CN105997986A - Application of baicalein and derivative 6,7-diacetyl radix scutellariae thereof - Google Patents
Application of baicalein and derivative 6,7-diacetyl radix scutellariae thereof Download PDFInfo
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- CN105997986A CN105997986A CN201610486260.3A CN201610486260A CN105997986A CN 105997986 A CN105997986 A CN 105997986A CN 201610486260 A CN201610486260 A CN 201610486260A CN 105997986 A CN105997986 A CN 105997986A
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- baicalin
- medicine
- diacetyl
- hyperuricemia
- baicalein
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
Abstract
The invention discloses application of baicalein and a derivative 6,7-diacetyl radix scutellariae thereof to preparation of medicine for treating hyperuricemia and/or preparation of medicine for treating renal injury caused by hyperuricemia. The baicalein and the derivative 6,7-diacetyl radix scutellariae thereof can remarkably lower the uric acid level, the creatinine level and the urea nitrogen level of hyperuricemia , and the 6,7-diacetyl radix scutellariae has a remarkable protection function on the kidney. The baicalein has a first-pass effect of liver sausage, the derivative 6,7-diacetyl radix scutellariae of the baicalein can inhibit the first-pass effect of liver sausage, and bioavailability is improved.
Description
Technical field
The present invention relates to baicalin and the purposes of derivant 6,7-diacetyl baicalin thereof.
Background technology
One, baicalin and the general characteristic of derivant 6,7-diacetyl baicalin thereof
The structural formula of baicalin is as shown in formula I:
Conventional medicament Radix Scutellariae is the dry root of labiate Scutellaria baicalensis Georgi." China
People's republic's pharmacopeia " record Radix Scutellariae and have " heat clearing and damp drying, eliminating fire and detoxication, hemostasis, antiabortive " effect, it is the conventional medicine of the traditional Chinese medical science
One of.Baicalin is one of flavone compound that in Radix Scutellariae, content is the highest, and chemical name is 5，6，7-trihydroxyflavone, country
Committee of pharmacopeia is officially named hundred can profit (English name is baicalein).Research proves, baicalin enters animal body
After Nei, it is quickly converted to baicalin and other metabolite in blood.After mouse mainline baicalin, main in Mice Body
Liver to be distributed in and lung tissue, be secondly the heart, kidney and skeletal muscle, and brain and spleen distribution are less.Modern study finds, yellow
A kind of reed mentioned in ancient books element has antibacterial, antiviral, scavenging activated oxygen, antioxidation, antipyretic-antalgic, antiinflammatory, antitumor, protection cardiovascular and nerve
Unit, protect the liver, and the kidney injuries such as diabetes, renal fibrosis, renal ischemia/reperfusion injury are had certain prevention and treatment make
With, there is multi-level, the pharmacological characteristic of multipath, Mutiple Targets.
But there is liver sausage first pass effect widely in oral baicalin, mainly show as II phase metabolism glucuronidation and
Sulphation metabolic response.There is research that the microsomal metabolism enzyme of rats'liver and intestinal is studied, find four differences of intestinal
The microsomal metabolism effect of position i.e. duodenum, jejunum, ileum and colon is better than hepatomicrosome.The first of this explanation intestinal closes effect
The first pass effect of liver should be better than.
The structural formula of 6,7-diacetyl baicalin is as shown in formula II:
This compound is the derivant of baicalin, achieved with national patent certificate, Patent No. 2008100795588.Mesh
Qian You seminar finds 6, and 7-diacetyl baicalin has significant Hepatocyte protection, and this effect may be with increase hepatic mitochondria
The activity of middle antioxidative SOD and GSH-PX, strengthens the ability of hepatocyte antagonism lipid peroxidation injury, stablizes mitochondrial membrane,
So that ALT with AST release reduces relevant.
Two, the novel scientific meaning preventing and treating hyperuricemia nephropathy medicine is researched and developed
Along with the raising of people's living standard, high purine food intake increases, and purine metabolism is easily sent out disorder, easily made hematuria
Acid raises, and causes hyperuricemia, and then causes kidney disease and gout.China's chronic kidney disease Epidemiological study cooperative groups
Report show, 2009-2010, the prevalence of Chinese Adult hyperuricemia is 8.4% (95%CI8.0%～8.8%),
Estimating accordingly, China has nearly 93,000,000 Patients with Hyperuricemias for more than 18 years old in crowd；The highest 1/3 horizontal crowd of GDP per capita
The prevalence of hyperuricemia is more up to 21.4%, has reached western developed country level.Additionally, extensive epidemiology grinds
Study carefully discovery, hyperuricemia also with generation and the development of the diseases such as hypertension, cardiovascular and cerebrovascular disease, diabetes, metabolism syndrome
Closely related, it has also become to threaten the serious metabolic disease of human health, also it is the independent hazard factor of kidney disease progress.Cause
This, research and develop novel hyperuricemia nephropathy medicine of preventing and treating and have important scientific meaning and clinical meaning.
Summary of the invention
It is an object of the invention to provide baicalin and derivant 6 thereof, the purposes of 7-diacetyl baicalin, baicalin of the present invention
And derivant 6, the uric acid of hyperuricemia, creatinine, urea nitrogen levels can be significantly reduced by 7-diacetyl baicalin, and wherein 6,
7-diacetyl baicalin has notable protective effect to kidney.
Baicalin and derivant 6,7-diacetyl baicalin thereof that the present invention provides are used for treating hyperuricemia in preparation
Medicine and/or for treating the purposes in the injury of kidney medicine that hyperuricemia causes.
Present invention also offers a kind of medicine, the active component of described medicine is described baicalin and derivant 6 thereof, 7-bis-
Acetyl baicalin.
In the present invention, described baicalin have liver sausage first pass effect；But the derivant 6,7-diacetyl of described baicalin
Baicalin, it can protect hydroxyl, it is to avoid glucuronidation and sulphation metabolic response, thus suppresses the first pass effect of intestinal, institute
The bioavailability of the derivant 6,7-diacetyl baicalin stating baicalin improves.
In above-mentioned medicine, described medicine is by the side injected, be administered orally, spray, permeate, absorb, physically or chemically mediate
Method imports body area；
Described body area includes at least one in muscle, Intradermal, subcutaneous, vein and mucosal tissue.
In the present invention, described medicine can also import machine after the mixing of pharmaceutical field other materials acceptable or parcel
Body.
In above-mentioned medicine, the dosage form of described medicine includes in injection, suspending agent, powder, tablet and granule extremely
Few one；
The dosage form of described medicine all can be prepared according to the conventional method of pharmaceutical field.
In above-mentioned medicine, described medicine can be additionally added one or more pharmaceutically acceptable carriers.
In above-mentioned medicine, described carrier includes the conventional diluent of pharmaceutical field, excipient, filler, binding agent, wet
At least one in profit agent, disintegrating agent, absorption enhancer, surfactant, absorption carrier and lubricant.
The new medicine use of baicalin of the present invention and derivant 6,7-diacetyl baicalin thereof is treatment hyperuricemia (fall
Low uric acid level) and the injury of kidney that causes.
In the present invention, the active component consumption of described medicine is generally: 50-300mg/ person/day (injection) or 50-300mg/
Person/day (being administered orally).
The invention have the advantages that
Baicalin of the present invention and derivant 6,7-diacetyl baicalin thereof can be to the uric acid of hyperuricemia, creatinine, carbamide
Nitrogen level significantly reduces, and wherein 6,7-diacetyl baicalin has notable protective effect to kidney.Baicalin of the present invention has liver
The first pass effect of intestinal, but the derivant of baicalin 6,7-diacetyl baicalin can suppress the first pass effect of intestinal, its biological utilisation
Degree improves.
Accompanying drawing explanation
Fig. 1 is that baicalin is combined with the simulation of rat derived Protein XOR.
Fig. 2 is that baicalin is combined with the simulation of people derived Protein XOR.
Fig. 3 is the steady-state model of baicalin and XOR.
Fig. 4 is the kinetic model of baicalin and XOR；In Fig. 4, curve is followed successively by the baicalin of variable concentrations from top to bottom,
It is respectively 200 μMs, 100 μMs, 50 μMs, 25 μMs, 12.5 μMs, 6.25 μMs, 3.125 μMs, 1.5625 μMs, 0.78125 μM.
Fig. 5 is the protective effect to kidney of the 6,7-diacetyl baicalin；Wherein, Fig. 5 a) it is serum uric acid level, Fig. 5 b) be
Blood urea nitrogen level, Fig. 5 c) it is serum creatinine level, marking M+50B in Fig. 5 is 6, and 7-diacetyl baicalin is administered 50mg/kg.
Fig. 6 is the baicalin protective effect to kidney；Wherein, Fig. 6 a) it is serum uric acid level, Fig. 6 b) it is blood urea nitrogen water
Flat, Fig. 6 c) it is serum creatinine level；In Fig. 6 mark M+50B be baicalin be administered 50mg/kg, M+100B be baicalin be administered
100mg/k。
Detailed description of the invention
Experimental technique used in following embodiment if no special instructions, is conventional method.
Material used in following embodiment, reagent etc., if no special instructions, the most commercially obtain.
Embodiment 1,6,7-diacetyl baicalin prevent and treat hyperuricemia and the pharmacodynamics test of kidney injury caused thereof
1, computer simulation prediction XOR and the combination of baicalin
Use software: SYBYL 6.92, Chimera, Microsoft Excel, data base: Protein Data Bank.
Protein Xanthine Dehydrogenase from Bovine Milk with Inhibitor is downloaded from PDB data base
The three dimensional structure (wherein comprising the structure of first wife body TEI) of TEI-6720Bound (PDB ID:1N5X).With Chimera by part
Carry out splitting and being preserved into by receptor protein the file of PDB form with receptor.Draw part TEI structure with SYBYL software to preserve
Become mol2 form.Put 2 pdb and 1 mol2 file into a new folder for future use.Open SYBYL software, import
1N5X.pdb file (comprises unit's part), deletes B chain, only stays A chain as docking material.Choose native ligand TEI, in it being
The heart generates active site pocket (involved parameter is software default numerical value).The mol2 part file drawn is imported,
Dock in the range of active pocket, symbiosis is set and becomes 50 result conformations.Generate 3D conformation and grade form after docking, comment
Sub-item has Total_SCORE, Crash, Polar, Similarity, D_SCORE, PMF_SCORE, G_SCORE, CHEM_
9 contents of SCORE, C_SCORE, select its marking feelings of an observation most like with first wife body position in 50 result conformations
Condition, and the foundation of every marking is understood by consulting literatures, common combination is made and is applicable to the screening that this experiment is optimal
Standard.
The three dimensional structure of white matter is downloaded identical with above-mentioned steps with fractionation.But 2 target protein XDH (PDB ID:1WYG
Source:rat and PDB ID:2E1Q source:human) there is no Mo-Pt center, it is therefore desirable to fill and dock again.With
Chimera opens 1VDV and 1WYG simultaneously, overlaps two protein, chooses Mo-Pt center and the overall structure of 1WYG of 1VDV,
Remainder is deleted in anti-choosing, preserves pdb file.Open the pdb file of just preservation, amendment numbering with text document, make in Mo-Pt
The heart becomes a chain and can be only used for docking with 1WYG.Subsequent step is similar to above.Best structure Chimera filtered out
Open and interact with target protein binding analysis.
As in Fig. 1 and Fig. 2, SYBYL docking result show: baicalin (Baicalein) and albumin X DH (PDB ID:1WYG,
Source:rat/human) binding site is in the active pocket of former native ligand, and position is almost identical.
2, surface plasma body resonant vibration (SPR) technology for detection XOR and the combination of baicalin
Biocore T200 (GE Healthcare) and CM5 sensing chip (GE Healthcare) is used to test.
Weigh 0.0108g baicalin to be dissolved in 1mL DMSO, be made into the baicalin solution of 40mM.Add ultra-pure water and be diluted to 200 μMs, join
Become the baicalin that 5%DMSO dissolves.With the baicalins of 200 μMs as maximum concentration, 10 concentration of proportional diluted.By 2.5mg XOR
It is dissolved in 500 μ L ultra-pure waters, is made into the XOR solution of 5mg/mL.Take XOR solution and the 200 μ L 4.0Acetate of 8 μ L 5mg/mL,
It is made into the XOR solution of 200 μ g/mL.This experiment uses amino coupled method, utilizes 1:1 steady-state model, records the two affinity constant
It is 6.749 × 10-5M.Additionally, kinetic model shows the binding constant 607.71/Ms of the two, dissociation constant is 0.009467
1/s, affinity constant is 1.558 × 10-5M, consistent with steady-state model, result is as shown in Figure 3 and Figure 4.
3, baicalin and 6,7-diacetyl baicalin are to hyperuricemia and the protective effect of injury of kidney
Laboratory animal is grouped: male ICR mouse 18,18-22g, and often group 6, is divided into matched group, model group (model group
To be only given Oteracil Potassium and hypoxanthine), baicalin administration group and 6,7-diacetyl baicalin administration group.
It is gastric infusion to the administering modes of above-mentioned three groups, is given daily 1 time that successive administration three weeks is administered a Zhou Houkai
Beginning modeling, baicalin dosage is 50mg/kg/d and 100mg/kg/d, and 6,7-diacetyl baicalin dosages are 50mg/
kg/d.Modeling mode is lumbar injection modeling, model group, baicalin administration group and 6, and 7-diacetyl baicalin administration group all gives
Oteracil Potassium and each 300mg/kg of hypoxanthine, inducing mouse obtains hyperuricemia；Matched group gives solvent normal saline.Finally
After single administration, each group mice is plucked eyeball and takes blood, hatches l h, 3000rpm for 37 DEG C and is centrifuged 10min separation serum.Measure each group little
Mus serum uric acid, creatinine, urea nitrogen levels, RNA isolation kit measures the activity of XOR in serum.
Result as shown in Figure 5 and Figure 6:
Model group Mouse Blood uric acid, creatinine, urea nitrogen levels are significantly raised；
It will be appreciated from fig. 6 that baicalin administration group result shows, it is invalid to hyperuricemia to be administered during 50mg/kg, is administered
During 100mg/kg, the level of blood uric acid, blood urea nitrogen and creatinine has a downward trend, but no difference of science of statistics, baicalin of the present invention is described
Protected effect, but protective effect is inconspicuous；
6,7-diacetyl baicalin administration group Mouse Blood uric acid, creatinine, urea nitrogen levels significantly reduce, and the present invention 6 is described,
7-diacetyl baicalin uric acid resisting effect and renal protection are obvious.
Claims (6)
1. baicalin and derivant 6,7-diacetyl baicalin thereof are used for treating antihyperuricemic disease drug and/or being used for controlling in preparation
Treat the purposes in the injury of kidney medicine that hyperuricemia causes.
2. a medicine, it is characterised in that: the active component of described medicine is described baicalin and derivant 6 thereof, 7-diacetyl
Baicalin.
Medicine the most according to claim 2, it is characterised in that: described medicine is by injecting, be administered orally, spray, permeate, inhaling
The method receive, physically or chemically mediated imports body area；
Described body area includes at least one in muscle, Intradermal, subcutaneous, vein and mucosal tissue.
4. according to the medicine according to any one of Claims 2 or 3, it is characterised in that: the dosage form of described medicine include injection,
At least one in suspending agent, powder, tablet and granule.
5. according to the medicine according to any one of claim 2-4, it is characterised in that: described medicine is additionally added one or more medicines
Acceptable carrier on.
Medicine the most according to claim 5, it is characterised in that: described carrier includes the diluent of pharmaceutical field routine, tax
In shape agent, filler, binding agent, wetting agent, disintegrating agent, absorption enhancer, surfactant, absorption carrier and lubricant extremely
Few one.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108309968A (en) * | 2018-05-11 | 2018-07-24 | 武汉轻工大学 | The application of qroxylin A or its pharmaceutically acceptable salt, solvate |
| CN108771672A (en) * | 2018-05-18 | 2018-11-09 | 武汉轻工大学 | The application of wogonin or its pharmaceutically acceptable salt, solvate |
| CN112451537A (en) * | 2020-11-16 | 2021-03-09 | 武汉轻工大学 | Application of baicalin in preparation of medicine for preventing and/or treating asymptomatic hyperuricemia and/or uric acid nephropathy |
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| CN101721405A (en) * | 2008-10-13 | 2010-06-09 | 车庆明 | Application of diacetylbaicalein in preparation of drugs used for curing or preventing liver diseases |
| WO2011108059A1 (en) * | 2010-03-01 | 2011-09-09 | 株式会社サウスプロダクト | Xanthine oxidase inhibitor |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101721405A (en) * | 2008-10-13 | 2010-06-09 | 车庆明 | Application of diacetylbaicalein in preparation of drugs used for curing or preventing liver diseases |
| WO2011108059A1 (en) * | 2010-03-01 | 2011-09-09 | 株式会社サウスプロダクト | Xanthine oxidase inhibitor |
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| DEQIANGLI等: "Screening of xanthine oxidase inhibitors in complex mixtures using online HPLC coupled with postcolumn fluorescence-based biochemical detection", 《JOURNAL OF SEPARATION SCIENCE》 * |
| F. BORGES等: "Progress Towards the Discovery of Xanthine Oxidase Inhibitors", 《CURRENT MEDICINAL CHEMISTRY 》 * |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108309968A (en) * | 2018-05-11 | 2018-07-24 | 武汉轻工大学 | The application of qroxylin A or its pharmaceutically acceptable salt, solvate |
| CN108771672A (en) * | 2018-05-18 | 2018-11-09 | 武汉轻工大学 | The application of wogonin or its pharmaceutically acceptable salt, solvate |
| CN112451537A (en) * | 2020-11-16 | 2021-03-09 | 武汉轻工大学 | Application of baicalin in preparation of medicine for preventing and/or treating asymptomatic hyperuricemia and/or uric acid nephropathy |
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Application publication date: 20161012 |