of NO etc.It has been generally acknowledged that continue NO (no matter the being endogenic or ectogenic) apoptosis capable of inhibiting cell of lower concentration in the body, pair cell has the effect of protection and short its growth; The NO of high density can produce cytotoxicity in the body, and inducing apoptosis of tumour cell stops the diffusion and the transfer of tumour cell.The NO donor is that a class can be in vivo discharges the compound of a certain amount of NO through enzyme or non-enzyme effect.Bibliographical information, some NO donors can discharge the NO of high density specifically in tumour cell, kill tumour cell (referring to Zhang Yihua target, Tian Jide, Peng Sixun. the nitric oxide donors of targeting and related drugs thereof. Acta Pharmaceutica Sinica, 2006,41 (6): 481-486).
Oleanolic Acid (be called for short OA, down with) extensively is present in vegitabilia, and it has the liver provide protection to tetracol phenixin and other poisonous substance inductive rodent liver poisoning and chronic liver cirrhosis.Discover, mainly distribute and metabolism after the administration of OA whole body at liver.China clinically with OA as the Chinese medicine hepatoprotective, be mainly used in chronic hepatic diseases such as treatment hepatitis, liver cirrhosis.Recent study is found, OA can also suppress tumor neogenetic blood vessels and generate, effects such as prevention invasion by tumor cells and transfer (referring to: Ovesna Z, Vachalkova A, Horvathova K, et al.Pentacyclic triterpenoic acids:new chemo-protectivecompounds.Neoplasma, 2004,51 (5): 327-333).Yet there are shortcomings such as bioavailability is low, curative effect is undesirable in OA.
3-{[4-(1-methyl-3-{[5-oxygen-4-(benzenesulfonyl)-1,2,5-oxazole-3-] oxygen } propoxy-)-4-oxygen succinyl with following structural] oxygen } Oleanolic Acid (CAS:875753-25-6 is called for short ZCVI4, down with),
And other nitric oxide donator type OA derivative mentions in the Chinese patent CN1594354A of bulletin on March 16th, 2005 that this patent is about using ZCVI4 and other a series of nitric oxide donator type OA derivatives for treatment hepatitis, liver cirrhosis and liver tumor.This patent will be incorporated by reference comprehensively at this.
Summary of the invention
The present invention is lead compound with ZCVI4, utilize 28 carboxyls of OA fragment and the different glycosyls or the glycosyl coupling of replacement in the ZCVI-4 structure, the glycosylation nitric oxide donator type Oleanolic Acid compounds of design, synthetic a series of novel structures, be used for the treatment of particularly people's tumour of Mammals, comprise giving one or more compounds or its pharmacy acceptable salt or the ester of above-mentioned Mammals with antitumour activity dosage.But the invention also discloses a kind of preparation method of suitability for industrialized production of new type antineoplastic medicine.
The present invention relates to glycosylation modified nitric oxide donator type Oleanolic Acid compounds or its pharmacy acceptable salt or the ester shown in the following formula (I):
Wherein, R represents glycosyl or replaces glycosyl.
In the compound, described R represents glucosyl group shown in the top formula (I), galactosyl, glucal acidic group, the glucosamine base, 2-deoxyglucose base, 2-deoxy-galactose base, xylosyl, Arabic glycosyl, fructosyl, rhamanopyranosyl, ribosyl, mannose group, sorb glycosyl, sucrose base, malt-base, cellobiose base, lactose base, the cotton seed glycosyl, dextran three glycosyls, and as shown in the formula (II) or the represented group of formula (III):
The various glycosyls of wherein said R are that saccharide compound is taken off the group that any locational hydroxyl forms later on.
A kind of embodiment preferred of the present invention is in above-mentioned compound, and the various glycosyls of its R representative are that saccharide compound is taken off the group that the hydroxyl on 1 forms later on.
A kind of embodiment preferred of the present invention is in above-mentioned compound, and its R is a glucosyl group, galactosyl, glucal acidic group, 2-deoxy-galactose base, 2-deoxyglucose base, lactose base, malt-base.
The present invention further optimization scheme is that its R is a galactosyl in the compound that such scheme uses.
Further preferred version of the present invention is that its R is that semi-lactosi is taken off the group that forms behind 1 hydroxyl in the compound that such scheme uses.
The another one aspect that the present invention relates to is glycosylation modified nitric oxide donator type Oleanolic Acid compounds and the pharmacy acceptable salt or the application of ester in the medicine of preparation prevention or treatment tumor disease of formula (I) expression.
Aforesaid tumor disease behaviour tumour.
Aforesaid glycosylation modified nitric oxide donator type Oleanolic Acid compounds and pharmacy acceptable salt or the application of ester in the medicine of preparation prevention or treatment tumor disease suc as formula (I) expression is characterized in that described tumor disease is liver tumor, liver cirrhosis, lung cancer, the esophageal carcinoma, cancer of the stomach, large bowel cancer, colorectal carcinoma, breast tumor, nasopharyngeal carcinoma, cervical cancer, lymphoma, tumor of prostate and leukemia.
The invention still further relates to a kind of pharmaceutical composition for the treatment of tumor disease, one or more that it is characterized in that comprising the glycosylation modified nitric oxide donator type Oleanolic Acid compounds shown in the formula (I) and pharmacy acceptable salt or ester are as effective constituent.Can also contain pharmaceutically acceptable carrier in addition, as Magnesium Stearate, sodium bisulfite, ten dimethyl cellulose sodium, micronization silica gel etc.
Among the present invention, giving Mammals formula (I) compound and pharmacy acceptable salt or ester, and during the solvate of these compounds (being referred to as " medicine " here), can use separately, perhaps preferably according to the pharmaceutical methods of standard with its be suitable for medicinal carrier or thinner and cooperate the back to use.Administering mode can be through various approach, comprise oral, parenteral administration or topical.Here the parenteral administration of indication includes, but are not limited to intravenous injection, intramuscular injection, abdominal injection, subcutaneous injection and transdermal administration.
Compound concrete structure and code name shown in the preferred formula (I) of the present invention's part is as follows:
The synthetic method of the compound shown in the formula of the present invention (I) is as follows: the hydroxyl in the glycan molecule carried out the acetylize protection under the effect of pyridylacetic acid(HPAC) acid anhydride; then under red phosphorus/bromine water effect, carry out 1 bromo; with the ZCVI4 condensation, condensation product deacetylation in sodium methylate/ethanol/methylene system makes compound shown in the formula (I) then.
Concrete synthetic route:
Preparation method when the R of the compound shown in the general formula (I) is 2-deoxy-galactose base: semi-lactosi acetylize under the effect of pyridylacetic acid(HPAC) acid anhydride; then under red phosphorus/bromine water effect, carry out 1 bromo; under the effect of zinc powder, copper sulfate and sodium acetate, 1,2 of sugar is reduced to glycal again; saturated benzole soln with HBr carries out addition reaction again; make 3; 4; 5-O-ethanoyl a-D-2-deoxy-galactose bromo-derivative; with the ZCVI4 condensation, deacetylation makes target compound (TM) in sodium methylate/ethanol/methylene system at last again.
Concrete synthetic route:
Preparation method when the R of the compound shown in the general formula (I) is formula (II) or the described group of formula (III): under the effect at triethylamine; with 1; 3; 4; amino a-D-glucose of 6-four-O-ethanoyl-2-and bromoacetyl bromide reaction; the intermediate of gained again under the effect of salt of wormwood with the ZCVI4 condensation, last deacetylation makes target compound (TM).
Concrete synthetic route:
Description of drawings
Fig. 1 is that compound ZCVI4-2 is to human liver cancer cell SMMC7721 nude mice xenografts of human.
Embodiment
Below be the embodiment of The compounds of this invention, these embodiment also do not mean that limitation of the present invention.
Embodiment 1
3-{[4-(1-methyl-3-{[5-oxygen-4-(benzenesulfonyl)-1,2,5-oxazole-3-] oxygen } propoxy-)-4-oxygen succinyl] oxygen }-preparation of 28-O-β-D-glucopyranosyl-Oleanolic Acid (ZCVI4-1)
2,3,4,6-four-O-ethanoyl-a-D-Glucopyranose bromide reference literature [Yunnan Institute for nationalities's journal (natural science edition), 2004,13 (2): 83-85] preparation.
ZCVI4 reference literature (J.Med.Chem.2008,51,4834-4838) preparation.
ZCVI4 852mg, 2,3,4,6-four-O-ethanoyl-a-D-Glucopyranose bromide 414mg, K
2CO
3200mg and cetyl trimethylammonium bromide 200mg are dissolved in 10mL water and 15mL CH
2Cl
2Mixing solutions in, vigorous stirring 48h tells organic layer under the room temperature, water layer CH
2Cl
2Extraction; the organic layer that merges; concentrate; rapid column chromatography gets pulpous state intermediate 3-{[4-(1-methyl-3-{[5-oxygen-4-(benzenesulfonyl)-1,2,5-oxazole-3-] oxygen } propoxy-)-4-oxygen succinyl] oxygen }-28-O-[2; 3; 4,6-four-O-ethanoyl]-β-D-glucopyranosyl-Oleanolic Acid, productive rate 52%.
Above-mentioned product is dissolved in 5mL CH
2Cl
2With 5mL CH
3In the mixing solutions of OH, 0 ℃ of methanol solution that drips the sodium methylate of 1mol/L down, control pH is no more than 10, be stirred to the raw material spot and disappear, the dichloromethane solution adjust pH that drips acetate is 7, concentrates, rapid column chromatography gets white powder ZCVI4-1, productive rate 21%, m.p.101-103 ℃.ESI-MS?1032[M+NH
4]
+，1049[M+Cl]
-；
1H?NMR(500MHz，DMSO)，d(ppm)：0.75(s，3H，CH
3)，0.82(s，6H，2×CH
3)，0.85(s，3H，CH
3)，0.89(s，6H，2×CH
3)，1.23(s，3H，CH
3)，2.67(s，4H，2×COCH
2)，2.77～2.88(m，1H，C
18-H)，3.65(m，1H，H
3)，3.78(m，1H，H
5)，4.09(m，1H，H
4)，4.18(brs，1H，3a-H)，4.21(t，2H，OCH
2，J＝6Hz)，4.43(m，1H，H
2)，4.76(d，1H，J＝4.5Hz，H
6’)，4.83(d，1H，J＝6.0Hz，H
6)，4.99～5.13(m，1H，OCH)，5.26(brs，1H，C
12-H)，5.49(d，1H，J＝8Hz，H
1)，7.61～7.64(m，2H，ArH)，7.73～7.76(m，1H，ArH)，8.06(d，2H，ArH，J＝8.2Hz)。
Embodiment 2
3-{[4-(1-methyl-3-{[5-oxygen-4-(benzenesulfonyl)-1,2,5-oxazole-3-] oxygen } propoxy-)-4-oxygen succinyl] oxygen }-preparation of 28-O-β-D-galactopyranose base-Oleanolic Acid (ZCVI4-2)
With reference to the preparation method of ZCVI4-1, with 2,3,4; 6-four-O-ethanoyl-a-D-galactopyranose bromide [Yunnan Institute for nationalities's journal (natural science edition), 2004,13 (2): 83-85] is a raw material; make white powder compound ZCVI4-2, productive rate 28%, m.p.121-124 ℃.ESI-MS?1032[M+NH
4]
+，1049[M+Cl]
-；
1H?NMR(500MHz，DMSO)，d(ppm)：0.67(s，3H，CH
3)，0.74(s，6H，2×CH
3)，0.83(s，3H，CH
3)，0.87(s，6H，2×CH
3)，1.1(s，3H，CH
3)，2.53(s，4H，2×COCH
2)，2.77～2.83(m，1H，C
18-H)，3.51(m，1H，H
3)，3.68(m，1H，H
5)，4.28(m，1H，H
4)，4.41(brs，1H，3a-H)，4.45(t，2H，OCH
2，J＝6Hz)，4.51(m，1H，H
2)，4.71(d，1H，J＝4.5Hz，H
6’)，4.93(d，1H，J＝6.0Hz，H
6)，4.99～5.03(m，1H，OCH)，5.16(brs，1H，C
12-H)，5.21(d，1H，J＝8Hz，H
1)，7.72～7.75(m，2H，ArH)，7.88～7.91(m，1H，ArH)，8.01(d，2H，ArH，J＝8Hz)。
Embodiment 3
3-{[4-(1-methyl-3-{[5-oxygen-4-(benzenesulfonyl)-1,2,5-oxazole-3-] oxygen } propoxy-)-4-oxygen succinyl] oxygen }-preparation of 28-O-β-D-glucal acidic group Oleanolic Acid (ZCVI4-3)
2,3,4-three-O-ethanoyl-a-D-glucuronic acid methyl ester bromide reference literature [organic chemistry, 1992,12,269-272] preparation.
2,3,4-three-O-ethanoyl-a-D-glucuronic acid methyl ester bromide 200mg, anhydrous K
2CO
3100mg and 414mgZCVI4 are dissolved in the 5mL dry DMF, N
2Protection is stirring at room 48h down.Reaction solution is poured in the 50mL water into CH
2Cl
2Extraction (20mL * 3); organic layer washs with the dilute hydrochloric acid of 1N again; dry; rapid column chromatography gets wax shape intermediate 3-{[4-(1-methyl-3-{[5-oxygen-4-(benzenesulfonyl)-1; 2,5-oxazole-3-] oxygen } propoxy-)-4-oxygen succinyl] oxygen }-28-O-[2,3; 4-three-O-ethanoyl-β-D-] glucuronic acid methyl ester-Oleanolic Acid, productive rate 41%.This intermediate is dissolved in the anhydrous THF of 4mL, adds LiOH20mg, stirred overnight at room temperature.Add anhydrous methanol 4mL again, 0 ℃ of methanol solution that drips the sodium methylate of 1mol/L down, control pH is no more than 10.After the TLC demonstration reacts completely, in reaction solution, drip the CH of acetate
2Cl
2The solution adjust pH be 7.Concentration of reaction solution, rapid column chromatography get wax shape ZCVI4-3, productive rate 15%.ESI-MS?1027[M-H]
-；
1H?NMR(300MHz，DMSO)，d(ppm)：0.68(s，3H，CH
3)，0.73(s，6H，2×CH
3)，0.83(s，3H，CH
3)，0.90(s，6H，2×CH
3)，1.11(s，3H，CH
3)，2.54(s，4H，2×COCH
2)，2.67～2.93(m，1H，C
18-H)，3.06-3.10(m，2H，H
3，H
4)，4.28(m，1H，3a-H)，4.39-4.43(m，2H，OCH
2)，4.91-5.12(m，2H，OCH，H
2)，5.12(d，2H，d＝5.7Hz)，5.16(brs，1H，C
12-H)，5.22(d，1H，J＝8Hz，H
1)，7.71～7.77(m，2H，ArH)，7.87～7.92(m，1H，ArH)，8.01(d，2H，ArH，J＝8Hz)。
3-{[4-(1-methyl-3-{[5-oxygen-4-(benzenesulfonyl)-1,2,5-oxazole-3-] oxygen } propoxy-)-4-oxygen succinyl] oxygen }-preparation of 28-O-β-D-2-acetylglucosamine base Oleanolic Acid (ZCVI4-4)
With reference to the preparation method of ZCVI4-1, with 3,4,6-three-O-ethanoyl-2-N-ethanoyl-a-D-glucosamine bromide [J.Org.Chem.2006,71,3619-3622] is a raw material, makes white powder ZCVI4-4, productive rate 36%, m.p.142-146 ℃.ESI-MS1078[M+Na]
+；
1H?NMR(500MHz，DMSO)，d(ppm)：0.73(s，3H，CH
3)，0.77(s，6H，2×CH
3)，0.89(s，3H，CH
3)，0.91(s，6H，2×CH
3)，1.21(s，3H，CH
3)，2.59(s，4H，2×COCH
2)，2.73～2.99(m，1H，C
18-H)，3.17(m，3H，COCH
3)，3.40～3.51(brs，1H，NH)，3.64～3.67(m，2H，H
3，H
5)，4.32～4.36(brs，1H，3a-H)，4.40～4.47(m，4H，OCH
2，H
2，H
4)，4.99(d，1H，J＝5.5Hz，H
6)，5.03-5.05(m，2H，OCH，H
6’)，5.20(brs，1H，C
12-H)，5.26(d，1H，J＝8.9Hz，H
1)，7.75～7.78(m，2H，ArH)，7.91～7.94(m，1H，ArH)，8.02～8.04(m，2H，ArH)。
3-{[4-(1-methyl-3-{[5-oxygen-4-(benzenesulfonyl)-1,2,5-oxazole-3-] oxygen } propoxy-)-4-oxygen succinyl] oxygen }-preparation of 28-O-β-D-2-deoxyglucose base Oleanolic Acid (ZCVI4-5)
With reference to the preparation method of ZCVI4-1, with 3,4,6-three-O-ethanoyl-a-D-2-deoxyglucose bromide [CarbohydrateResearch, 2005,340:2670-2674] is a raw material, makes pulpous state compound ZCVI4-5, productive rate 27%.ESI-MS?997[M-H]
-；
1H?NMR(500MHz，DMSO)，d(ppm)：0.57(s，3H，CH
3)，0.69(s，6H，2×CH
3)，0.77(s，3H，CH
3)，0.81(s，6H，2×CH
3)，0.98(s，3H，CH
3)，2.57(s，4H，2×COCH
2)，2.87～2.93(m，1H，C
18-H)，4.43～3.51(m，1H，H
4)，3.62-3.79(3m，3H，H
5，H
6，H
6’)，3.86～4.01(m，1H，H
3)，4.42(brs，1H，3a-H)，4.43(t，2H，OCH
2，J＝6Hz)，4.68～4.98(m，1H，OCH)，5.18(brs，1H，C
12-H)，5.24(dd，1H，H1)，7.73～7.74(m，2H，ArH)，7.88～7.95(m，1H，ArH)，7.99～8.07(m，2H，ArH)。
3-{[4-(1-methyl-3-{[5-oxygen-4-(benzenesulfonyl)-1,2,5-oxazole-3-] oxygen } propoxy-)-4-oxygen succinyl] oxygen }-preparation of 28-O-β-D-2-deoxy-galactose base Oleanolic Acid (ZCVI4-6)
With reference to the preparation method of ZCVI4-1, with 3,4,6-three-O-ethanoyl-a-D-2-deoxy-galactose bromide [Journal ofcarbohydrate chemistry, 1996,15 (8): 955-964] is a raw material, makes pulpous state compound ZCVI4-6, productive rate 21%.ESI-MS?1016[M+NH
4]
+；
1H?NMR(500MHz，DMSO)，d(ppm)：0.61(s，3H，CH
3)，0.71(s，6H，2×CH
3)，0.82(s，3H，CH
3)，0.85(s，6H，2×CH
3)，1.2(s，3H，CH
3)，2.58(s，4H，2×COCH
2)，2.67～2.81(m，1H，C
18-H)，4.53～3.61(m，1H，H
4)，3.65～3.82(m，3H，H
5，H
6，H
6’)，3.90～4.0(m，1H，H
3)，4.41(brs，1H，3a-H)，4.45(t，2H，OCH
2，J＝6Hz)，4.78～5.00(m，1H，OCH)，5.14(brs，1H，C
12-H)，5.21(dd，1H，H
1)，7.72～7.74(m，2H，ArH)，7.88～7.91(m，1H，ArH)，7.99～8.01(m，2H，ArH)。
Embodiment 7
3-{[4-(1-methyl-3-{[5-oxygen-4-(benzenesulfonyl)-1,2,5-oxazole-3-] oxygen } propoxy-)-4-oxygen succinyl] oxygen }-preparation of 28-O-β-D-xylosyl-Oleanolic Acid (ZCVI4-7)
With reference to the preparation method of ZCVI4-1, with 2,3,5-three-O-ethanoyl-a-D-wood sugar bromide [Carbohydrate Research, 2005,340:2670-2674] is a raw material, makes white powder compound ZCVI4-7, productive rate 20%, m.p.103-106 ℃.ESI-MS?1007[M+Na]
+，1019[M+Cl]
-；
1H?NMR(500MHz，DMSO)，d(ppm)：0.65(s，3H，CH
3)，0.74(s，6H，2×CH
3)，0.85(s，3H，CH
3)，0.91(s，6H，2×CH
3)，1.18(s，3H，CH
3)，2.54(s，4H，2×COCH
2)，2.62～2.73(m，1H，C
18-H)，3.68～3.78(m，2H，H
3，H
4)，4.28～4.34(m，1H，3a-H)，4.48～4.55(m，2H，OCH
2)，4.67～4.81(m，2H，H
5，H
5’)，4.91～5.00(m，1H，OCH)，5.12～5.22(m，1H，H
2)，5.28(brs，1H，C
12-H)，5.32(d，1H，J＝5Hz，H
1)，7.71～7.76(m，2H，ArH)，7.89～7.90(m，1H，ArH)，7.99～8.02(m，2H，ArH)。
Embodiment 8
3-{[4-(1-methyl-3-{[5-oxygen-4-(benzenesulfonyl)-1,2,5-oxazole-3-] oxygen } propoxy-)-4-oxygen succinyl] oxygen }-preparation of the Arabic glycosyl Oleanolic Acid of 28-O-β-D-(ZCVI4-8)
With reference to the preparation method of ZCVI4-1, with 2,3,5-three-O-ethanoyl-a-D-pectinose bromide [CarbohydrateResearch, 2005,340:2670-2674] is a raw material, makes white powder compound ZCVI4-8, productive rate 25%, m.p.117-120 ℃.ESI-MS?983[M-H]
-，1019[M+Cl]
-；
1H?NMR(500MHz，DMSO)，d(ppm)：0.68(s，3H，CH
3)，0.79(s，6H，2×CH
3)，0.81(s，3H，CH
3)，0.89(s，6H，2×CH
3)，1.08(s，3H，CH
3)，2.52(s，4H，2×COCH
2)，2.67～2.73(m，1H，C
18-H)，3.68～3.70(m，2H，H
3，H
4)，4.29～4.30(m，1H，3a-H)，4.41～4.44(m，2H，OCH
2)，4.57～4.71(m，2H，H
5，H
5’)，4.98～5.02(m，1H，H
2)，4.99～5.08(m，1H，OCH)，5.21(brs，1H，C
12-H)，5.33(d，1H，J＝5Hz，H
1)，7.72～7.76(m，2H，ArH)，7.88～7.89(m，1H，ArH)，7.99～8.01(m，2H，ArH)。
Embodiment 9
3-{[4-(1-methyl-3-{[5-oxygen-4-(benzenesulfonyl)-1,2,5-oxazole-3-] oxygen } propoxy-)-4-oxygen succinyl] oxygen }-preparation of 28-O-β-D-malt-base Oleanolic Acid (ZCVI4-9)
With reference to the preparation method of ZCVI4-1, with 2,3,6,2 ', 3 ', 4 ', 6 '-seven-O-ethanoyl-a-D-maltose bromide [Carbohydrate Research, 2005,340:2670-2674] is a raw material, makes waxy compound ZCVI4-9, productive rate 29%.ESI-MS?1194[M+NH
4 +]
+，1199[M+Na]
+；
1H?NMR(500MHz，DMSO)，d(ppm)：0.69(s，3H，CH
3)，0.71(s，6H，2×CH
3)，0.81(s，3H，CH
3)，0.85(s，6H，2×CH
3)，1.1(s，3H，CH
3)，2.53(s，4H，2×COCH
2)，2.71～2.83(m，1H，C
18-H)，3.41～3.43(m，1H，H
4)，3.61～3.67(m，2H，H
5’，H
2’)，3.71～3.78(m，1H，H
2)，4.13～4.32(m，2H，H
5，H
4’)，4.38～4.46(m，2H，H
3，H
3’)，4.54～4.61(m，1H，H
6b’)，4.67～4.83(m，1H，H
6b)，5.00～5.03(m，2H，H
6a，H
6a’)，5.09～5.21(m，4H，OCH，3a-H，OCH
2)，5.23～5.31(m，2H，C
12-H，H
1’)，5.62(d，1H，J＝8Hz，H
1)，7.72～7.75(m，2H，ArH)，7.88～7.91(m，1H，ArH)，7.98～8.00(m，2H，ArH)。
3-{[4-(1-methyl-3-{[5-oxygen-4-(benzenesulfonyl)-1,2,5-oxazole-3-] oxygen } propoxy-)-4-oxygen succinyl] oxygen }-preparation of 28-O-β-D-cellobiose base Oleanolic Acid (ZCVI4-10)
With reference to the preparation method of ZCVI4-1, with 2,3,6,2 '; 3 ', 4 ', 6 '-seven-O-ethanoyl-a-D-cellobiose bromide [Carbohydrate Research, 2005; 340:2670-2674] be raw material, make white powder compound ZCVI4-10, productive rate 23%, m.p.126-129 ℃.ESI-MS?1175[M-H]
-；
1H?NMR(500MHz，DMSO)，d(ppm)：0.65(s，3H，CH
3)，0.78(s，6H，2×CH
3)，0.89(s，3H，CH
3)，0.95(s，6H，2×CH
3)，1.13(s，3H，CH
3)，2.53(s，4H，2×COCH
2)，2.76～2.83(m，1H，C
18-H)，3.42～3.43(m，1H，H
4)，3.62～3.67(m，2H，H
5’，H
2’)，3.74～3.78(m，1H，H
2)，4.23～4.33(m，2H，H
5，H
4’)，4.38～4.46(m，2H，H
3，H
3’)，4.50～4.61(m，1H，H
6b’)，4.67～4.77(m，1H，H6b)，5.00～5.03(m，2H，H
6a，H
6a’)，5.09～5.18(m，4H，OCH，3a-H，OCH
2)，5.27～5.31(m，2H，C
12-H，H
1’)，5.61(d，1H，J＝8Hz，H
1)，7.72～7.75(m，2H，ArH)，7.88～7.91(m，1H，ArH)，7.98～8.00(m，2H，ArH)。
Embodiment 11
3-{[4-(1-methyl-3-{[5-oxygen-4-(benzenesulfonyl)-1,2,5-oxazole-3-] oxygen } propoxy-)-4-oxygen succinyl] oxygen }-preparation of 28-O-β-D-lactose base Oleanolic Acid (ZCVI4-11)
With reference to the preparation method of ZCVI4-1, with 2,3,6,2 '; 3 ', 4 ', 6 '-7-O-ethanoyl-a-D-lactose bromide [CarbohydrateResearch, 2005; 340:2670-2674] be raw material, make white powder compound ZCVI4-11, productive rate 23%, m.p.150-153 ℃.ESI-MS?1175[M-H]
-；
1H?NMR(500MHz，DMSO)，d(ppm)：0.65(s，3H，CH
3)，0.78(s，6H，2×CH
3)，0.89(s，3H，CH
3)，0.95s，6H，2×CH
3)，1.13(s，3H，CH
3)，2.53(s，4H，2×COCH
2)，2.76～2.83(m，1H，C
18-H)，3.39～3.43(m，1H，H
4)，3.59～3.67(m，2H，H
5’，H
2’)，3.74～3.80(m，1H，H
2)，4.13～4.33(m，2H，H
5，H
4’)，4.36～4.46(m，2H，H
3，H
3’)，4.50～4.67(m，1H，H
6b’)，4.67～4.77(m，1H，H6b)，4.89～5.02(m，2H，H
6a，H
6a’)，5.09～5.16(m，4H，OCH，3a-H，OCH
2)，5.27～5.32(m，2H，C
12-H，H
1’)，5.54(d，1H，J＝8Hz，H
1)，7.72～7.76(m，2H，ArH)，7.88～7.91(m，1H，ArH)，7.98～8.01(m，2H，ArH)。
3-{[4-(1-methyl-3-{[5-oxygen-4-(benzenesulfonyl)-1,2,5-oxazole-3-] oxygen } propoxy-)-4-oxygen succinyl] oxygen }-preparation of 28-O-acetyl-(2-deoxyglucose) amino Oleanolic Acid (ZCVI4-12)
With reference to the preparation method of ZCVI4-3, with N-acetyl bromide-1,3,4,6-four-O-acetylamino glucose [J.Med.Chem.1978,21 (12): 1222-1225] is raw material, makes waxy compound ZCVI4-12, productive rate 19%.ESI-MS?1071[M-H]
-；
1H?NMR(500MHz，DMSO)，d(ppm)：0.67(s，3H，CH
3)，0.77(s，6H，2×CH
3)，0.83(s，3H，CH
3)，0.89(s，6H，2×CH
3)，1.2(s，3H，CH
3)，2.58(s，4H，2×COCH
2)，2.79～2.83(m，1H，C
18-H)，3.52～3.59(m，2H，H
5，H
3)，3.72～3.74(m，1H，H
4)，3.81(m，1H，H
2)，4.28(m，1H，H
4)，4.44～4.45(m，4H，3a-H，OCH
2，H
6，H
6’)，4.93～4.94(m，1H，OCH)，5.00(brs，1H，C
12-H)，5.21(m，1H，H
1)，7.72～7.76(m，2H，ArH)，7.88～7.91(m，1H，ArH)，8.00(d，2H，ArH，J＝7.8Hz)。
3-{[4-(1-methyl-3-{[5-oxygen-4-(benzenesulfonyl)-1,2,5-oxazole-3-] oxygen } propoxy-)-4-oxygen succinyl] oxygen }-preparation of 28-O-acetyl-(2-deoxy-galactose) amino Oleanolic Acid (ZCVI4-13)
With reference to the preparation method of ZCVI4-3, with N-acetyl bromide-1,3,4,6-four-O-ethanoyl-galactosamine [J.Med.Chem.1978,21 (12): 1222-1225] is a raw material, makes waxy compound ZCVI4-13, productive rate 30%.ESI-MS?1071[M-H]
-；
1H?NMR(500MHz，DMSO)，d(ppm)：0.68(s，3H，CH
3)，0.78(s，6H，2×CH
3)，0.84(s，3H，CH
3)，0.89(s，6H，2×CH
3)，1.1(s，3H，CH
3)，2.58(s，4H，2×COCH
2)，2.57～2.83(m，1H，C
18-H)，3.53～3.59(m，2H，H
5，H
3)，3.72～3.74(m，1H，H
4)，3.92(m，1H，H
2)，4.34(m，1H，H
4)，4.34～4.45(m，4H，3a-H，OCH
2，H
6，H
6’)，4.80～4.94(m，1H，OCH)，5.10(brs，1H，C
12-H)，5.21(d，1H，H
1，J＝1.5Hz)，7.72～7.76(m，2H，ArH)，7.88～7.91(m，1H，ArH)，8.00(d，2H，ArH，J＝7.8Hz)。
The external pharmacodynamic study of embodiment 14 ZCVI4-2
Purpose: select 4 kinds of tumor cell of liver strains that ZCVI4-2 is carried out the extracorporeal anti-tumor function screening.
Sample and reagent: prepare during the test of ZCVI4-2 injection liquid temporarily; Hydroxycamptothecin injection liquid (Hubei Hua Yuan century medicine company); Cell culture medium RPMI-1640, F12, MEM, DMEM (high sugar) are available from GIBCO company; Foetal calf serum (clear company limited of the Hangzhou four seasons); Tetramethyl-azo azoles indigo plant (MTT) and DMSO are all available from Sigma company; Other common agents is commercially available analytical pure.
Cell strain: human hepatoma cell strain SMMC-7721, human hepatoma cell strain HepG2, human hepatoma cell strain IM3, human hepatoma cell strain BEL-7402 are all available from Chinese Academy of Medical Sciences's cell bank and Shanghai cell institute of the Chinese Academy of Sciences.
The cultivation of cell strain: each experimental cell strain (Shanghai Inst. of Cytobiology, Chinese Academy of Sciences provides) is gone down to posterity frozen by this laboratory.Cell is at 37 ℃, 5%CO
2The conventional cultivation in the incubator of saturated humidity.Nutrient solution is for containing 10% heat-inactivated fetal bovine serum, the RPMI1640 cell culture medium of penicillin 100u/ml and Streptomycin sulphate 100u/ml.48h changes nutrient solution, when cell converges, goes down to posterity with 0.25% tryptic digestion.Experiment all is in logarithmic phase with cell, and the trypan blue exclusion method shows cell viability＞95%.Experimental technique: get and be in one bottle in logarithmic phase cell in good condition, add Digestive system (0.125% trypsinase+0.01%EDTA) digestion, counting 2～4 * 10
4Individual/ml, make cell suspension inoculation on 96 orifice plates, 180 μ L/ holes are put in the constant temperature CO2 incubator and were cultivated 24 hours.Change liquid, adding is subjected to the reagent thing, and cultivated 72 hours in 20 μ L/ holes.MTT is added in 96 orifice plates, and hatched in the incubator 4 hours in 20 μ L/ holes.Supernatant liquor is removed in suction, adds DMSO, 150 μ L/ holes, and jolting is 10 minutes on the dull and stereotyped shaking table.Being tried thing and investigate 3 concentration (0.1,1.0,10 μ M), is the absorbancy that the 570nm place measures every hole with the enzyme linked immunological monitor at wavelength, calculates the cell inhibitory rate under each concentration respectively.
The inhibiting rate method of calculation:
The absolute OD value of the relative OD value=negative control hole of the negative control hole-absolute OD value in blank hole
The relative OD value in the susceptibility hole=absolute OD value in susceptibility hole-absolute OD value in blank hole
Experimental result
As known from Table 1, ZCVI4-2 has the anti-liver tumor effect of remarkable vitro, obviously is better than positive control drug Hydroxycamptothecin (HCPT).
Table 1.ZCVI4-2 is to 4 kinds of human liver tumor cell's restraining effect results
Pharmacodynamic study in the body of embodiment 15 ZCVI4-2
1, the ZCVI4-2 intraperitoneal administration is to the experimental therapy effect of mouse H22 liver cancer
Purpose: test ZH-2 is to the growth-inhibiting effect of mouse H22 liver cancer.
Animal: the ICR mouse, 18-22g is provided by animal housing of China Medicine University, conformity certification number: kinoplaszm SCX (Soviet Union) 2002--0011 of Soviet Union.
The knurl kind: mouse H22 knurl kind is provided by institute of materia medica, Chinese Academy of Sciences Shanghai.
Tester: the ZCVI4-2 injection liquid is provided by medicament teaching and research room of China Medicine University Zhang Jianjun.
The medication and the course of treatment:
Select for use 18-22 to restrain the H22 knurl kind of female ICR mouse and well-grown 7-11 days, it is subcutaneous to be inoculated in the right side of mice armpit, about 4.5-5 * 10
6Cell/only, inoculate and divide cage at random, intraperitoneal injection after 24 hours.Pressed the various dose successive administration 7 days.Put to death animal on the 10th day, weigh, knurl is heavy, calculate that respectively to organize average knurl heavy, press formula and obtain tumor control rate and carry out the T check.
Result and conclusion
As shown in table 2, ZCVI4-2 has certain growth-inhibiting effect to mouse H22 liver cancer.
Table 2.ZCVI4-2 is to the growth-inhibiting effect of mouse H22 liver cancer
2, the ZCVI4-2 intravenously administrable is to the experimental therapy effect of mouse S180 sarcoma
Experimental technique
Select for use 18-22 to restrain the S180 knurl kind of female ICR mouse and well-grown 7-11 days, it is subcutaneous to be inoculated in the right side of mice armpit, about 4.5-5 * 10
6Cell/only, inoculate and divide cage at random after 24 hours, the tail intravenously administrable.Pressed same dosage successive administration 7 days.Put to death animal on the 8th day, weigh, knurl is heavy, calculate that respectively to organize average knurl heavy, press formula and obtain tumor control rate and carry out the T check.
Experimental result
As table 3 data presentation, compare with blank group and control group, ZCVI4-2 is inhibited to the growth of mouse S180 sarcoma.
Table 3.ZCVI4-2 is to the growth-inhibiting effect of mouse S180 sarcoma
Annotate: D1, D8: inoculation back the 1st, 8 day
3, the ZCVI4-2 intravenously administrable is to the experimental therapy effect of people's liver cancer SMMC-7721 Nude Mice
Because animal knurl and human tumor are not quite identical, animal knurl test-results exist and clinical effectiveness between difference.For this reason, we have selected people's liver cancer SMMC7721 Nude Mice to carry out ZCVI4-2 anti-tumor in vivo effect research on the basis of above-mentioned two kinds of animal knurls test.
Tried thing: the ZCVI4-2 injection liquid provides lot number by preparation teaching and research room of China Medicine University Zhang Jianjun: 070327.The blank solvent contrast provides lot number by preparation teaching and research room of China Medicine University Zhang Jianjun: 070327-0.Positive control drug is 5 FU 5 fluorouracil (5-Fu), and Tianjin gold credit amino acid company limited produces lot number: 0505241, be diluted to administration concentration with physiological saline before using.Transplanted tumor: select human liver cell liver cancer SMMC-7721 Nude Mice for use, it is subcutaneous and set up to be inoculated in nude mouse by human liver cell liver cancer SMMC-7721 cell strain.The cell inoculation amount is 2 * 10
6, inoculation is used after forming and passing for 3 generations again in the nude mouse body behind the transplanted tumor.
Animal: female BALB/cA nude mouse, age in days 35-40 days, body weight 18-22g was provided by Chinese Academy of Sciences's Shanghai Experimental Animal Center.The conformity certification numbering: Shanghai is moving closes the card word No. 122.12 of the negative control groups of every treated animal number, 6 of administration groups.
Experimental technique
The tumor tissue of getting the growth animated period cuts into 1.5mm
3About, under aseptic condition, it is subcutaneous to be inoculated in nude mouse right side armpit.Nude Mice is treated tumor growth to 100～300mm with vernier caliper measurement transplanted tumor diameter
3After with the animal random packet.Use the method for measuring the knurl footpath, dynamic observe the antineoplastic effect of tested thing.The measurement number of times of diameter of tumor is that each the measurement also need claim mouse heavy simultaneously 3 times weekly.The administration group is intravenously administrable 3 times weekly, and administration volume 0.4ml/ only.Positive controls is intravenously administrable 3 times weekly, and negative control group is given equivalent physiological saline simultaneously.
Detect index and method of calculation
(1) (tumor volume, TV), calculation formula is gross tumor volume: TV=1/2 * a * b
2
Wherein a, b represent length and width respectively.
(2) relative tumour volume (relative tumor volume, RTV), calculation formula is:
RTV＝TV
t/TV
0。
TV wherein
0(d during for minute cage administration
0) gross tumor volume, TV
tGross tumor volume when measuring each time.
(3) relative tumor proliferation rate T/C (%), calculation formula is:
T
RTV: treatment group RTV; C
RTV: negative control group RTV.
Test-results is with the evaluation index of relative tumor proliferation rate T/C (%) as anti-tumor activity.
Experimental result:
As table 4 and shown in Figure 1, the ZCVI4-2 injection liquid has certain growth-inhibiting effect to human liver cell liver cancer SMMC-7721 Nude Mice.ZCVI4-2 injection liquid 25mg/kg and 12.5mg/kg dosage group are respectively 44.1% and 50.0% to the T/C of SMMC-7721.
Table 4.ZCVI4-2 injection liquid is to the experimental therapy effect of people's liver cancer SMMC-7721 Nude Mice
D0: divide the cage administration time
Claims (10)
1, glycosylation modified nitric oxide donator type Oleanolic Acid compounds and pharmacy acceptable salt or the ester shown in following general formula I:
Among its Chinese style I, R represents the group of glucosyl group, galactosyl, glucal acidic group, glucosamine base, 2-deoxyglucose base, 2-deoxy-galactose base, xylosyl, Arabic glycosyl, fructosyl, rhamanopyranosyl, ribosyl, mannose group, sorb glycosyl, sucrose base, malt-base, cellobiose base, lactose base, cotton seed glycosyl, dextran three glycosyls or following formula II and formula III:
2, glycosylation modified nitric oxide donator type Oleanolic Acid compounds as claimed in claim 1 and pharmacy acceptable salt or ester is characterized in that described R is glucosyl group, galactosyl, glucal acidic group, 2-deoxy-galactose base, 2-deoxyglucose base, lactose base, malt-base.
3, glycosylation modified nitric oxide donator type Oleanolic Acid compounds as claimed in claim 2 and pharmacy acceptable salt or ester is characterized in that described R is a galactosyl.
4, glycosylation modified nitric oxide donator type Oleanolic Acid compounds as claimed in claim 1 and pharmacy acceptable salt or ester, the glycosyl that it is characterized in that described R representative are that saccharide compound is taken off the group that any locational hydroxyl forms later on.
5, glycosylation modified nitric oxide donator type Oleanolic Acid compounds as claimed in claim 4 and pharmacy acceptable salt or ester is characterized in that described hydroxyl is the hydroxyl on 1 of saccharide compound.
6, glycosylation modified nitric oxide donator type Oleanolic Acid compounds as claimed in claim 3 and pharmacy acceptable salt or ester is characterized in that described galactosyl is that semi-lactosi is taken off the group that forms behind 1 hydroxyl.
7, glycosylation modified nitric oxide donator type Oleanolic Acid compounds and pharmacy acceptable salt or the application of ester in the medicine of preparation prevention or treatment tumor disease of representing as general formula I.
8, application as claimed in claim 7 is characterized in that described tumor disease includes but not limited to liver tumor, liver cirrhosis, lung cancer, the esophageal carcinoma, cancer of the stomach, large bowel cancer, colorectal carcinoma, breast tumor, nasopharyngeal carcinoma, cervical cancer, lymphoma, tumor of prostate or leukemia.
9, as application, it is characterized in that described tumor disease is a liver tumor according to claim 8.
10, the synthetic method of the compound shown in a kind of general formula 1 may further comprise the steps:
Under the effect of pyridylacetic acid(HPAC) acid anhydride, the hydroxyl in the glycan molecule carried out the acetylize protection; then under the effect of red phosphorus/bromine water, carry out 1 bromo; with the ZCVI4 condensation, condensation product deacetylation in sodium methylate/ethanol/methylene makes compound of Formula I then.
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| CN101812059A (en) * | 2010-04-14 | 2010-08-25 | 中国药科大学 | Nitric oxide donor-type farnesyl thiosalicylic acid derivative, and preparation method and medical application thereof |
| CN107501272A (en) * | 2017-09-05 | 2017-12-22 | 中国药科大学 | Imidazo isoindoles IDO1 inhibitor, its preparation method and application |
| CN110669223A (en) * | 2019-09-19 | 2020-01-10 | 暨南大学 | Glucan grafted dendritic polyamide-amine polymer and preparation method and application thereof |
| CN111789855A (en) * | 2020-07-27 | 2020-10-20 | 大理大学 | Medicinal use of 3β-methanesulfonyloxyoleanolic acid for preparing antiviral hepatitis B |
| CN112175014A (en) * | 2020-10-10 | 2021-01-05 | 中国药科大学 | Nitric oxide donor type tetravalent platinum derivative, preparation method and medical application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101812059A (en) * | 2010-04-14 | 2010-08-25 | 中国药科大学 | Nitric oxide donor-type farnesyl thiosalicylic acid derivative, and preparation method and medical application thereof |
| CN101812059B (en) * | 2010-04-14 | 2012-05-02 | 中国药科大学 | nitric oxide donor type farnesyl thiosalicylic acid derivative, preparation method and medical application thereof |
| CN107501272A (en) * | 2017-09-05 | 2017-12-22 | 中国药科大学 | Imidazo isoindoles IDO1 inhibitor, its preparation method and application |
| CN107501272B (en) * | 2017-09-05 | 2020-03-31 | 中国药科大学 | Imidazoisoindole IDO1 inhibitor, and preparation method and application thereof |
| CN110669223A (en) * | 2019-09-19 | 2020-01-10 | 暨南大学 | Glucan grafted dendritic polyamide-amine polymer and preparation method and application thereof |
| CN111789855A (en) * | 2020-07-27 | 2020-10-20 | 大理大学 | Medicinal use of 3β-methanesulfonyloxyoleanolic acid for preparing antiviral hepatitis B |
| CN112175014A (en) * | 2020-10-10 | 2021-01-05 | 中国药科大学 | Nitric oxide donor type tetravalent platinum derivative, preparation method and medical application thereof |
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