CN101805390B - Tripterine derivate and use thereof - Google Patents
Tripterine derivate and use thereof Download PDFInfo
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Abstract
The invention discloses a tripterine derivate and use thereof. The tripterine derivate has a structure as shown by a formula I. When R2 is H, R1 is alkyl, amine radical, alcohol, aryl, mixed aryl or heterocyclic radical connected with tripterine through ester bonds or amido bonds, and R2 is acyl or organic acid radical when R1 is OH. The tripterine derivate can be used for preparing anticancer medicine, anti-inflammatory medicine or medicine for treating central nervous system diseases. The medicine can be made into tablets, capsules, granules, fine grains, powder, pills, plaser, oral liquid or injections.
Description
Technical field
The invention belongs to technical field of traditional Chinese medicines, particularly a kind of tripterine derivate and uses thereof.
Background technology
With advancing age, the oxidation defense mechanism of body is disorderly, and the oxidative damage that active oxygen radical (ROS) causes also increases thereupon, and research shows that oxidative damage is for example cancer, a local asphyxia etc. of one of reason of numerous disease generation.It is the defense mechanism at center that aerobiont has possessed with the antioxidase the oxidative damage that causes owing to radical, and this balance suffers that destruction will produce oxidative stress and cause cell injury.The oxidative stress effect to as if lipid, protein, nucleic acid.
Brain and nerve are the higher organs of OCR, because contain a large amount of lipids, easily because radical causes the oxidative stress fragility that becomes, neurocyte is owing to being well differentiated division thesocyte, thereby causes accumulating of damage easily.Neurodegenerative disorders is one of the most common disease of neural system, like presenile dementia (AD), and parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD) etc.Along with the increase of elderly population, these diseases relevant with the age are also raising.Cause the reason of these diseases not clear, except patient parkinson possibly treat, other several kinds of diseases can't be treated at all.Found out at present the primary hazard factor that causes these diseases: aging is the most common factor of AD, PD, ALS and HD, and aging is relevant with the oxidative damage that the forfeiture and the radical of mitochondrial function cause.In addition, chronic, the programmed cell death of aging, plastosome loss of function and oxidative damage pair cell play an important role.
Heat shock protein(HSP) (HSP) is the protein of one type of high conservative, is prevalent in the biomass cells, and wherein of paramount importance is Hsp70; It is in stress response, and particularly when thermal stimulus, inducibility is the most remarkable; Resultant quantity is maximum, is one type of heat shock protein(HSP) that people stress to study.Its major function be the protection various stress due to cell injury.Its provide protection mechanism is: 1. as Chaperones Molecular, help proteinic correct folding; 2. function and the indirect expression level that improves anti-withering protein BCL2 through the short apoptosis protein of direct inhibition suppresses apoptosis.Multiple stressors can be induced the expression of Hsp70.
Trypterygine (Trypterygium wilfordii Hook F.) is the perennial vine of Celastraceae Thunder God Calamus, and its plant resources is distributed in all province on the south the Changjiang river, because of all poisonous event of its stem, leaf and root Fujian people is called " mountain arsenic ".The 1950's, domesticly begin to have the traditional Chinese medical science that trypterygine is used to treat rheumatoid arthritis, chronic nephritis, lupus erythematosus and psoriatic.Tripterine (Celastrol, Tripterine) has another name called celastrin, is one and has multiple bioactive natural product, derives from the root skin of Chinese medicine trypterygine.Triterpene compound, red crystalloid powder.Structure is following:
Tripterine action range in the traditional Chinese medicine; Have anti-inflammatory and immunosuppressive action; It is sick to be mainly used in treatment of arthritis, lupus, amyotrophia spinalis progressiva and Alzheimer ' s, and Tripterine has antiproliferative effect, can be used for the hyperplasia of various tumor cell lines.
Tripterine is first monomer that from trypterygine, is separated to, and its pharmacological research had sporadicly in the seventies in last century to be carried out.To the latter stage eighties, affirm in curative effect aspect the clinical application because of trypterygine, further promoted pharmacological research to this effective ingredients in plant.
The eighties of last century latter stage eighties, the trypterygine clinical application shows that this conventional medicament rheumatism is evident in efficacy.Rheumatosis and inflammation close association are so to the influence of inflammation, become red pigment pharmacological research preferred object.This research in period shows that red pigment is inhibited to multiple inflammation/immunity-associated cell.Comprise macrophage phagocytic function is suppressed, lymphopoiesis is suppressed, and to the inhibition of inflammatory model in the body etc.To the nineties, begin that red pigment is suppressed the immunity-associated cell mechanism of proliferation and study, the result finds why other red pigment of micromole's level can suppress cell proliferation, is cell death inducing.Discover that further micromole's rank red pigment all has apoptosis-induced effect to various kinds of cell, caused 2 results thus: 1. red pigment is developed dim future as anti-inflammatory drug.Because apoptosis-induced have killing action to various kinds of cell exactly, is toxic action, use in vivo, will cause severe side effect, particularly prolonged application.2. adjust research direction.Apoptosis-induced new application, the i.e. antitumor action of having inspired of red pigment.From the later stage nineties, the main body of relevant red pigment research has turned to antitumor.Along with carrying out of this area research, red pigment has also wide-scale distribution of highly toxic idea, and influence so far.According to Zhang Lifen, Tripterine can suppress Interleuk in (IL)-1 β reduces the NF-kB activity, and downward modulation cyclooxygenase-2 (CoX-2) mRNA makes the release of PGE2 be suppressed and reduce the secretion and the expression of cell adhesion molecule, alleviates local inflammation.Xu Weimin etc. have reported that Tripterine 0.1-1.0g/ml can reduce the outer activity with the interior interleukin-1 (IL-1) of cell of LPS inductive Turnover of Mouse Peritoneal Macrophages in vitro; Also can suppress the interleukin II (IL-2) that ConA inductive mouse boosting cell produces; In addition, Tripterine can reduce the rabbit synovial cell and discharges PGE
2(PEGE
2).Tripterine also can play anti-inflammatory action through suppressing NF-κ B and NO product.The Tripterine of lower concentration (2-200nM) does not have CDCC, and opposite expression that but can the inflammation-inhibiting factor comprises the NOS (iNOS) of IL-1 β, TNF-α, PGE2 and induction type.In LPS inductive BV-2 neurogliocyte, Tripterine can the MAPK signal transduction and NF-κ B suppress the generation of a series of inflammatory factors such as NO and TNF-α, IL-1 β.
As far back as the sixties in 20th century, people have found that Tripterine has stronger antitumor action.CASnet report on May 18th, 2006: Wuhan Botanical Garden, Chinese Acadmey of Sciences and U.S. scientist coact and have carried out the anticancer research of Chinese medicine trypterygine; In body, the research of external anticancer mechanism confirms: the anticancer active constituent Tripterine in the trypterygine is through the proteasome of control cancer cell and then brings out the suppressor factor of cancer cell-apoptosis that the experiment proof has effectively suppressed the hyperplasia of nude mice prostate cancer.Research finds that also in Panc-1 cell Celastrol can inducible protein enzyme body target protein p27 and the accumulation of InBa; And; Celastrol is different from other classical proteasome inhibitors (MG132 and lactacystin), thereby it is through interrupting the downward modulation of Hsp90 and Cdc37 interaction causing Hsp90 " client " protein expression.Tripterine (the IC of high density
50=2.5 μ M) can cell death inducing, shown anti-tumor activity.
Tested the active compound that 1040 NINDS (U.S. state-run sacred disease institute) collect in " chemical inhibitor of accumulation is regulated in the reverse of total length variation huntington neuronal cell phenotype through polymerization L-glutamic acid ", only found the half inhibiting rate IC of 10 compounds polymerization L-glutamic acid adjusting accumulation
50Less than the chemical inhibitor of 15 μ M, wherein Tripterine can also reverse total length variation huntington neuronal cell phenotype, is expected to be used for the Heng Tingdunshi treatment of diseases.Research shows that Tripterine is effective at aspects such as treatment nerve degenerative diseases ALS, PD, AD and huntingtons.In the fruit bat DJ-IA parkinson model, Tripterine can effectively alleviate the decline of DNs and dopamine level, can improve memory and learning capacity in Alzheimer ' the s rat model.The expression of the Hsp70 of Tripterine in can the Induction of dopaminergic neurone; Suppress tumor necrosis factor TNF-alpha, the expression of nuclear factor NF-κ B and the hyperplasia of astroglia cell; Protection is expected to become a neuroprotective and is used for treating parkinson's disease and Heng Tingdunshi disease by MPTP and 3-nitropropionic acid inductive neurotoxicity.In amyotrophic lateral sclerosis ALS transgene mouse model, the apoptosis that Tripterine can suppress neuronal cell prolongs the living life-span of mouse.Therefore, to be used to treat various nerve degenerative diseases prospects as neuroprotective drug extensive for Tripterine.
Publication number is that the Chinese patent of CN00107779.1 discloses the application of a kind of tripterygium plant extract aspect prevention and treatment nervous system disorders; Said nervous system disorders comprises alzheimer disease, Parkinson's disease, Heng Tingdunshi nerve degenerative diseases and Spinal injury, lateral spinal sclerosis disease; But this patent not illustrative Tripterine is an effective constituent, does not also have the content of illustrative Tripterine.Publication number is that the one Chinese patent application of CN200610200582.3 discloses " prevention and treatment disease of nerve damage tripterine capsule and preparation method thereof and usage "; The utilization Tripterine is the composite trehalose of main raw material, processes capsule and is used to treat nerve injury property disease.USA patent 5,880116 (1999) " Tripterine is used to treat alzheimer's disease ", this patent relate to Radix Tripterygii Wilfordii extract for taking medicine, relevant dose with take method.Application number is 20040220267 USA patent " verivate of five rings demethyl three obedient quinones is used for inflammation, nerve damage and tumor disease "; This patented claim discloses uses the Tripterine and the verivate of Celastrol,methyl ester such as the acetylate of their dihydro thing and dihydro thing to treat inflammation, nerve damage and tumor disease, and the preparation method of verivate.Present domestic patent mainly concentrates on the research of preparation liposome, crosslinked body, capsule and salt and pharmacologically active aspect about the research of Tripterine.
Summary of the invention
For overcoming the deficiency that exists in the above-mentioned prior art, primary and foremost purpose of the present invention is to provide a kind of tripterine derivate.
Another purpose of the present invention is to provide the purposes of above-mentioned tripterine derivate.
The object of the invention is realized through following technical proposals: a kind of tripterine derivate has suc as formula the structure shown in the I:
Wherein, when R2 was H, R1 was alkyl, amido, alcohol, aryl, heteroaryl or the heterocyclic radical that links to each other with Tripterine with ester bond or amido linkage;
When R1 was OH, R2 was acyl group or organic acid.
Said alkyl is that carbonatoms is 1～10 hydrocarbon; Said amido is methylamino, ethylamino-, Propylamino, isopropylamine base, butylamine base, piperazinyl or N-substituted piperazinyl; Said alcohol is first hydroxyl, second hydroxyl, third hydroxyl, different third hydroxyl or fourth hydroxyl; Said aryl is a phenyl or naphthyl; Said heteroaryl is pyrryl, pyridyl, 2-furyl or thienyl; Said heterocyclic radical is 5 yuan～6 yuan rings of nitrogenous, oxygen or sulphur; Said acyl group is the acyl group that has sulfur heterocyclic ring, nitrogen heterocyclic ring and oxygen heterocyclic ring; Said organic acid is fatty acid radical or fragrant acid group, and said fatty acid radical is acetate moiety, propionate, butyric acid root, malonate, acetone acid group, cinnamate, amber acid radical, citrate, lactate, glucose acid group, Thioctic Acid root, N-acetylcystein or amino acid group; Said fragrant acid group is benzoate anion or pyrazine acid group.
Said amido is preferably piperazinyl or N-substituted piperazinyl; Said organic acid is preferably Thioctic Acid root or pyrazine acid group.
Said tripterine derivate is preferably:
Said tripterine derivate also is preferably:
Said tripterine derivate also is preferably:
Above-mentioned tripterine derivate is as the purposes of preparation cancer therapy drug.
Above-mentioned tripterine derivate is as the purposes of preparation anti-inflammatory drug.
Above-mentioned tripterine derivate is as the purposes of the medicine of preparation treatment central nervous system disease.Said central nervous system disease comprises Parkinson's disease (PD), alzheimer disease (AD), Heng Tingdunshi disease (HD), lateral spinal sclerosis nerve degenerative diseases such as (ALS).
Said medicine is processed tablet, capsule, granule, granula subtilis, pulvis, pill, patch, oral liquid or injection.
" pharmaceutically acceptable " refers in compound such as salt or vehicle does not have unacceptable toxicity.Pharmacy acceptable salt comprises inorganic anion, for example cl ions, bromide anion, iodide ion, sulfate radical, inferior sulfate radical, nitrate radical, nitrite anions, phosphate radical etc.Organic anion comprises acetate moiety, acetone acid group, propionate, cinnamate, tosylate, citrate, lactate, glucose acid group etc.Pharmaceutically acceptable vehicle is referring to E.W.Martin, in Remington ' s PharmaceuticalSciences Mack Publishing Company (1995), Philadelphia, PA, 19
ThAmong the ed.
Compared with prior art, the present invention has following beneficial effect: (1) the present invention has carried out structural modification to Tripterine and has measured some biological activitys of verivate; External anti-tumor activity shows that wherein most of tripterine derivate all shows stronger anti tumor activity in vitro to knurl strain PC12 and C6; Wherein compound 1～7 and compound 13 are suitable basically with parent compound; But no matter parent compound or prodrug, all active strong than positive control drug cis-platinum; The IC of Cel-1, Cel-3, Cel-6 and Cel-13
50Value is less than Tripterine, so the anti tumor activity in vitro of these several compounds is all strong than parent.(2) to Tripterine and verivate thereof to t-BHP inductive cell injury provide protection research in; All compounds comprise that the parent Tripterine does not all play a protective role at lower concentration in the concentration of being tested; The high density part of compounds shows provide protection; And Tripterine does not act in high density, and wherein Cel-6, Cel-7 and Cel-13 show stronger provide protection; (3) the present invention has studied the expression that Tripterine and tripterine derivate of the present invention are induced Hsp70; Measured the expression amount of Hsp70 earlier through Western Blotting Assay; T-BHP induces after the PC12 cell injury, and the expression amount of Hsp70 is obviously reduced, and after with Tripterine and Cel-13 pre-treatment; Expressing quantity significantly raises, and expression amount has surpassed control group under some concentration.To sum up, tripterine derivate of the present invention can provide than the effective more medicine of Tripterine.
Description of drawings
Fig. 1 is the synthetic route chart of tripterine derivate Cel-1～Cel-6 and Cel-14.
Fig. 2 is the synthetic route chart of tripterine derivate Cel-7～Cel-10.
Fig. 3 is the synthetic route chart of tripterine derivate Cel-11 and Cel-13.
Fig. 4 is the synthetic route chart of tripterine derivate Cel-12.
Fig. 5 is the provide protection synoptic diagram of tripterine derivate to t-BHP inductive cell injury; Wherein Fig. 5 a is the provide protection synoptic diagram of tripterine derivate Cel-1～Cel-6 to t-BHP inductive cell injury, and Fig. 5 b is the provide protection synoptic diagram of tripterine derivate Cel-7～Cel-13 to t-BHP inductive cell injury.
Fig. 6 is the regulating effect synoptic diagram of tripterine derivate to Hsp70.
Embodiment
Below in conjunction with embodiment the present invention is done further detailed description, but embodiment of the present invention is not limited thereto.
(20mg 0.044mmol) is dissolved in N to Tripterine, and dinethylformamide (1ml) stirring and dissolving adds NaHCO
3(19mg, 0.22mmol), the back adds methyl iodide (0.22mmol).Stirring reaction is 2 hours under the room temperature, and stopped reaction adds deionized water (15ml), ethyl acetate extraction 3 times, and the combined ethyl acetate layer, ethyl acetate layer is washed 3 times with saturated NaCl then, anhydrous Na
2SO
4Drying, Rotary Evaporators concentrate scarlet oily matter.(ETHYLE ACETATE: method separation and purification normal hexane), product gets dark red solid Cel-1 17mg, productive rate 83% through vacuum-drying to crude product through rapid column chromatography.
The mass spectroscopy of Compound C el-1 is as follows: MS (EI) [M+H]
+M/z 465.6.MS (EI) [M+Na-H]
+M/z 487.4.
1H NMR (CDCl
3, 400MHz): δ 7.09 (1H, dd, J=1,7Hz, H-6), 6.52 (1H, d, J=1Hz, H-1), 6.28 (1H, d, J=7Hz, H-7), 2.15 (3H, s, 4-CH3), 1.37 (3H, s, 9-CH
3), 1.21,1.18,1.03 (3 * 3H, s, 13-CH
3, 14-CH
3, 17-CH
3), 0.52 (3H, s, 20-CH
3).
(20mg 0.044mmol) is dissolved in N to Tripterine, and dinethylformamide (1ml) stirring and dissolving adds NaHCO
3(19mg, 0.22mmol), the back adds monobromethane (0.22mmol).Stirring reaction is 24 hours under the room temperature, and stopped reaction adds deionized water (15ml), ethyl acetate extraction 3 times, and the combined ethyl acetate layer, ethyl acetate layer is washed 3 times with saturated NaCl then, anhydrous Na
2SO
4Drying, Rotary Evaporators concentrate scarlet oily matter.(ETHYLE ACETATE: method separation and purification normal hexane), product gets dark red solid Cel-2 19mg, productive rate 90% through vacuum-drying to crude product through rapid column chromatography.
The mass spectroscopy of Compound C el-2 is as follows: MS (EI) [M+H]
+M/z 479.9.
1H NMR (CDCl
3, 400MHz): δ 7.03 (1H, dd, J=1.3,7.1Hz, H-6), 6.56 (1H, d, J=1.4Hz, H-1), 6.37 (1H, d, J=7.2Hz, H-7), 4.0 (2H, m, H-1 '), 2.23 (3H, s, 4-CH3), 1.48 (3H, s, 9-CH
3), 1.29 (3H, s, 13-CH
3), 1.22 (3H, t, 2 '-CH
3), 1.20 (3H, s, 14-CH
3), 1.12 (3H, s, 17-CH
3), 0.59 (3H, s, 20-CH
3) .HRMS m/z: [M+H] calcd forC
31H
42O
4, 479.3156; Found, 479.3169.
(20mg 0.044mmol) is dissolved in N to Tripterine, and dinethylformamide (1ml) stirring and dissolving adds NaHCO
3(19mg, 0.22mmol), the back adds N-PROPYLE BROMIDE (0.22mmol).Stirring reaction is 24 hours under the room temperature, and stopped reaction adds deionized water (15ml), ethyl acetate extraction 3 times, and the combined ethyl acetate layer, ethyl acetate layer is washed 3 times with saturated NaCl then, anhydrous Na
2SO
4Drying, Rotary Evaporators concentrate scarlet oily matter.(ETHYLE ACETATE: method separation and purification normal hexane), product gets dark red solid Cel-3 16mg, productive rate 74% through vacuum-drying to crude product through rapid column chromatography.
The mass spectroscopy of Compound C el-3 is as follows: MS (EI) [M+H]
+M/z493.6.
1H NMR (CDCl
3, 400MHz): δ 7.04 (1H, dd, J=1.4,7.1Hz, H-6), 6.60 (1H, d, J=1.4Hz, H-1), 6.37 (1H, d, J=7.2Hz, H-7), 3.94 (2H, m, H-1 '), 1.85 (1H, m, H-2 ' a), 1.73 (1H, m, H-2 ' b), 2.23 (3H, s, 4-CH
3), 1.48 (3H, s, 9-CH
3), 1.25 (3H, s, 13-CH
3), 1.20 (3H, s, 14-CH
3), 1.10 (3H, s, 17-CH
3), 0.96 (3H, s, 3 '-CH
3), 0.90 (3H, s, 20-CH
3).
(20mg 0.044mmol) is dissolved in N to Tripterine, and dinethylformamide (1ml) stirring and dissolving adds NaHCO
3(19mg, 0.22mmol), the back adds butyl iodide (0.22mmol).Stirring reaction is 24 hours under the room temperature, and stopped reaction adds deionized water (15ml), ethyl acetate extraction 3 times, and the combined ethyl acetate layer, ethyl acetate layer is washed 3 times with saturated NaCl then, anhydrous Na
2SO
4Drying, Rotary Evaporators concentrate scarlet oily matter.(ETHYLE ACETATE: method separation and purification normal hexane), product gets dark red solid Cel-4 13mg, productive rate 58% through vacuum-drying to crude product through rapid column chromatography.
The mass spectroscopy of Compound C el-4 is as follows: MS (EI) [M+H]
+M/z 507.8.
1H NMR (CDCl
3, 400MHz): δ 7.03 (1H, dd, J=1.4,7.1Hz, H-6), 6.55 (1H, d, J=1.4Hz, H-1), 6.36 (1H, d, J=7.2Hz, H-7), 3.95 (2H, m, H-1 '), 2.23 (3H, s, 4-CH
3), 1.47 (3H, s, 9-CH
3), 1.28 (3H, s, 13-CH
3), 1.19 (3H, s, 14-CH
3), 1.11 (3H, s, 17-CH
3), 0.94 (3H, s, 4 '-CH
3), 0.58 (3H, s, 20-CH
3) .HRMS m/z: [M+H] calcd forC
33H
46O
4, 507.1569; Found, 507.1469.
(20mg 0.044mmol) is dissolved in N to Tripterine, and dinethylformamide (1ml) stirring and dissolving adds NaHCO
3(19mg, 0.22mmol), the back adds bromotoluene (0.22mmol).Stirring reaction is 24 hours under the room temperature, and stopped reaction adds deionized water (15ml), ethyl acetate extraction 3 times, and the combined ethyl acetate layer, ethyl acetate layer is washed 3 times with saturated NaCl then, anhydrous Na
2SO
4Drying, Rotary Evaporators concentrate scarlet oily matter.(ETHYLE ACETATE: method separation and purification normal hexane), product gets dark red solid Cel-5 22mg, productive rate 92% through vacuum-drying to crude product through rapid column chromatography.
The mass spectroscopy of Compound C el-5 is as follows: MS (EI) [M+H]
+M/z 542.0.
1H NMR (CDCl
3, 400MHz): δ 7.62 (2H, m, H-4 ', 6 '), 7.26 (3H, m, H-3 '; 5 ', 7 '), 6.94 (1H, d, J=6.9Hz, H-6), 6.29 (1H, d; J=6.0Hz, H-1), 5.43 (1H, s, H-7), 4.97 (1H, d, J=12.4Hz; H-1 ' a), 4.85 (1H, d, J=12.4Hz, H-1 ' b), 2.10 (3H, s, 4-CH
3), 1.53 (3H, s, 9-CH
3), 1.36 (3H, s, 13-CH
3), 1.14 (3H, s, 14-CH
3), 1.05 (3H, s, 17-CH
3), 0.43 (3H, s, 20-CH
3) .HRMS m/z: [M+H] calcd for C
36H
44O
4, 540.5350; Found, 540.5354.
(20mg 0.044mmol) is dissolved in N to Tripterine, and dinethylformamide (1ml) stirring and dissolving adds catalyzer EDCI (43mg; 0.22mmol), HOBT (30mg, 0.22mmol) stirring makes its dissolving, adds N methyl piperazine (13mg; 0.13mmol) stirring at room reacted about 36 hours, stopped reaction adds deionized water (15ml), ethyl acetate extraction 3 times; The combined ethyl acetate layer, ethyl acetate layer is washed 3 times with saturated NaCl then, anhydrous Na
2SO
4Drying, Rotary Evaporators concentrate garnet oily matter.(ETHYLE ACETATE: method separation and purification normal hexane), product gets garnet solid Cel-6, productive rate 34% through vacuum-drying to crude product through rapid column chromatography
The mass spectroscopy of Compound C el-6 is as follows: MS (EI) [M+H]
+M/z 534.1.
1H NMR (CDCl
3, 400MHz): δ 7.03 (1H, dd, J=1.3,7.2Hz, H-6), 6.53 (1H, d, J=1.3Hz, H-1), 6.37 (1H, d, J=7.2Hz, H-7), 3.6 (2H, t, J=10.2,1 '-H), 3.42 (2H, t, J=12.5,4 '-H), 2.3 (3H, s, 5 '-CH
3), 2.23 (3H, s, 4-CH
3), 2.17 (2H, t, J=14,2 '-H), 1.48 (3H, s, 9-CH
3), 1.31 (3H, s, 13-CH
3), 1.30 (3H, s, 14-CH
3), 1.17 (3H, s, 17-CH
3), 0.60 (3H, s, 20-CH
3) .HRMS m/z: [M+H] calcd for C
34H
48N
2O
3, 533.5014; Found, 533.5020.
(20mg 0.044mmol) is dissolved in methylene dichloride (2ml) and adds and mix dissolving Tripterine, adds triethylamine (100 μ l); Add corresponding Acetyl Chloride 98Min., reaction 30min, stopped reaction adds deionized water (15ml); Dichloromethane extraction 3 times; The combined dichloromethane layer, dichloromethane layer is washed 3 times with saturated NaCl then, anhydrous Na
2SO
4Drying, Rotary Evaporators concentrate yellow solid.(ETHYLE ACETATE: method separation and purification normal hexane), product gets yellow solid Cel-7 11mg, productive rate 51% through vacuum-drying to crude product through rapid column chromatography.
The mass spectroscopy of Compound C el-7 is as follows: MS (EI) [M+H]
+M/z 493.9.
1H NMR (CDCl
3, 400MHz): δ 7.06 (1H, dd, J=1.3,7.1Hz, H-6), 6.54 (1H, d, J=1.3Hz, H-1), 6.33 (1H, d, J=7.1Hz, H-7), 2.37 (3H, s, 4-CH
3), 2.17 (3H, s, 1 '-CH
3), 1.49 (3H, s, 9-CH
3), 1.25 (3H, s, 13-CH
3), 1.12 (3H, s, 14-CH
3), 1.0 (3H, s, 17-CH
3), 0.71 (3H, s, 20-CH
3).
(20mg 0.044mmol) is dissolved in methylene dichloride (2ml) and adds and mix dissolving Tripterine, adds triethylamine (100 μ l); DMAP (22mg, 0.22mmol) add corresponding propionic anhydride (29 μ l, 0.22mmol); Reaction 30min, stopped reaction adds deionized water (15ml), dichloromethane extraction 3 times; The combined dichloromethane layer, dichloromethane layer is washed 3 times with saturated NaCl then, anhydrous Na
2SO
4Drying, Rotary Evaporators concentrate yellow solid.(ETHYLE ACETATE: method separation and purification normal hexane), product gets yellow solid Cel-8 13mg, productive rate 58% through vacuum-drying to crude product through rapid column chromatography.
The mass spectroscopy of Compound C el-8 is as follows: MS (EI) [M+H]
+M/z 507.9.
1H NMR (CDCl
3, 400MHz): 7.04 (1H, dd, J=1.4,7.1Hz, H-6), 6.60 (1H, d, J=1.4Hz, H-1), 6.37 (1H, d, J=7.2Hz, H-7), 3.94 (2H, m, H-1 '), 1.85 (1H, m, H-2 '), 2.23 (3H, s, 4-CH
3), 1.48 (3H, s, 9-CH
3), 1.25 (3H, s, 13-CH
3), 1.20 (3H, s, 14-CH
3), 1.10 (3H, s, 17-CH
3), 0.96 (3H, s, 3 '-CH
3), 0.90 (3H, s, 20-CH
3).
(20mg 0.044mmol) is dissolved in methylene dichloride (2ml) and adds and mix dissolving Tripterine, adds triethylamine (100 μ l); DMAP (22mg, 0.22mmol) add corresponding butyryl oxide (36 μ l, 0.22mmol); Reaction 30min, stopped reaction adds deionized water (15ml), dichloromethane extraction 3 times; The combined dichloromethane layer, dichloromethane layer is washed 3 times with saturated NaCl then, anhydrous Na
2SO
4Drying, Rotary Evaporators concentrate yellow solid.(ETHYLE ACETATE: method separation and purification normal hexane), product gets yellow solid Cel-9 9mg, productive rate 39% through vacuum-drying to crude product through rapid column chromatography.
The mass spectroscopy of Compound C el-9 is as follows: MS (EI) [M+H]
+M/z 521.8.
1H NMR (CDCl
3, 400MHz): 7.05 (1H, dd, J=1.2,7.0Hz, H-6), 6.50 (1H, d, J=1.3Hz, H-1), 6.33 (1H, d, J=7.1Hz, H-7), 2.16 (3H, s, 4-CH
3), 2.05 (2H, m, H-2 '), 1.82 (2H, m, H-3 '), 1.49 (3H, s, 9-CH
3), 1.45 (3H, s, 13-CH
3), 1.26 (3H, s, 14-CH
3), 1.08 (3H, s, 17-CH
3), 0.91 (3H, t, 4 '-CH
3), 0.72 (3H, s, 20-CH
3).
(20mg 0.044mmol) is dissolved in methylene dichloride (2ml) stirring and dissolving to Tripterine, adds triethylamine (100 μ l); DMAP (22mg, 0.22mmol) add corresponding isobutyric anhydride (37 μ l, 0.22mmol); Reaction 30min, stopped reaction adds deionized water (15ml), dichloromethane extraction 3 times; The combined dichloromethane layer, dichloromethane layer is washed 3 times with saturated NaCl then, anhydrous Na
2SO
4Drying, Rotary Evaporators concentrate yellow solid.(ETHYLE ACETATE: method separation and purification normal hexane), product gets yellow solid Cel-10 17mg, productive rate 74% through vacuum-drying to crude product through rapid column chromatography.
The mass spectroscopy of Compound C el-10 is as follows: MS (EI) [M-H]
+M/z 519.4.
1H NMR (CDCl
3, 400MHz): 7.04 (1H, dd, J=1.4,7.0Hz, H-6), 6.49 (1H, d, J=1.4Hz, H-1), 6.33 (1H, d, J=7.1Hz, H-7), 2.91 (1H, m, H-2 '), 2.15 (3H, s, 4-CH
3), 1.49 (3H, s, 9-CH
3), 1.38 (3H, s, 13-CH
3), 1.36 (3H, s, 14-CH
3), 1.13 (3H, s, 17-CH
3), 0.99 (6H, m, 3 '-CH
3, 4 '-CH
3), 0.73 (3H, s, 20-CH
3).
(46mg 0.22mmol) is dissolved in N to Thioctic Acid, and dinethylformamide (1ml) stirring and dissolving adds catalyzer DCC (46mg; 0.22mmol), DMAP (27mg, 0.22mmol) stirring makes its dissolving, and activation is 40 minutes under the ice bath; Then reaction is placed under the room temperature, and the adding Tripterine (20mg, 0.044mmol); Stirring at room was reacted about 24 hours, reaction system color flavescence gradually in the reaction process, and constantly have solid to separate out.Reaction stops, and insolubles is removed by filter, and adds deionized water then, adds dichloromethane extraction 3 times, the combined dichloromethane layer, and dichloromethane layer is washed 3 times with frozen water, anhydrous Na
2SO
4Drying, Rotary Evaporators concentrate yellow oil.(ETHYLE ACETATE: method separation and purification normal hexane), product gets yellow oily solid Cel-11, productive rate 25% through vacuum-drying to crude product through rapid column chromatography.
The mass spectroscopy of Compound C el-11 is as follows: MS (EI) [M+H]
+M/z 639.9.
1H NMR (CDCl
3, 400MHz): 7.57 (1H, dd, J=3.4,9.0Hz, H-6), 7.15 (1H, d, J=7.0Hz, H-1), 6.30 (1H, d, J=6.4Hz, H-7), 2.10 (3H, s, 4-CH3), 1.42 (3H, s, 9-CH
3), 1.24 (3H, s, 13-CH
3), 1,21 (3H, s, 14-CH
3), 1.19 (3H, s, 17-CH
3), 0.62 (3H, s, 20-CH
3).
Tripterine (20mg, 0.044mmol) room temperature is dissolved in 450 μ L pyridines, stirring and dissolving, (7mg, 2equiv), 70 ℃ of heated and stirred are spent the night to add oxammonium hydrochloride.Reaction stops, and adds toluene 20ml in the reaction system, and Rotary Evaporators concentrates, and this step repeats 3 times at least, is tied to form oily liquids to reactant.Reaction solution is dissolved in methylene dichloride, and saturated NaCl washes 3 times, anhydrous Na
2SO
4Drying, Rotary Evaporators concentrates.(ETHYLE ACETATE: method separation and purification normal hexane), product gets garnet look solid Cel-12 12mg, productive rate 58% through vacuum-drying to crude product through rapid column chromatography.
The mass spectroscopy of Compound C el-12 is as follows: MS (EI) [M+H]
+M/z 467.7.
1H NMR (CDCl
3, 400MHz): 7.55 (1H, dd, J=1,7.6Hz, H-6), 7.3 (1H, d, J=1.3Hz, H-1), 7.07 (1H, d, J=7Hz, H-7), 2.15 (3H, s, 4-CH3), 1.37 (3H, s, 9-CH
3), 1.24 (3H, s, 13-CH
3), 1.21 (3H, s, 14-CH
3), 1.19 (3H, s, 17-CH
3), 0.90 (3H, s, 20-CH
3).
(20mg 0.044mmol) is dissolved in N to Tripterine, and dinethylformamide (1ml) stirring and dissolving adds catalyzer DCC (46mg; 0.22mmol), DMAP (27mg, 0.22mmol) stirring makes its dissolving, adds TMP acid (37mg; 0.22mmol 5equiv) stirring at room was reacted about 36 hours, stopped reaction adds deionized water (15ml), ethyl acetate extraction 3 times; The combined ethyl acetate layer, ethyl acetate layer is washed 3 times with saturated NaCl then, anhydrous Na
2SO
4Drying, Rotary Evaporators concentrate garnet oily matter.(ETHYLE ACETATE: method separation and purification normal hexane), product gets garnet solid Cel-13, productive rate 23% through vacuum-drying to crude product through rapid column chromatography.
The mass spectroscopy of Compound C el-13 is as follows: MS (EI) [M+H]
+M/z 599.7. δ 7.40 (1H, d, J=6.7Hz, H-6), 6.85 (1H, s, H-1), 6.00 (1H, d, J=6.0Hz, H-7), 2.21 (3H, s, 2 '-CH
3), 2.14 (3H, s, 4 '-CH
3), 2.10 (3H, s, 5 '-CH
3), 2.00 (3H, s, 4-CH
3), 1.47 (3H, s, 9-CH
3), 1.27 (3H, s, 13-CH
3), 1.24 (3H, s, 14-CH
3), 1.20 (3H, s, 17-CH
3), 0.69 (3H, s, 20-CH
3).
Embodiment 14 preparation 28-Ligustrazine Tripterine ester Cel-14 (synthetic route chart is as shown in Figure 1)
Tripterine (20mg 0.044mmol) is dissolved in methylene dichloride (2ml) and adds and mix dissolving, add catalyzer DCC (46mg, 0.22mmol); DMAP (27mg 0.22mmol) stirs and to make its dissolving, room temperature activation 30min, add come by the TMP oxidation (3; 5,6-trimethylpyrazin-2-yl) methanol (20mg, 0.132mmol); Stirring at room reaction 24 hours, stopped reaction adds deionized water (15ml), ethyl acetate extraction 3 times; The combined ethyl acetate layer, ethyl acetate layer is washed 3 times with saturated NaCl then, anhydrous Na
2SO
4Drying, Rotary Evaporators concentrate garnet oily matter.(ETHYLE ACETATE: method separation and purification normal hexane), product gets faint yellow solid 11mg through vacuum-drying to crude product, productive rate 44% through rapid column chromatography.
The mass spectroscopy of compound is as follows: MS (EI) [M+H]
+M/z 571.
The anti tumor activity in vitro test that the Tripterine of the present invention that embodiment 15 prepares is biological
With PC12 cell (1.0 * 10
5Cells/mL) be inoculated in (100 μ L/ hole) in 96 well culture plates respectively, place 37 ℃, 5%CO
2Cultivate in the incubator and add tripterine derivate and the positive control medicine cis-platinum (DDP, 10 μ L/ holes) that contains serial ratio of two term weaker concn after 24 hours.Place 37 ℃, at 5%CO
2With cultivate 48h in the incubator of saturated humidity.
With C6 cell (3.0 * 10
4Cells/mL) be inoculated in (100 μ L/ hole) in 96 well culture plates respectively, place 37 ℃, 5%CO
2Cultivate in the incubator and add tripterine derivate and the positive control medicine cis-platinum (DDP, 10 μ L/ holes) that contains serial ratio of two term weaker concn after 24 hours.Place 37 ℃, at 5%CO
2With cultivate 48h in the incubator of saturated humidity.The MTT (20 μ L/ hole) that adds 5mg/mL, behind the mixing under 37 ℃, 5%CO
2Hatched under the condition 4 hours.Add DMSO (150 μ L/ hole), the crystallization of dissolving hyacinthine is measured (570/490nm) absorbancy (OD value) with ELIASA.Calculate the inhibiting rate of compound pair cell.
Verivate of the present invention is seen table 1. to the anti-tumor activity result of PC12 cell, C6
The anti tumor activity in vitro test that table 1. Tripterine is biological
Can find out by table 1; Tripterine derivate Compound C el 1-7 of the present invention and Compound C el-13 all have restraining effect to PC12 cell and C6 cell, and these tripterine derivates all the anti-tumor activity than antitumour drug cis-platinum (DDP) commonly used clinically is strong.Visible from the result, tripterine derivate Cel 8-12 does not have tangible anti-tumor activity.
The tripterine derivate of the present invention that embodiment 16 prepares is to the provide protection of t-BHP inductive cell injury
With PC12 cell (1.0 * 10
5Cells/mL) be inoculated in (100 μ L/ hole) in 96 well culture plates respectively, place 37 ℃, 5%CO
2Cultivation adds the tripterine derivate that contains serial ratio of two term weaker concn in the incubator after 24 hours, places 37 ℃, 5%CO
2Cultivate 1h in the incubator, replace the substratum (final concentration of t-BHP is 200 μ M) that 100 μ L/ holes contain tertbutyl peroxide (t-BHP) then, place 37 ℃, 5%CO
2Cultivated 24 hours in the incubator, add the MTT (20 μ L/ hole) of 5mg/mL, behind the mixing 37 ℃, 5%CO
2Hatched under the condition 4 hours.Add DMSO (150 μ L/ hole), the crystallization of dissolving hyacinthine is measured (570/490nm) absorbancy (OD value) with ELIASA.Calculate the survival rate of respectively organizing cell.
Experimental result (synoptic diagram is as shown in Figure 5 as a result) shows that tripterine derivate of the present invention can play a protective role to the cell injury that t-BHP causes in the concentration degree scope of this experiment.
Embodiment 17 tripterine derivates are to the adjusting of Hsp70
With PC12 cell (1.5-2.0 * 10
6Cells/mL) be inoculated in respectively in the plate of 75mm (1ml/ plate), place 37 ℃, 5%CO
2Cultivation adds the tripterine derivate that contains serial ratio of two term weaker concn in the incubator after 24 hours, places 37 ℃, 5%CO
2Cultivate 1h in the incubator, replace the Medium (final concentration of t-BHP is 200 μ M) that the 4ml/ plate contains t-BHP then, place 37 ℃, 5%CO
2Cultivated 24 hours in the incubator.Conventional method extracts albumen, adopts the BCA method to carry out protein quantification, sample-20 ℃ preservation.Carry out the SDS-PAGE electrophoresis, operate according to Western blot standard step, experimental result adopts Image J software analysis OD value.
Western blot experimental result (synoptic diagram is as shown in Figure 6 as a result) shows, thereby tripterine derivate can play the effect of protection cell through the expression of inducing Hsp70.
The foregoing description is a preferred implementation of the present invention; But embodiment of the present invention is not restricted to the described embodiments; Other any do not deviate from change, the modification done under spirit of the present invention and the principle, substitutes, combination, simplify; All should be the substitute mode of equivalence, be included within protection scope of the present invention.
Claims (4)
1. tripterine derivate is characterized in that: have suc as formula the structure shown in the I:
2. a kind of tripterine derivate according to claim 1 is as the purposes of preparation cancer therapy drug.
3. a kind of tripterine derivate according to claim 1 is as the purposes of preparation anti-inflammatory drug.
4. a kind of tripterine derivate according to claim 1 is as the purposes of the medicine of preparation treatment central nervous system disease.
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| CN114395010B (en) * | 2022-02-18 | 2023-03-17 | 宁夏医科大学 | Tripterine derivative and application thereof in tumor resistance |
| CN114516897B (en) * | 2022-02-18 | 2023-04-28 | 宁夏医科大学 | Tripterine derivative, and preparation method and application thereof |
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