CN110066218B - Bromophenol compound containing isoprene, and preparation method and application thereof - Google Patents
Bromophenol compound containing isoprene, and preparation method and application thereof Download PDFInfo
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- CN110066218B CN110066218B CN201810064534.9A CN201810064534A CN110066218B CN 110066218 B CN110066218 B CN 110066218B CN 201810064534 A CN201810064534 A CN 201810064534A CN 110066218 B CN110066218 B CN 110066218B
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- RRHGJUQNOFWUDK-UHFFFAOYSA-N Isoprene Chemical compound CC(=C)C=C RRHGJUQNOFWUDK-UHFFFAOYSA-N 0.000 title claims abstract description 50
- -1 Bromophenol compound Chemical class 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 40
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 38
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 16
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 13
- 239000003480 eluent Substances 0.000 claims description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 8
- 239000000741 silica gel Substances 0.000 claims description 8
- 229910002027 silica gel Inorganic materials 0.000 claims description 8
- 241000920690 Polysiphonia urceolata Species 0.000 claims description 7
- 238000000605 extraction Methods 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 6
- 239000003801 protein tyrosine phosphatase 1B inhibitor Substances 0.000 claims description 6
- 238000010828 elution Methods 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 102000002727 Protein Tyrosine Phosphatase Human genes 0.000 claims description 4
- 238000001514 detection method Methods 0.000 claims description 4
- 239000012153 distilled water Substances 0.000 claims description 4
- XELZGAJCZANUQH-UHFFFAOYSA-N methyl 1-acetylthieno[3,2-c]pyrazole-5-carboxylate Chemical compound CC(=O)N1N=CC2=C1C=C(C(=O)OC)S2 XELZGAJCZANUQH-UHFFFAOYSA-N 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- 108020000494 protein-tyrosine phosphatase Proteins 0.000 claims description 4
- 238000002791 soaking Methods 0.000 claims description 4
- 239000000725 suspension Substances 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 238000004440 column chromatography Methods 0.000 claims description 3
- 238000011161 development Methods 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 239000000499 gel Substances 0.000 claims description 3
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 3
- 238000011084 recovery Methods 0.000 claims description 3
- 239000012085 test solution Substances 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 2
- 238000003810 ethyl acetate extraction Methods 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- 238000010898 silica gel chromatography Methods 0.000 claims description 2
- 239000000469 ethanolic extract Substances 0.000 claims 2
- 101001087394 Homo sapiens Tyrosine-protein phosphatase non-receptor type 1 Proteins 0.000 abstract description 21
- 230000000694 effects Effects 0.000 abstract description 16
- 102100033001 Tyrosine-protein phosphatase non-receptor type 1 Human genes 0.000 abstract description 15
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 abstract description 6
- 239000002532 enzyme inhibitor Substances 0.000 abstract description 6
- 229940125532 enzyme inhibitor Drugs 0.000 abstract description 6
- 150000002611 lead compounds Chemical class 0.000 abstract description 3
- 241000206572 Rhodophyta Species 0.000 abstract description 2
- 230000002218 hypoglycaemic effect Effects 0.000 abstract description 2
- 241000699670 Mus sp. Species 0.000 description 8
- 238000002386 leaching Methods 0.000 description 7
- 206010022489 Insulin Resistance Diseases 0.000 description 6
- 239000008280 blood Substances 0.000 description 6
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- 238000002474 experimental method Methods 0.000 description 6
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- 102000003746 Insulin Receptor Human genes 0.000 description 3
- 108010001127 Insulin Receptor Proteins 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- VIYFPAMJCJLZKD-UHFFFAOYSA-L disodium;(4-nitrophenyl) phosphate Chemical compound [Na+].[Na+].[O-][N+](=O)C1=CC=C(OP([O-])([O-])=O)C=C1 VIYFPAMJCJLZKD-UHFFFAOYSA-L 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
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- 239000000843 powder Substances 0.000 description 3
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- 241001474374 Blennius Species 0.000 description 2
- 241000195493 Cryptophyta Species 0.000 description 2
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- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical group N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
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- 230000008569 process Effects 0.000 description 2
- 238000004611 spectroscopical analysis Methods 0.000 description 2
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- 239000000758 substrate Substances 0.000 description 2
- 229940126585 therapeutic drug Drugs 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- CPLJMHUGPUAZPQ-UHFFFAOYSA-N CC(C(C(C(CC(C=C1O)=CC(Br)=C1O)=C1Br)=CC(O)=C1O)=C)=C Chemical compound CC(C(C(C(CC(C=C1O)=CC(Br)=C1O)=C1Br)=CC(O)=C1O)=C)=C CPLJMHUGPUAZPQ-UHFFFAOYSA-N 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 1
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 238000009924 canning Methods 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
- OAIVIYSBZFEOIU-UHFFFAOYSA-N chloroform;propan-2-one Chemical compound CC(C)=O.ClC(Cl)Cl OAIVIYSBZFEOIU-UHFFFAOYSA-N 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000000081 effect on glucose Effects 0.000 description 1
- 230000001516 effect on protein Effects 0.000 description 1
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000035558 fertility Effects 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 230000006801 homologous recombination Effects 0.000 description 1
- 238000002744 homologous recombination Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000001823 molecular biology technique Methods 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 238000012289 standard assay Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- IHIXIJGXTJIKRB-UHFFFAOYSA-N trisodium vanadate Chemical compound [Na+].[Na+].[Na+].[O-][V]([O-])([O-])=O IHIXIJGXTJIKRB-UHFFFAOYSA-N 0.000 description 1
- 208000035408 type 1 diabetes mellitus 1 Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/004—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by obtaining phenols from plant material or from animal material
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/68—Purification; separation; Use of additives, e.g. for stabilisation
- C07C37/685—Processes comprising at least two steps in series
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/68—Purification; separation; Use of additives, e.g. for stabilisation
- C07C37/70—Purification; separation; Use of additives, e.g. for stabilisation by physical treatment
- C07C37/72—Purification; separation; Use of additives, e.g. for stabilisation by physical treatment by liquid-liquid treatment
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/68—Purification; separation; Use of additives, e.g. for stabilisation
- C07C37/70—Purification; separation; Use of additives, e.g. for stabilisation by physical treatment
- C07C37/82—Purification; separation; Use of additives, e.g. for stabilisation by physical treatment by solid-liquid treatment; by chemisorption
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
- C07C39/24—Halogenated derivatives
- C07C39/373—Halogenated derivatives with all hydroxy groups on non-condensed rings and with unsaturation outside the aromatic rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Botany (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses an isoprene-containing bromophenol compound, and a preparation method and application thereof, and belongs to the technical field of medical chemistry. The invention aims to find a lead compound with PTP1B enzyme inhibitor function, and a new compound, namely an isoprene-containing bromophenol compound, is extracted, separated and purified from the marine red algae multicystis multicinctus, and the isoprene-containing bromophenol compound has the Chinese name: 5- (2-bromo-3,4-dihydroxy-6- (3-methylbutadien-1, 3-dien-2-yl) benzyl) -3-bromobenzene-1, 2-diol; the structural formula of the compound is shown as a formula I; meanwhile, the invention provides a preparation method of the bromine phenol compound containing isoprene. The compound has PTP1B enzyme inhibitor activity and hypoglycemic activity.
Description
Technical Field
The invention belongs to the technical field of medical chemistry, and particularly relates to an isoprene-containing bromophenol compound, and a preparation method and application thereof.
Background
Diabetes is clinically divided into two types, type 1 and type 2, with type 1 being insulin-dependent diabetes mellitus, type 2 being non-insulin-dependent diabetes mellitus, and about 90% of patients being type 2 diabetes mellitus. With the rapid improvement of living standard, the living style of residents in China is greatly changed, the physical labor is gradually reduced, the daily working intensity is obviously reduced, the number of people sitting still is large, the people lack of exercise and the number of obese people is increased rapidly, the incidence rate of diabetes is further increased, and all in all, the number of diabetes patients, especially type 2 patients, is increased year by year, and effective medicines and treatment are urgently needed.
So far, clinical and basic experimental experts have acknowledged that insulin resistance is a key factor in the development and change process of type 2 diabetes, and a medicament capable of effectively improving insulin resistance can obviously improve clinical symptoms of type 2 diabetes and improve the quality of life. Research on drugs for improving insulin resistance is also a hot research.
With the rapid development of molecular biology techniques, the research on diabetes therapeutic drugs has turned to new drugs targeting specific molecular targets. The literature indicates that the action site of protein tyrosine phosphatase (PTP1B) is an insulin receptor, negatively regulates an insulin signal transduction pathway, and becomes an exact target for researching insulin resistance therapeutic drugs. The most powerful evidence is reported by elchelly et al, who knock out the PTP1B gene of mice to create animal models deficient in the PTP1B gene, and then the PTP1B gene-knocked out mice generated by homologous recombination grow normally, have normal fertility, have significantly enhanced insulin sensitivity compared to the PTP1B gene-containing mice, and this enhancement is associated with the enhancement of the phosphorylation levels of insulin receptors and insulin receptor substrate I in liver and skeletal muscle [ elchelly m. Similar results were obtained in experiments performed by Klaman et al [ Klaman L.D., et al, molecular and Cellular Biology, 20(15): 5479-. These experiments fully demonstrate the important role of PTP1B in insulin sensitivity. Meanwhile, the medicine is an effective medicine action target point for treating type 2 diabetes.
Disclosure of Invention
In order to find a lead compound with the effect of a PTP1B enzyme inhibitor, the invention aims at providing an isoprene-containing bromophenol compound, which is a novel compound extracted, separated and purified from the marine red algae multicystis multocida, and has the activity of the PTP1B enzyme inhibitor and the hypoglycemic activity through activity determination.
Another object of the present invention is to provide a process for producing the above-mentioned isoprene-containing bromophenol compound.
Still another object of the present invention is to provide the use of the above-mentioned isoprene-containing bromophenol compound. The compound can be used as a PTP1B enzyme inhibitor for treating type 2 diabetes, and has pharmacological activity of reducing blood sugar in animal experiments.
The purpose of the invention is realized by the following technical scheme:
an isoprene-containing bromophenol compound, the structure of which is shown in formula I:
english name:
5-(2-bromo-3,4-dihydroxy-6-(3-methylbuta-1,3-dien-2-yl)benzyl)-3-bromobenz ene-1,2-diol；
chinese name:
5- (2-bromo-3,4-dihydroxy-6- (3-methylbutadien-1, 3-dien-2-yl) benzyl) -3-bromobenzene-1, 2-diol.
A preparation method of the bromine phenol compound containing isoprene specifically comprises the following steps: soaking and extracting the multicladium, using 60% -99% ethanol to extract, decompressing and recovering ethanol until no ethanol smell exists, then adding the residual residue into sufficient distilled water to fully suspend, using an ethyl acetate solvent to fully extract the suspension, combining the ethyl acetate solvents, recovering the ethyl acetate to obtain the residue after the ethyl acetate extraction, subjecting the residue to silica gel column chromatography, using chloroform-acetone gradient elution and chloroform-methanol as eluent, and using Sephadex-LH20 to purify to obtain the compound. The compound is determined to be 5- (2-bromo-3,4-dihydroxy-6- (3-methylbuta-1,3-dien-2-yl) benzyl) -3-bromobenzene-1,2-diol by the spectroscopic means of nuclear magnetic resonance NMR, mass spectrum MS, infrared spectrum IR and the like.
The Polysiphonia urceolata is a large economic alga Polysiphonia urceolata (Polysiphonia urceolata).
The ethanol soaking and extracting method comprises air drying Polysiphonia urceolata in shade, extracting with ethanol (food grade) at room temperature for 3 times, filtering after each extraction to obtain ethanol leaching solution, and mixing the 3 times ethanol leaching solutions.
The decompression recovery is preferably carried out at the temperature of less than or equal to 45 ℃.
The number of extraction times for said sufficient extraction is preferably 3 to 6.
The specific steps of the chromatographic column chromatography on the silica gel column are as follows: the residue was applied to a silica gel column, and the mixture was purified with chloroform: gradient elution is carried out by using acetone as eluent in different proportions, the acetone is respectively collected, and thin-layer plates are unfolded for detection and combination to be divided into 8 coarse parts (1-8); applying silica gel column to the 5 th part, adding chloroform: methanol is used as eluent to obtain the compound of the invention, and gel column Sephadex-LH20 is used for purification (elution by methanol) to obtain the pure compound.
The compound was, by spectroscopic analysis:
5- (2-bromo-3,4-dihydroxy-6- (3-methybruta-1, 3-dien-2-yl) benzyl) -3-bromobenz e-1,2-diol (English); 5- (2-bromo-3,4-dihydroxy-6- (3-methylbutadien-1, 3-dien-2-yl) benzyl) -3-bromobenzene-1,2-diol (Chinese).
The chloroform: the different volume ratios of the acetone are respectively as follows: 100:0, 50:1, 20:1, 10: 1,5:1,2:1,0:100.
The color developing agent adopted by the thin layer plate for detection after expansion is ferric trichloride test solution.
The chloroform: methanol as eluent, chloroform: the volume ratio of methanol is 20: 1.
the application of the bromine phenol compound containing isoprene can be used as a protein tyrosine phosphatase PTP1B inhibitor.
Based on the efficacy of the PTP1B inhibitor, the further application of the bromine compound containing isoprene is used for preparing the medicament of the protein tyrosine phosphatase PTP1B inhibitor.
Based on that PTP1B is an effective drug action target for treating type 2 diabetes, the further application of the bromine phenol compound containing isoprene is used for preparing the drug for treating type 2 diabetes.
The application of the bromine phenol compound containing isoprene can prepare the bromine phenol compound into any conventional medicament, such as tablets, pills, capsules, granules, oral liquid and powder injection for treating type 2 diabetes.
The inventor carries out systematic research on large economic seaweed aiming at searching a lead compound with PTP1B enzyme inhibitor effect, obtains a new compound from the large economic seaweed multicipillar algae, tests on molecular biological activity show that the compound has good inhibition effect on PTP1B enzyme, and pharmacological research shows that the compound has good effect of treating type 2 diabetes on model mice.
The invention has the following advantages:
the bromine phenol compound containing isoprene is a new compound, contains an isoprene structure, is easy to prepare and industrially apply, has a better inhibiting effect on protein tyrosine phosphatase PTP1B, and the results of molecular biology experiments show that IC50 is 2.9M, which is superior to the same compound skeleton type compound IC50 is 4.6M reported in the previous patent (a patent number of 200410087506.7 a bromine phenol compound and preparation and application thereof), and the analysis is that an isoprene substituent has a better affinity effect on PTP1B enzyme. The compounds of the invention have application value in the treatment of type 2 diabetes as selective PTP1B inhibitors.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Example 1
The invention is implemented by the following steps:
the invention is obtained by extracting and separating the macrotype economic alga multitubular algae (Polysiphonia urceolata). Drying Polysiphonia urceolata in the shade, taking 20Kg, leaching with ethanol (food grade) at room temperature for 3 times, leaching with 40 liters of ethanol each time, filtering after leaching each time to obtain ethanol leaching liquor, then combining the ethanol leaching liquor for 3 times, recovering ethanol under reduced pressure at the temperature of less than or equal to 45 ℃ until no ethanol smell exists, adding a proper amount of distilled water into the residual extract after recovering ethanol to form suspension, sequentially extracting with ethyl acetate for 3-6 times, and recovering ethyl acetate under reduced pressure at the temperature of less than or equal to 45 ℃ to obtain 250g of brown extract. Applying 250g of the extract to a silica gel column, mixing the extract with chloroform: gradient elution is carried out on acetone in different ratios as eluent (100:0, 50:1, 20:1, 10: 1, 5:1, 2:1 and 0:100), the acetone is collected respectively, and is developed by a thin-layer plate to be detected (ferric trichloride test solution is a color developing agent) and is combined to be divided into 8 coarse parts (1-8). The 5 th portion (28.0g) was applied to a silica gel column and purified by column chromatography with chloroform: methanol (20:1) was used as eluent to obtain the compound of the present invention, which was purified on gel column Sephadex-LH20 (eluted with methanol) to obtain about 120 mg of the pure compound.
The compound was, by spectroscopic analysis:
5- (2-bromo-3,4-dihydroxy-6- (3-methybruta-1, 3-dien-2-yl) benzyl) -3-bromobenz e-1,2-diol (English); 5- (2-bromo-3,4-dihydroxy-6- (3-methylbutadien-1, 3-dien-2-yl) benzyl) -3-bromobenzene-1,2-diol (Chinese).
The above compound has the following physicochemical characteristics:
the compound is white amorphous powder with molecular formula of C18H16Br2O4；
UV(MeOH)：λmax(logε)239.8(logε4.97)，293.2(logε4.85)，325.1(logε3.93)nm；
IR(KBr)νmax：3492，2935，1616，1504，1420，1342，1237，1088cm-1；
EI-MS：458\456\454([M+4]+:[M+2]+:[M]+＝1:2:1)；
1H NMR(400MHz,acetone-d6)：6.97(1H，s，H-6),4.08(2H，s，H-7)，6.73d(1H，J＝2.4Hz，H-2’),6.49d(1H，J＝2.4Hz，H-6’)；5.36(1H，H-1”)，
5.39(1H，H-1”)，4.99(1H，H-4”)，4.98(1H，H-4”)
13C NMR(100MHz,acetone-d6)：144.2(s，C-1),142.9(s，C-2)，114.5(s，C-3),129.7(s，C-4)，130.1(s，C-5)，115.8(d，C-6)，36.1(t，C-7)，133.1(s，C-1’)，123.2(d，C-2’)，109.6(s，C-3’)，141.4(s，C-4’)，146.1(s，C-5’)，114.7(d,C-6’)，115.1(t，C-1”),149.4(s，C-2”)，146.3(s，C-3”)，111.2(t，C-4”)，20.0(q，C-5”)。
Example 2 PTP1B inhibitor activity assay:
the test principle is as follows: the method adopts a literature method, a molecular biological means is used for expressing a human protein tyrosine phosphatase 1B (hPTP1B) catalytic activity domain in an escherichia coli system, the purified hPTP1B recombinant protein can hydrolyze the phosphoester bond of a substrate p-nitrophenyl phosphate disodium salt (pNPP), and the obtained product has strong light absorption at 410nm, so that the change of the enzyme activity and the inhibition condition of the compound on the enzyme activity can be observed by directly detecting the change of the light absorption at 410 nm. The standard assay systems are as follows: 10mM Tris.HCl, pH7.6, 10mM pNPP, 2% DMSO,100nM hPTP 1B.
Observation indexes are as follows: the light absorption at a wavelength of 410nm was measured dynamically for 3 minutes, and the slope of the first order reaction of the kinetic curve was used as an indicator of the activity of the enzyme.
And (3) judging and explaining the experimental results:
the screening result is that when the concentration of the compound is 10g/ml, the percent inhibition rate of the enzyme activity is achieved, and when the inhibition activity is higher than 50 percent, the IC is screened out according to the conventional method50Positive control of sodium orthovanadate IC5050 is 2M.
The experimental results are as follows: the IC50 of the compounds of the invention for the PTP1B enzyme inhibitory activity was 2.9. mu.M
And (4) conclusion: through molecular biological tests, the compound has a good inhibition effect on protein tyrosine phosphatase PTP 1B.
Because the compound of the invention has the activity of inhibiting protein tyrosine phosphatase PTP1B, the compound can be prepared into any conventional medicament, such as tablets, pills, capsules, granules, oral liquid, powder injection for injection and the like, according to the conventional pharmaceutical technology.
Example 3 Effect on glucose tolerance in Normal mice
The experimental method takes 40 male mice with the weight of 24-28 g, the fasting blood glucose value of the mice is firstly measured before the experiment, and then, the 40 mice are randomly divided into 4 experimental groups: a normal saline control group; ② a low dose group of the compound of the invention; ③ high dose group of the compounds of the invention; fourthly, a positive control drug of a beigliping group. 0.5mL of the medicinal liquid is respectively used for each component, 0.5mL of ig starch (10g/kg) is used after 10min, blood is respectively taken from the tail of the mouse after 0.5, 1 and 2h of the starch administration, and the change of the blood sugar value is measured.
As can be seen from Table 1, the blood glucose levels of normal mice increased significantly after starch administration for 0.5 hour and 1 hour. The compound can obviously reduce the blood sugar value of a mouse 0.5 h and 1h after the mouse is given starch.
Table 1 effect of the compounds of the present invention on normal mouse glucose tolerance (x ± s, n ═ 10)
P <0.05 x P <0.01 as compared to control group
Application example 1
Precisely weighing 500 mg of the compound of the present invention prepared in example 1, adding 14500 mg of pharmaceutical starch as an excipient for pharmaceutical production, mixing well, granulating, tabletting to obtain 50 tablets of 0.3 g, each tablet containing 10 mg of the compound of the present invention.
Application example 2
Precisely weighing 1 g of the compound prepared in example 1, completely transferring the compound to 999 g of distilled water, adding a proper amount of solubilizer, flavoring agent and preservative, canning and sterilizing to prepare 100 oral liquids with the specification of 10ml, wherein each oral liquid contains 10 mg of the compound.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (7)
1. An isoprene-containing bromophenol compound characterized by: the structural formula of the compound is shown as a formula I:
formula I.
2. A method for producing an isoprene containing bromophenol compound according to claim 1, characterized in that: the method specifically comprises the following steps: soaking and extracting the multicladium giganteum with 60-99% ethanol, recovering ethanol under reduced pressure until ethanol smell disappears, adding the residual residue into sufficient distilled water for full suspension, sequentially and fully extracting the suspension with an ethyl acetate solvent, merging the ethyl acetate solvents, recovering the ethyl acetate to obtain the residue after ethyl acetate extraction, and subjecting the residue to silica gel column chromatography;
the specific steps of the chromatographic column chromatography on the silica gel column are as follows: the residue was applied to a silica gel column, and the mixture was purified with chloroform: gradient elution is carried out by using acetone as eluent in different proportions, the acetone is respectively collected, and thin-layer plates are unfolded for detection and combination to be divided into 8 coarse parts; applying silica gel column to the 5 th part, adding chloroform: methanol is used as eluent to obtain the compound of the invention, and gel column Sephadex-LH20 is used for purification to obtain a pure compound;
the chloroform: the different volume ratios of the acetone are respectively as follows: 100:0, 50:1, 20:1, 10: 1, 5:1, 2:1, 0: 100;
the color developing agent adopted by the thin layer plate for development and detection is ferric trichloride test solution;
the chloroform: methanol as eluent, chloroform: the volume ratio of methanol is 20: 1.
3. the method for producing an isoprene containing bromophenol compound according to claim 2, characterized in that: the ethanol soaking extraction comprises the following specific steps: drying Polysiphonia urceolata in the shade, extracting with ethanol at room temperature for 3 times, filtering after each extraction to obtain ethanol extract, and mixing the 3 ethanol extracts.
4. The method for producing an isoprene containing bromophenol compound according to claim 2, characterized in that: the reduced pressure recovery is reduced pressure recovery at the temperature of less than or equal to 45 ℃.
5. The method for producing an isoprene containing bromophenol compound according to claim 2, characterized in that: the extraction times of the full extraction are 3-6 times.
6. Use of the isoprene containing bromophenol compound of claim 1, characterized by: is used for preparing medicaments containing protein tyrosine phosphatase PTP1B inhibitors.
7. Use of the isoprene containing bromophenol compound of claim 1, characterized by: can be used for preparing medicine for treating type 2 diabetes.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1772721A (en) * | 2004-11-10 | 2006-05-17 | 中国科学院海洋研究所 | Bromophenol compound and its prepn and application |
| CN1853618A (en) * | 2005-04-20 | 2006-11-01 | 中国科学院海洋研究所 | Use of bromphenol compound in protein-tyrosine phosphonatease inhibitor |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1772721A (en) * | 2004-11-10 | 2006-05-17 | 中国科学院海洋研究所 | Bromophenol compound and its prepn and application |
| CN1853618A (en) * | 2005-04-20 | 2006-11-01 | 中国科学院海洋研究所 | Use of bromphenol compound in protein-tyrosine phosphonatease inhibitor |
Non-Patent Citations (2)
| Title |
|---|
| BPN, a marine-derived PTP1B inhibitor, activates insulin signaling and improves insulin resistance in C2C12 myotubes;Dayong Shi 等;《International Journal of Biological Macromolecules》;20170812;第106卷;379-386 * |
| HPN, a Synthetic Analogue of Bromophenol from Red Alga Rhodomela confervoides: Synthesis and Anti-Diabetic Effects in C57BL/KsJ-db/db Mice;Dayong Shi 等;《Mar. Drugs》;20131231;第11卷;350-362 * |
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