CN102657693B - SH2-containing tyrosine phosphatase 1(SHP-1) inhibitor and preparation thereof - Google Patents
SH2-containing tyrosine phosphatase 1(SHP-1) inhibitor and preparation thereof Download PDFInfo
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Abstract
The invention provides an SH2-containing tyrosine phosphatase (SHP-1)1 inhibitor and preparation thereof. With dalbergia odorifera branches or/and dalbergia odorifera leaves as raw materials, the SHP-1 inhibitor is prepared by the following steps: crushing the dalbergia odorifera branches or/and the dalbergia odorifera leaves, soaking with water, filtering and separating, heating, evaporating, concentrating, drying, dissolving by adding water to obtain water extract, mixing with a conventional amount of medical excipients, and preparing pharmaceutically-acceptable capsules, dissolved medicine, tablets, pills or oral liquids according to conventional methods. The catalytic structural domain of the SHP-1 (delta SHP-1) is applied as a target, inhibiting effect of the dalbergia odorifera water extract on the delta SHP-1 is detected in vitro, and accordingly results show that the dalbergia odorifera water extract is capable of inhibiting the activity of the SHP-1 in vitro. Therefore, dalbergia odorifera water extract can be used to prepare various medicines or compositions of the medicines which can be used for treating related diseases caused by overexpression or over-high activity of the SHP-1.
Description
Technical field
The present invention relates to a kind of protein tyrosine phosphatase inhibitors, particularly a kind of inhibitor that can suppress Protein Tyrosine Phosphatases SHP-1 vitro enzyme vigor, belongs to biological technical field.
background technology
SHP-1 is Protein Tyrosine Phosphatases-1 (the SH2-containing tyrosine phosphatase 1 containing SH2 structural domain, SHP-1), being called again HCP, SHPTP1, PTP1C or PTPN6, is the important member in Protein Tyrosine Phosphatases (PTPs) family of containing SH2 structural domain.Early 1990s, by the separation and purification in succession of the study group such as University of Washington, and successfully clone its cDNA, Protein Tyrosine Phosphatases SHP-1 total length is totally 641 amino-acid residues, and molecular weight is 70510Da.Studies have shown that, cancer of the stomach and acquired immunodeficiency syndrome vigor most and SHP-1 increases closely related extremely, and therefore, SHP-1 has become the important target of exploitation treatment cancer of the stomach and acquired immunodeficiency syndrome medicine.Research in recent years is also found, SHP-1 can play a role aspect control blood sugar, investigator is with the Ptpn6me-v/me-v mouse of congenital functional deficiency SHP-1 and compare the rear discovery of research with the wild-type mice that this mouse is born simultaneously, the mouse of congenital functional deficiency SHP-1 has obvious glucose tolerance and insulin sensitivity, this is indicating by suppressing SHP-1 activity in vivo, is likely recovering the controllability of diabetics to blood sugar.In addition, researchist also finds, near the decomposition of SHP-1 meeting inhibition Regular Insulin liver, and this has explained why because metabolic disturbance causes fat patient's insulin concentration, can raise.Therefore study, find the specific inhibitor for SHP-1, not only on exploitation treatment cancer of the stomach and acquired immunodeficiency syndrome medicine, there is application prospect, also be expected to improve the susceptibility of human body to Regular Insulin, effectively treat the diseases such as diabetes B, insulin resistant and obesity.Because SHP-1 holoenzyme activity is very low, therefore, the catalyst structure domain (SHP-1, molecular weight 4.5kD) of application SHP-1 is target, by vitro enzyme reaction kinetics, test, from Chinese medicine, screening has efficient single-minded inhibiting Chinese medicine to have actual application value to it.
In recent years, a lot of researchist both domestic and external is finding efficient, single-minded Protein Tyrosine Phosphatases PTPs inhibitor always, although Protein Tyrosine Phosphatases PTPs inhibitor product special and safety does not also have appearance, but the research of PTPs inhibitor, especially the research of PTP1B inhibitor makes some progress, but not yet finds the relevant report of SHP-1 inhibitor at present.
The another name of dalbergia odorifera is Huanghua Pear, rosewood or lake-wood or dalbergia wood, and dalbergia odorifera is half deciduous tree, high 10-25 rice, and the diameter of a cross-section of a tree trunk 1.3 meters above the ground can reach 80 centimetres; Tree crown is extensively umbrella shape, and branch is lower, and bark ecru is slightly coarse.Mainly be distributed in the subtropics that long-term temperature is higher, in Hainan of south China, all there is distribution in the province such as Yunnan.The rudiment power of dalbergia odorifera is stronger, and existing forest mostly is germinating undersized log, and natural forest growth is slower, and tame tree growth is very fast, grows fine.Dalbergia odorifera is general annual changes leaf once, and when arid especially, leaf falls entirely, and during first rain, dalbergia odorifera floral leaf is extracted out simultaneously, and annual fruit in 10~December is ripe successively.Dalbergia odorifera is that the pharmaceutical use of dalbergia wood is at < < Compendium of Materia Medica > >, < < Hainan book on Chinese herbal medicine > >, < < class is demonstrate,proved in herbal > > all on the books, there is promoting flow of QI and blood, hemostasis and pain-relieving, ward off the effects such as dirty, among the peoplely be used for the treatment of vomiting, heart peratodynia, coronary heart disease and hypertension and allergic etc., not yet find at present the report of dalbergia odorifera aspect inhibition SHP-1.
Summary of the invention
The object of the present invention is to provide a kind of Protein Tyrosine Phosphatases SHP-1 inhibitor and preparation method thereof.
The present invention is to provide a kind of like this Protein Tyrosine Phosphatases SHP-1 inhibitor, it is characterized in that take dalbergia odorifera branch or/and dalbergia odorifera leaf is raw material, process the following step:
A, be dried routinely, be crushed to 40~60 mesh sieves, obtain dalbergia odorifera powder;
B, press dalbergia odorifera powder: the volume ratio of water=1:3~5, after adding water stir in dalbergia odorifera powder, soak 1~3 hour, filter to isolate residue, obtain dalbergia odorifera soak solution;
C, the dalbergia odorifera soak solution of step B is heated to 100 ℃, evaporative removal moisture, obtains dalbergia odorifera the water extracted immersing paste;
D, the dalbergia odorifera the water extracted immersing paste of step C is dried to and is removed after moisture at 80~150 ℃, be ground into powder, obtain dalbergia odorifera extract powder;
E, press dalbergia odorifera extract powder: the mass ratio of water=1:10~100, the dalbergia odorifera extract powder water dissolution by step D, obtains dalbergia odorifera aqueous extract.
After the dalbergia odorifera aqueous extract of described step e mixes with the medical auxiliary materials of convention amount, be prepared into routinely pharmaceutically acceptable any preparation, as oral preparations such as capsule, electuary, tablet, pill, oral liquids, obtain Protein Tyrosine Phosphatases SHP-1 inhibitor.
The water of described step B is tap water.
The churning time of described step B is 0.5~1 hour, and stirring velocity is 60~300 revs/min.
The water of described step e is distilled water.
The human dose of described Protein Tyrosine Phosphatases SHP-1 inhibitor is recommended as 2~5 grams of dalbergia odorifera extract powder/people/days (by 60 kilograms of body weight per capita).
The present invention has following advantages and effect: the dalbergia odorifera aqueous extract that adopts such scheme to obtain, after ordinary method is prepared into pharmaceutically acceptable any preparation, the catalyst structure domain SHP-1 of application SHP-1 is target, in vitro dalbergia odorifera aqueous extract is detected the restraining effect of SHP-1, result shows: dalbergia odorifera aqueous extract is the activity of arrestin matter tyrosine phosphatase SHP-1 in vitro.Therefore, available dalbergia odorifera aqueous extract, crosses and expresses or the various medicines of the relative disease of vigor due to too high or the moiety of medicine for the preparation for the treatment of SHP-1.
Accompanying drawing explanation
Fig. 1 is the IC50:233.5ug/ml of dalbergia odorifera branch aqueous extract to SHP-1;
Fig. 2 is the IC50:333.6ug/ml of dalbergia odorifera leaf aqueous extract to SHP-1;
Fig. 3 is the phosphorylation of dalbergia odorifera branch aqueous extract to ERK;
Fig. 4 is the phosphorylation of dalbergia odorifera leaf aqueous extract to ERK.
Embodiment
Below by embodiment, the present invention will be further described.
Embodiment 1
Protein Tyrosine Phosphatases SHP-1 inhibitor provided by the invention, take dalbergia odorifera branch as raw material, process the following step:
A, be dried routinely, be crushed to 40 mesh sieves, obtain dalbergia odorifera powder;
B, the volume ratio of pressing dalbergia odorifera powder: water=1:3 add tap water in dalbergia odorifera powder, in speed, are under 60 revs/min, to stir 1 hour, soak 1 hour, filter to isolate soak solution and residue, obtain dalbergia odorifera water extraction liquid;
C, the water extraction liquid of step B is heated to 100 ℃, with evaporative removal moisture, obtains dalbergia odorifera the water extracted immersing paste;
D, the dalbergia odorifera the water extracted immersing paste of step C is dried to and is removed after moisture at 80 ℃, be ground into powder, obtain dalbergia odorifera extract powder;
E, press dalbergia odorifera extract powder: water=1:10 mass ratio, the dalbergia odorifera extract powder of step D is dissolved with distilled water, obtain dalbergia odorifera aqueous extract.
In the dalbergia odorifera aqueous extract of step e, with addition of conventional medical auxiliary materials, and be prepared into routinely capsule.
Embodiment 2
Protein Tyrosine Phosphatases SHP-1 inhibitor provided by the invention, take dalbergia odorifera leaf as raw material, process the following step:
A, be dried routinely, be crushed to 60 mesh sieves, obtain dalbergia odorifera powder;
B, the volume ratio of pressing dalbergia odorifera powder: water=1:5 add tap water in dalbergia odorifera powder, in speed, are under 300 revs/min, to stir 0.5 hour, soak 3 hours, filter to isolate soak solution and residue, obtain dalbergia odorifera water extraction liquid;
C, the water extraction liquid of step B is heated to 100 ℃, with evaporative removal moisture, obtains dalbergia odorifera the water extracted immersing paste;
D, the dalbergia odorifera the water extracted immersing paste of step C is dried to and is removed after moisture at 150 ℃, be ground into powder, obtain dalbergia odorifera extract powder;
E, press dalbergia odorifera extract powder: water=1:40 mass ratio, the dalbergia odorifera extract powder of step D is dissolved with distilled water, obtain dalbergia odorifera aqueous extract.
In the dalbergia odorifera aqueous extract of step e, with addition of conventional medical auxiliary materials, and be prepared into routinely tablet.
Embodiment 3
Protein Tyrosine Phosphatases SHP-1 inhibitor provided by the invention, take dalbergia odorifera branch and dalbergia odorifera leaf is raw material, through the following step:
A, be dried routinely, be crushed to 50 mesh sieves, obtain dalbergia odorifera powder;
B, the volume ratio of pressing dalbergia odorifera powder: water=1:4 add tap water in dalbergia odorifera powder, in speed, are under 150 revs/min, to stir 0.8 hour, soak 2 hours, filter to isolate soak solution and residue, obtain dalbergia odorifera water extraction liquid;
C, the water extraction liquid of step B is heated to 100 ℃, with evaporative removal moisture, obtains dalbergia odorifera the water extracted immersing paste;
D, the dalbergia odorifera the water extracted immersing paste of step C is dried to and is removed after moisture at 100 ℃, be ground into powder, obtain dalbergia odorifera extract powder;
E, press dalbergia odorifera extract powder: water=1:50 mass ratio, the dalbergia odorifera extract powder of step D is dissolved with distilled water, obtain dalbergia odorifera aqueous extract.
In the dalbergia odorifera aqueous extract of step e, with addition of conventional medical auxiliary materials, and be prepared into routinely oral liquid.
Embodiment 4
Protein Tyrosine Phosphatases SHP-1 inhibitor provided by the invention, take dalbergia odorifera branch and dalbergia odorifera leaf is raw material, through the following step:
A, be dried routinely, be crushed to 60 mesh sieves, obtain dalbergia odorifera powder;
B, the volume ratio of pressing dalbergia odorifera powder: water=1:4 add tap water in dalbergia odorifera powder, in speed, are under 100 revs/min, to stir 1 hour, soak 2 hours, filter to isolate soak solution and residue, obtain dalbergia odorifera water extraction liquid;
C, the water extraction liquid of step B is heated to 100 ℃, with evaporative removal moisture, obtains dalbergia odorifera the water extracted immersing paste;
D, the dalbergia odorifera the water extracted immersing paste of step C is dried to and is removed after moisture at 120 ℃, be ground into powder, obtain dalbergia odorifera extract powder;
E, press dalbergia odorifera extract powder: water=1:40 mass ratio, the dalbergia odorifera extract powder of step D is dissolved with distilled water, obtain dalbergia odorifera aqueous extract.
In the dalbergia odorifera aqueous extract of step e, with addition of conventional medical auxiliary materials, and be prepared into routinely electuary.
For showing the restraining effect of the present invention to Protein Tyrosine Phosphatases SHP-1, the present invention is through check, and result is as follows:
1), measuring principle and method:
SHP-1 is a kind of Starch phosphorylase, and it can make the albumen dephosphorylation of phosphorylation.P-oil of mirbane disodic alkaliine (pNPP) can be become p-nitrophenols by SHP-1 dephosphorylation, and it is yellow that color is.Therefore,, by detecting the variation of 410nm place absorbance value, carry out the changing conditions of the enzymic activity of indirect detection Protein Tyrosine Phosphatases SHP-1.Mensuration system is as follows: 25mM morpholino propane sulfonic acid (MOPS), 1mM bovine serum albumin (BSA), 1mM dithiothreitol (DTT) (DTT), 0.1mM disodium EDTA (EDTA), the p-oil of mirbane phosphoric acid of 20mM (p-NPP), 5nM PTP1B, at 37 ℃ of reaction 30min, adds 100 μ l 0.2M NaHCO
3termination reaction, at the changing value of 410nm place mensuration photoabsorption;
2) dalbergia odorifera aqueous extract is measured the inhibition ability of SHP-1:
By the embodiment of the present invention 1, implement the aqueous extract investigation to the inhibition ability of SHP-1 respectively of 2 E step, be by measuring half-inhibition concentration (IC
50) weigh.The aqueous extract of the E step of embodiment 1, enforcement 2 is pressed respectively to 2 times of gradient distilled water dilutings, aqueous extract after dilution is added in reaction system, the blank sample that does not add aqueous extract is set simultaneously, measure 37 ℃, in 30min, the changing value of photoabsorption, is divided by the absorption value of the absorption value of each gradient and blank sample afterwards, and the numerical value drawing is for suppressing percentage ratio, when reaching 50%, the multiple of corresponding dilution gradient is as IC
50(referring to Fig. 1 and Fig. 2).Specifically:
The aqueous extract of the E step of embodiment 1, enforcement 2, respectively by 2 times of gradient distilled water dilutings, is measured to the inhibition ability of each weaker concn to SHP-1, record IC
50, using the concentration (mg/ml) of water extraction liquid as IC
50unit, after measured, the IC of the dalbergia odorifera branch aqueous extract of the E step of embodiment 1
50for 233.5ug/ml, the IC of the aqueous extract of the dalbergia odorifera leaf of the E step of enforcement 2
50for 333.6ug/ml.Both IC
50be not both separately due to the effective constituent difference of contained inhibition SHP-1.
Cell-based assay is found, the aqueous extract of the E step of embodiment 1, enforcement 2 all has rising effect to the phosphorylation level of ERK albumen in HepG2 cell, illustrated that they have affected cell signalling by suppressing the vigor of PTPs, have brought into play biological action (referring to Fig. 3 and Fig. 4).
Claims (4)
1. a preparation method for Protein Tyrosine Phosphatases SHP-1 inhibitor, is characterized in that take dalbergia odorifera branch or/and dalbergia odorifera leaf is raw material, process the following step:
A, be dried routinely, be crushed to 40~60 mesh sieves, obtain dalbergia odorifera powder;
B, press dalbergia odorifera powder: the volume ratio of water=1:3~5, after adding water stir in dalbergia odorifera powder, soak 1~3 hour, filter to isolate residue, obtain dalbergia odorifera soak solution; Described churning time is 0.5~1 hour, and stirring velocity is 60~300 revs/min;
C, the dalbergia odorifera soak solution of step B is heated to 100 ℃, evaporative removal moisture, obtains dalbergia odorifera the water extracted immersing paste;
D, the dalbergia odorifera the water extracted immersing paste of step C is dried to and is removed after moisture at 80~150 ℃, be ground into powder, obtain dalbergia odorifera extract powder;
E, press dalbergia odorifera extract powder: the mass ratio of water=1:10~100, the dalbergia odorifera extract powder water dissolution by step D, obtains dalbergia odorifera aqueous extract.
2. the preparation method of Protein Tyrosine Phosphatases SHP-1 inhibitor as claimed in claim 1, after the dalbergia odorifera aqueous extract that it is characterized in that described step e mixes with the medical auxiliary materials of convention amount, be prepared into routinely capsule, electuary, tablet, pill or the oral liquid pharmaceutically accepted.
3. the preparation method of Protein Tyrosine Phosphatases SHP-1 inhibitor as claimed in claim 1, the water that it is characterized in that described step B is tap water.
4. the preparation method of Protein Tyrosine Phosphatases SHP-1 inhibitor as claimed in claim 1, the water that it is characterized in that described step e is distilled water.
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Citations (4)
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CN1791604A (en) * | 2003-05-15 | 2006-06-21 | 霍夫曼-拉罗奇有限公司 | Diaminopyrroloquinazolines compounds as protein tyrosine phosphatase inhibitors |
CN101099566A (en) * | 2007-08-13 | 2008-01-09 | 中国科学院新疆理化技术研究所 | Lactucin and its preparation method and application |
CN101129497A (en) * | 2007-09-17 | 2008-02-27 | 中国科学院新疆理化技术研究所 | Pharmaceutical uses of black-seed grass-seed oil of tuberculate fruit |
CN102793714A (en) * | 2012-08-30 | 2012-11-28 | 吉林大学 | Application of mecobalamine and analogue to protein tyrosine phosphatases SHP-1 inhibitor |
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
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CN1791604A (en) * | 2003-05-15 | 2006-06-21 | 霍夫曼-拉罗奇有限公司 | Diaminopyrroloquinazolines compounds as protein tyrosine phosphatase inhibitors |
CN101099566A (en) * | 2007-08-13 | 2008-01-09 | 中国科学院新疆理化技术研究所 | Lactucin and its preparation method and application |
CN101129497A (en) * | 2007-09-17 | 2008-02-27 | 中国科学院新疆理化技术研究所 | Pharmaceutical uses of black-seed grass-seed oil of tuberculate fruit |
CN102793714A (en) * | 2012-08-30 | 2012-11-28 | 吉林大学 | Application of mecobalamine and analogue to protein tyrosine phosphatases SHP-1 inhibitor |
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