CN108186625A - Ramosissimone A are in the application for preparing drugs for rheumatoid arthritis - Google Patents
Ramosissimone A are in the application for preparing drugs for rheumatoid arthritis Download PDFInfo
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- CN108186625A CN108186625A CN201810044365.2A CN201810044365A CN108186625A CN 108186625 A CN108186625 A CN 108186625A CN 201810044365 A CN201810044365 A CN 201810044365A CN 108186625 A CN108186625 A CN 108186625A
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- rheumatoid arthritis
- ramosissimone
- synoviocytes
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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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Abstract
The present invention relates to a kind of compound R amosissimone A in the application for preparing drugs for rheumatoid arthritis.First passage pharmacological evaluation of the present invention proves that ramosissimone A have the significant activity for inhibiting synoviocytes in rheumatoid arthritis proliferation and induction synoviocytes in rheumatoid arthritis apoptosis, available for preparing the drug of prevention and/or treatment rheumatoid arthritis, therefore it has higher clinical value and development prospect.The invention discloses a kind of purposes of compound ramosissimone A in resisting rheumatoid arthritis drug is prepared.Shown in formula I, it is isolated from Tamarix ramosissima branch to the structural formula of Ramosissimone A.Present invention firstly discovers that ramosissimone A can significantly inhibit the proliferation of synoviocytes in rheumatoid arthritis, the apoptosis of synoviocytes in rheumatoid arthritis is induced.
Description
Technical field
The present invention relates to a kind of compound R amosissimone A in the application for preparing drugs for rheumatoid arthritis.
Background technology
Rheumatoid arthritis (rheumatoid arthritis, RA) is a kind of chronic systemic based on arthropathy
Property autoimmune disease, at present its pathogenesis remain unknown, clinic think RA morbidity mainly due to patient itself
Immune dysfunction leads to allergic reaction, and anti-inflammatory cells is made to go bad denaturation, be deposited on joint part and make joint tissue deformity,
Disable.According to investigations, the incidence of RA is about 1-2% in world wide, and China RA patient populations fall ill more than 4,000,000
Rate is still in rising trend.
At present, rheumatoid arthritis mainly using non-steroidal anti-inflammatory drugs (diclofenac sodium, aspirin etc.) and is immunized
Inhibitor (Ismipur etc.) is treated, but these drugs are there are apparent adverse reaction, as the former damages gastrointestinal tract
Mucous membrane leads to peptic ulcer, and the latter's selective action is poor, is easy to induce infection etc..Therefore, safe and effective control is researched and developed
It is a current urgent task to treat rheumatoid arthritis drug.
In recent years, domestic and foreign scholars have made extensive and intensive studies in terms of autonomic drug treats RA, find many days
Right drug such as tripterygium glycosides, total glucoside, malicious rattan alkali etc. have preferable RA therapeutic effects.Therefore, it is developed from autonomic drug
Go out safe and efficient RA medicines to have broad prospects.
Invention content
The object of the present invention is to provide a kind of compound R amosissimone A to prepare drugs for rheumatoid arthritis
Application.
Applications of the Ramosissimone A in prevention or drugs for rheumatoid arthritis is prepared, wherein compound
The structural formula of Ramosissimone A is as follows：
Ramosissimone A are preparing the application in inhibiting synoviocytes in rheumatoid arthritis hyperproliferation agent, wherein changing
The structural formula for closing object Ramosissimone A is as follows：
First passage pharmacological evaluation of the present invention proves that there is ramosissimone A significant inhibition rheumatoid arthritis to slide
Theca cell is proliferated and the activity of induction synoviocytes in rheumatoid arthritis apoptosis, available for preparing prevention and/or treatment rheumatoid
Arthritic drug, therefore it has higher clinical value and development prospect.
The invention discloses a kind of use of compound ramosissimone A in resisting rheumatoid arthritis drug is prepared
On the way.Shown in formula I, it is isolated from Tamarix ramosissima branch to the structural formula of Ramosissimone A.The present invention is for the first time
It was found that ramosissimone A can significantly inhibit the proliferation of synoviocytes in rheumatoid arthritis, induction rheumatoid arthritis is slided
The apoptosis of theca cell.Therefore, which can be used for the drug for preparing prevention and/or treatment rheumatoid arthritis, have higher
Clinical value and development prospect.
Description of the drawings
Fig. 1 is that the ramosissimone A of various concentration in the embodiment of the present invention 1 increase synoviocytes in rheumatoid arthritis
Grow the statistical results chart of inhibiting effect.
Fig. 2 is that the ramosissimone A of various concentration in the embodiment of the present invention 2 wither to synoviocytes in rheumatoid arthritis
Die the statistical results chart of facilitation.
Specific embodiment
The present invention provides a kind of compound ramosissimone A inhibit synoviocytes in rheumatoid arthritis proliferation with
And the application in prevention and/or treatment rheumatoid arthritis.
Compound ramosissimone A structural formulas according to the present invention are shown in formula I：
Above compound be it is isolated from Tamarix ramosissima (Tamarix ramosissima Ledeb.) (ginger into
Handsome red buildings resisting rheumatoid disease arthritis chemical constitution study [D] Ningxia Medical University, 2016).Tamarix ramosissima is excellent windproof
Sand-fixation plant and the fine tree species of saline-alkali soil forestation, it is extensive in NORTHWEST CHINA Area distribution, it is resourceful.
The application of ramosissimone A provided by the present invention includes two aspects：1) it is preparing prevention for it and/or is controlling
Treat the application in the product of rheumatoid arthritis；2) in its product in preparation inhibition synoviocytes in rheumatoid arthritis proliferation
Application.
It is in particular in that ramosissimone A can significantly inhibit the proliferation of synoviocytes in rheumatoid arthritis, induces
The apoptosis of synoviocytes in rheumatoid arthritis, available for preparing the drug of prevention and/or treatment rheumatoid arthritis.
In addition, the following products prepared using ramosissimone A as active ingredient：1) prevent and/or treat rheumatoid
Arthritic product；2) inhibit the product of synoviocytes in rheumatoid arthritis proliferation, also belong to protection scope of the present invention.
Prevent and/or treat the drug of rheumatoid arthritis in the present invention and synoviocytes in rheumatoid arthritis is inhibited to increase
The drug grown can be imported by the method injecting, spray, permeate, absorb, physically or chemically mediate body for example muscle, it is intradermal,
Subcutaneously, vein, mucosal tissue；Or imported body after other material mixings or package.
When needs, one or more pharmaceutically acceptable carriers can also be added in said medicine.The load
Diluent of the body including pharmaceutical field routine, excipient, filler, adhesive, wetting agent, disintegrant, sorbefacient, surface
Activating agent, absorption carrier, lubricant etc..
A variety of shapes such as parenteral solution, tablet, pulvis, granule, capsule, oral liquid, paste, creme can be made in said medicine
Formula.The drug of any of the above dosage form can be prepared according to the conventional method of pharmaceutical field.
In order to make the purpose , technical scheme and advantage of the present invention be clearer, with reference to embodiments, to the present invention
It is further elaborated.It should be appreciated that the specific embodiments described herein are merely illustrative of the present invention, it is not used to
Limit the present invention.
Embodiment 1：
The inhibiting effect that Ramosissimone A are proliferated synoviocytes in rheumatoid arthritis.
Cell：Human rheumatoid arthritis synovial cell (RA-FLS)；
Drug：ramosissimone A；
Method：The recovery of 1.RA-FLS
RA-FLS cryopreservation tubes are taken out rapidly from liquid nitrogen filling, put the thermostat water bath that temperature is 37 DEG C into, it is continual to shake
It shakes, accelerates cell and thaw.After thawing completely, the RA-FLS suspension in cryopreservation tube is moved to pipettor in super-clean bench
In 10mL sterile centrifugation tubes, 5min, rotating speed 1000r/min are centrifuged.Supernatant is outwelled, 5mL complete culture solutions is added in, uses pipettor
It is lasting to blow and beat to uniform cell suspension, RA-FLS is inoculated in 25mL Tissue Culture Flasks, is put into cell incubator and cultivates,
Incubator condition setting be 37 DEG C of temperature, CO2Concentration 5%.The growing state of RA-FLS is observed after for 24 hours under the microscope, works as hair
Existing cell is adherent, triangular in shape and irregular fusiformis when, show that cell growth status is good.
The passage of 2.RA-FLS
It observes under the microscope, when RA-FLS adherent growths are to account for entire Tissue Culture Flask bottom 80% or so, i.e.,
It can carry out cell passage.The original fluid in culture bottle is outwelled, is rinsed 2 times with PBS, it is therefore an objective to original fluid be cleaned, avoided
Influence cell dissociation；It adds in 0.25% tryptic digestive juice to be digested, and situation is digested in micro- Microscopic observation RA-FLS,
It treats to see that most cells become bowlder and add in suitable fetal calf serum (FBS) termination digestion under mirror, then add in a certain amount of complete
Full nutrient solution blows and beats culture bottle inner wall with aseptic straw repeatedly in culture bottle, in uniform cell suspension；Use cell counting board
Cell is counted, after counting, RA-FLS is inoculated in 2 new culture bottles, and add in suitable complete culture
Liquid is put into cell incubator and cultivates, incubator condition setting be 37 DEG C of temperature, CO2Concentration 5%, i.e., one mode for passing two pass
It is commissioned to train foster.
3.MTT methods measure cell inhibitory rate
The culture solution that suitable ramosissimone A is taken to be made into 0.01,0.1,1,5,10 μM respectively with DMEM.It takes and is in
The RA-FLS of exponential phase outwells the original fluid in culture bottle, is rinsed 2 times with PBS, adds in 0.25% trypsin digestion
Liquid is digested, and digests situation in micro- Microscopic observation RA-FLS, treats to see that cell largely becomes bowlder and adds in right amount under mirror
FBS terminate digestion, then add in a certain amount of culture solution in culture bottle, ceaselessly blown and beaten in culture bottle with aseptic straw
Wall in uniform cell suspension, is counted with cell counting board, and it is 1 × 10 to adjust cell concentration with culture solution5A/mL, will
RA-FLS is inoculated in 96 hole steril cell culture plates, per 100 μ L of hole, is put into cell incubator and is cultivated, incubator condition is set
It is set to 37 DEG C of temperature, CO2Concentration 5%.Be incubated for 24 hours after, by 96 orifice plates be divided into 6 groups (i.e. blank control group, 0.01,0.1,1,5,
10 μM of medicine groups, every group of 6 multiple holes), the original fluid in hole is sopped up, is separately added into the DMEM of equivalent and the drug containing of various concentration
Culture medium is put into cell incubator and intervenes.Intervene for 24 hours and after 48h, 20 μ LMTS, 37 DEG C of incubation 1.5h added in each hole,
Absorbance of each hole at 540nm wavelength is measured with enzyme-linked immunosorbent assay instrument, calculates the inhibiting rate of each group cell.
Calculation formula is as follows：
Cell inhibitory rate/%=(1- blank control group OD values/each acute drug group OD values) × 100%
As a result：A concentration of 0.1~10 μM of ramosissimone A can significantly inhibit the proliferation of RA-FLS, and inhibit
Effect enhances with the increase of drug concentration.
Embodiment 2：
Ramosissimone A are to the facilitation of synoviocytes in rheumatoid arthritis apoptosis.
Cell：Human rheumatoid arthritis synovial cell (RA-FLS)；
Drug：ramosissimone A；
Method：The recovery of 1.RA-FLS
It is same as Example 1.
The passage of 2.RA-FLS
It is same as Example 1.
3.TUNEL methods measure Apoptosis
The fracture of chromosomal DNA is a progressive process stage by stage in Apoptosis, and chromosomal DNA is first in endogenous
Hydrolase nucleic acid under the action of be degraded to the large fragment of 50-300kb.Then about 30% chromosomal DNA is in Ca2+And Mg2+
It under the endonuclease enzyme effect of dependence, is cut off at random between nucleosomal units, forms 180~200bp nucleosome DNA polies
Body.As long as a series of 3 '-OH ends of DNA for notch occur on DNA double chain fracture or a chain and generating can be in deoxyribose
Under the action of nucleotide terminal enzyme (DNA) (TdT), by deoxyribonucleotide and fluorescein, peroxidase, alkaline phosphatase
The derivative that enzyme or biotin are formed is tagged to 3 '-end of DNA, so as to carry out the detection of apoptotic cell, this kind of method one
As be known as deoxyribonucleotide terminal enzyme (DNA) mediation Nick End labelling method (TUNEL).
The culture solution that suitable ramosissimone A is taken to be made into 0.1 and 1 μM respectively with DMEM, RA-FLS cells are in sky
48h is incubated in bletilla drug containing culture solution, fixes 30min using 4% paraformaldehyde at room temperature.It is floated with phosphate buffer (PBS)
It washes 3 times, adds in cell membrane penetration liquid (0.1% sodium citrate, 0.1%Triton X-100) and act on 2min.Using de- at 37 DEG C
Oxygen ribonucleotide terminal enzyme (DNA) (TdT) and biotin -11- deoxyuridine triphosphates (biotin-11-dUTP) are marked
React 1h.Using fluorescence microscope cellular morphology and calculate apoptotic index.
Calculation formula is as follows：
Apoptotic index/%=(apoptosis cell/1000 in 1000 cells) × 100%.
The RamosissimoneA of present invention Ramosissimone in the application for preparing drugs for rheumatoid arthritis
The dosage of A is 0.2~1.0mg/kg/day, and usage is oral.
Claims (2)
- Applications of the 1.Ramosissimone A in prevention or drugs for rheumatoid arthritis is prepared, wherein compound The structural formula of Ramosissimone A is as follows：
- 2.Ramosissimone A are preparing the application in inhibiting synoviocytes in rheumatoid arthritis hyperproliferation agent, wherein chemical combination The structural formula of object Ramosissimone A is as follows：
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810044365.2A CN108186625B (en) | 2018-01-17 | 2018-01-17 | Application of RamosisimoneA in preparing medicine for treating rheumatoid arthritis |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810044365.2A CN108186625B (en) | 2018-01-17 | 2018-01-17 | Application of RamosisimoneA in preparing medicine for treating rheumatoid arthritis |
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| CN108186625A true CN108186625A (en) | 2018-06-22 |
| CN108186625B CN108186625B (en) | 2022-02-15 |
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| CN201810044365.2A Active CN108186625B (en) | 2018-01-17 | 2018-01-17 | Application of RamosisimoneA in preparing medicine for treating rheumatoid arthritis |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106581092A (en) * | 2016-11-28 | 2017-04-26 | 宁夏医科大学 | Tamarix ramosissima Ledeb extract and application thereof in preparation of medicine for treatment of rheumatoid arthritis |
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2018
- 2018-01-17 CN CN201810044365.2A patent/CN108186625B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106581092A (en) * | 2016-11-28 | 2017-04-26 | 宁夏医科大学 | Tamarix ramosissima Ledeb extract and application thereof in preparation of medicine for treatment of rheumatoid arthritis |
Non-Patent Citations (3)
| Title |
|---|
| WOLFGANG STADLBAUER UND THOMAS KAPPE: "Oxidative Hydroxylierung von heterocyclischen β-Dicarbonylberbindungen", 《MONATSHEFTE FUR CHEMIE》 * |
| 姜成帅: "红柳抗类风湿关节炎化学成分研究", 《中国优秀硕士学位论文全文数据库 医药卫生科技辑》 * |
| 李娟等: "多枝柽柳中的酚酸类化学成分", 《中国中药杂志》 * |
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| CN108186625B (en) | 2022-02-15 |
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