CN110483463A - Aurora kinase-B antagonist and its application - Google Patents
Aurora kinase-B antagonist and its application Download PDFInfo
- Publication number
- CN110483463A CN110483463A CN201910846645.XA CN201910846645A CN110483463A CN 110483463 A CN110483463 A CN 110483463A CN 201910846645 A CN201910846645 A CN 201910846645A CN 110483463 A CN110483463 A CN 110483463A
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- Prior art keywords
- compound
- pharmaceutically acceptable
- aurora
- acceptable salt
- aurora kinase
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
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- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides 2 kinds of aurora kinase-B antagonists and its application, external biological experiment finds it with aurora kinase-B antagonistic activity.
Description
Technical field
The invention belongs to small-molecule drug fields, more particularly, to 2 kinds of aurora kinase-B antagonists and its application.
Background technique
Kinases inhibitor is a kind of compound for inhibiting protein kinase activity.According to the type of protein kinase, can divide
For serine/threonine protein kitase inhibitor or tyrosine kinase inhibitor, the former can be divided into three according to site of action again
Group, one group acts on catalytic domain, and one group acts on regulatory region, and another group has effect to regulatory region and catalytic domain.Numerous researchs
Report, kinases inhibitor can be used for treating by diseases such as protein kinase-activated caused malignant tumour, arthritis, together
When, it can also prevent the activation of T lymphocyte, have therapeutic effect to panimmunity disease.
Aurora kinase (aurora) is one of mitotic kinase, it belong to serine/threonine kinase family at
Member, in recent years the study found that the expression of aurora kinase has up-regulation phenomenon, therefore, pole in most tumour cell
Effect of the light kinases in the generation, development and therapeutic process of tumour causes the extensive concern of people.Aurora kinase mainly has
Aurora A, Aurora B and 3 kinds of hypotypes of Aurora C.Studies have found that Aurora-B plays the role of proto-oncogene.
Aurora-B kinases is made of 344 amino acid residues, which is encoded by AKU RB (STK12) gene, chromosome mapping
It is a transposition, missing or the active chromosome segment of amplification in 17p13.1.Aurora-B during cell mitogen
It is in DYNAMIC DISTRIBUTION, early period and mid-term were assembled on the centromere of chromosome before this, and gradually migrated into mitosis anaphase
To spindle, finally gather on the intermediate for connecting two daughter cells.
In recent years, Aurora-B report of unconventionality expression in samples of human glioma gradually increases, and Aurora-B has become mesh
A preceding molecular targeted hot spot for inhibiting research.
Summary of the invention
In view of this, the present invention is directed to propose 2 kinds of aurora kinase-B antagonists and its application.
In order to achieve the above objectives, the technical scheme of the present invention is realized as follows:
The present invention provides structural formula (I, II) compound and its pharmaceutically acceptable salt for indicating:
Entitled hesperetin is commonly used, the entitled Tangeretin of English, No. CAS is 481-53-8, molecular formula C20H20O7, molecule
Amount is 372.369.
Commonly use entitled artemetine, English entitled 5-Hydroxy-3,3 ', 4 ', 6,7-pentamethoxyflavone, CAS
Number be 479-90-3, molecular formula C20H20O8, molecular weight 388.368.
Above compound and its pharmaceutically acceptable salt preparation for treat or prevent the expression of aurora kinase-B height or
The purposes of the drug of related disease caused by hyperactivity or illness.
The purposes of above compound and its pharmaceutically acceptable salt in preparation treatment colloid tumor medicine.
A kind of pharmaceutical composition, including above compound and its pharmaceutically acceptable salt and its pharmaceutically acceptable tax
Shape agent.
Described pharmaceutical composition further includes pharmaceutically acceptable excipient, diluent or carrier.It is specific as syrup, I
Primary glue and starch etc..The pharmaceutical composition can by vein, it is oral, sublingual, given through muscle or subcutaneous, skin and mucosa approach
Medicine.
The dosage form of described pharmaceutical composition is liquid preparation or solid pharmaceutical preparation.Specific such as tablet, capsule and injection
Agent etc..Each dosage form can be prepared with pharmacy conventional method.
A kind of compound medicine includes above compound and its pharmaceutically acceptable salt and can be with medicine associated with it
Object.
Compared with the existing technology, 2 kinds of aurora kinase-B antagonists of the present invention and its application have the advantage that
The IC of the aurora kinase-B functional experiment (Aurora-B kinase assay) of 2 kinds of compounds of the present invention50
At 10 μM hereinafter, the IC of compound 481-53-850It is 8.856 μM, the IC of compound 479-90-350It is 6.74 μM.
Detailed description of the invention
Fig. 1 is the compounds of this invention 481-53-8 in functional experiment to the inhibiting rate curve of aurora kinase-B；
Fig. 2 is the compounds of this invention 479-90-3 in functional experiment to the inhibiting rate curve of aurora kinase-B；
Specific embodiment
In addition to being defined, technical term used in following embodiment has universal with those skilled in the art of the invention
The identical meanings of understanding.Test reagent used in following embodiment is unless otherwise specified conventional biochemical reagent；It is described
Experimental method is unless otherwise specified conventional method.
The present invention relates to compound 481-53-8 and 479-90-3 to be purchased from Chengdu De Site Bioisystech Co., Ltd.
Below with reference to embodiment, the present invention will be described in detail.
Embodiment
Experimental procedure
1,1x kinase reaction buffer is prepared:
The 5X kinase reaction buffer of 1 times of volume and the water of 4 times of volumes；5mM MgCl2；1mM DTT.
2, screening compound:
A) compound diluted with Echo 550 to the every hole transfer 10nl of reaction plate (784075, Greiner)；
B) reaction plate is sealed with sealing plate film, 1000g is centrifuged 1 minute.
C) it is prepared with the enzyme reaction buffer solution of 1X and prepares 2X Aurora-B.
D) into reaction plate, 5 μ l Aurora-B kinases (preparing in step 3) are added in every hole.Plank is sealed with sealing plate film
1000g is centrifuged 1 minute, is placed at room temperature for 10 minutes.
E) 2x STK2-substrate-biotin and ATP mixed liquor is prepared with the enzyme reaction buffer solution of 1X, mixed, to anti-
It answers and 5 μ l STK2-substrate-biotin/ATP mixed liquors is added in plate.
F) plank 1000g is sealed with sealing plate film to be centrifuged 30 seconds, react at room temperature 30 minutes.
G) buffer 2X Sa-XL 665 and STK-antibody-Cryptate is detected with HTRF.
H) 10 μ l Sa-XL 665/STK-antibody-Cryptate, 1000g is added centrifugation 1 minute in every hole, and room temperature is anti-
It answers 1 hour.
I) fluorescence signal of 615nm (Cryptate) and 665nm (XL665) are read with Envision 2104.
Through this embodiment, it was found that two kinds of aurora kinase-B antagonists, the external inhibitory activity of compound 481-53-8 are
8.856 μM, the external inhibitory activity of compound 479-90-3 is 6.74 μM.
Claims (7)
1. compound and its pharmaceutically acceptable salt that structure formula (I) indicates:
2. compound and its pharmaceutically acceptable salt that structure formula (II) indicates:
3. any one of the claim 1-2 compound and its pharmaceutically acceptable salt are in preparation for treating or preventing aurora
The purposes of the drug of related disease caused by the expression of kinases-B height or hyperactivity or illness.
4. the use that any one of the claim 1-2 compound and its pharmaceutically acceptable salt treat colloid tumor medicine in preparation
On the way.
5. a kind of pharmaceutical composition, it is characterised in that: including any one of claim 1-2 as the active constituent compound
Or its pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient.
6. a kind of compound medicine, it is characterised in that: comprising the described in any item aurora kinase-B antagonists of claim 1-2 and
It can be with drug associated with it.
7. pharmaceutical composition according to claim 5 is in preparation for treating or preventing the expression of aurora kinase-B height or activity
The purposes of the drug of related disease caused by excessively high or illness.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910846645.XA CN110483463A (en) | 2019-09-09 | 2019-09-09 | Aurora kinase-B antagonist and its application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910846645.XA CN110483463A (en) | 2019-09-09 | 2019-09-09 | Aurora kinase-B antagonist and its application |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN110483463A true CN110483463A (en) | 2019-11-22 |
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| CN201910846645.XA Pending CN110483463A (en) | 2019-09-09 | 2019-09-09 | Aurora kinase-B antagonist and its application |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002087567A2 (en) * | 2001-05-02 | 2002-11-07 | Kgk Synergize Inc. | Polymethoxylated flavones for treating insulin resistance |
| JP2012232916A (en) * | 2011-04-28 | 2012-11-29 | Tokyo Univ Of Agriculture & Technology | Composition for prevention or treatment of bone disease |
| CN106562954A (en) * | 2016-11-11 | 2017-04-19 | 黄冈师范学院 | Application of (demethylated) polymethoxylated flavones and paclitaxel drugs in preparation of drugs for treating non-small cell lung cancer |
| CN107007591A (en) * | 2017-03-03 | 2017-08-04 | 黄冈师范学院 | A kind of application of polymethoxyflavone on the medicine for preparing treatment melanoma |
-
2019
- 2019-09-09 CN CN201910846645.XA patent/CN110483463A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002087567A2 (en) * | 2001-05-02 | 2002-11-07 | Kgk Synergize Inc. | Polymethoxylated flavones for treating insulin resistance |
| JP2012232916A (en) * | 2011-04-28 | 2012-11-29 | Tokyo Univ Of Agriculture & Technology | Composition for prevention or treatment of bone disease |
| CN106562954A (en) * | 2016-11-11 | 2017-04-19 | 黄冈师范学院 | Application of (demethylated) polymethoxylated flavones and paclitaxel drugs in preparation of drugs for treating non-small cell lung cancer |
| CN107007591A (en) * | 2017-03-03 | 2017-08-04 | 黄冈师范学院 | A kind of application of polymethoxyflavone on the medicine for preparing treatment melanoma |
Non-Patent Citations (1)
| Title |
|---|
| LI-LI MA等: "Tangeretin induces cell cycle arrest and apoptosis through upregulation of PTEN expression in glioma cells", 《BIOMEDICINE & PHARMACOTHERAPY》 * |
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