CN108853113A - The purposes of oxa- rutaecarpin derivative - Google Patents
The purposes of oxa- rutaecarpin derivative Download PDFInfo
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- CN108853113A CN108853113A CN201810601573.8A CN201810601573A CN108853113A CN 108853113 A CN108853113 A CN 108853113A CN 201810601573 A CN201810601573 A CN 201810601573A CN 108853113 A CN108853113 A CN 108853113A
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- rutaecarpin
- oxa
- derivative
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- 0 CN(C1N2CCC3=C1*c1ccccc31)c(cccc1)c1C2=O Chemical compound CN(C1N2CCC3=C1*c1ccccc31)c(cccc1)c1C2=O 0.000 description 1
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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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with heterocyclic ring systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/06—Free radical scavengers or antioxidants
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
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- Neurosurgery (AREA)
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- Bioinformatics & Cheminformatics (AREA)
- Toxicology (AREA)
- Hospice & Palliative Care (AREA)
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Abstract
The present invention relates to the purposes of pharmaceutical technology field more particularly to oxa- rutaecarpin derivative.The present invention provides the antioxidations of oxa- rutaecarpin derivative, and provide its application in the drug that preparation improves dementia symptom.Experiment shows that the antioxidant activity of oxa- rutaecarpin derivative and the effect of improvement dementia are all significantly better than rutaecarpin, and reduces cytotoxicity.
Description
Technical field
The present invention relates to the purposes of pharmaceutical technology field more particularly to oxa- rutaecarpin derivative.
Background technique
Evodia rutaecarpa is China's conventional Chinese medicine, has the multiple efficacies such as eliminating cold to stop pain, stopping nausea and vomiting by lowering the adverse flow of QI, supporing yang antidiarrheal.Evodia rutaecarpa
Contained chemical component is numerous, and rutaecarpin is one of its main active, structure such as Formula V.
In recent years, the research of the bioactivity of rutaecarpin is made great progress.Such as research shows that：Wu Zhu
Cornel alkali has stomach invigorating, analgesia, stops retch and only rising up of acid from the stomach and other effects；There is diuresis；There is the inhibiting effect of strength to Escherichia coli；
There is significant insecticidal action to ascaris suum；There are also contraction uterus and boostings, and study discovery rutaecarpin and can reduce cell
Factor IL-1 β, IL-6, TNF-α overexpression, inhibit inflammatory reaction, inhibit brain tissue No microglial overactivity,
Improve the ability of learning and memory of APPswe/PS △ E9 Model of Dementia mouse.
But the cytotoxicity of rutaecarpin is larger, and physicochemical property is bad, limits it and further studies.Study table
It is bright, aromatization reaction is removed using EDCI induction, it, can be with one-step synthesis using carboline and substituted septichen as raw material
Corresponding oxa- rutaecarpin derivative.The method is directly efficient, and post-processing is easy, does not need additional protecting group.About oxygen
The biological Mars of miscellaneous rutaecarpin, that has verified at present is that oxa- rutaecarpin derivative can have anti-tumor activity, but
Document report is had no in other respects.
Summary of the invention
In view of this, the technical problem to be solved in the present invention is that providing the purposes of oxa- rutaecarpin derivative, this hair
Bright the study found that oxa- rutaecarpin derivative has the function of that treatment is dull-witted, and cytotoxicity is lower, will with rutaecarpin
The dull-witted better effect than treatment.
The present invention provides oxa- rutaecarpin derivatives to prepare the application in oxidation resistant preparation.
In the embodiment of the present invention, the oxa- rutaecarpin derivative is the compound of structure shown in Formulas I~IV：
The present invention studies have shown that concentration be 0.05 μ g/mL Formulas I~IV shown in structure compound to hydrogen peroxide at
The cell of reason has good protective effect, and the compound of structure shown in formula I~IV has good antioxidant activity.
The cell is human neuroblastoma cells shy5y.And test display, the compound of structure shown in Formulas I~IV it is anti-oxidant
Activity is significantly better than rutaecarpin.Compared with rutaecarpin, Formulas I compound, Formula II compound, formula III compound, formula IV
It closes object and 50%, 40%, 30% and 50% has been increased separately to the antioxidant activity of shy5y.
The present invention also provides application of the oxa- rutaecarpin derivative in the drug that preparation improves dementia symptom.
In the embodiment of the present invention, the oxa- rutaecarpin derivative is the compound of structure shown in Formulas I~IV：
The present invention is studies have shown that the compound that dosage is structure shown in Formulas I~IV of 1.6mg/kg body weight/day can mention
The female APP/PS1 double transgenic Model of Dementia mouse at high 4 monthly age is and small in the residence time of water maze laboratory target quadrant
Mouse is all apparently higher than vehicle control group in the number for passing through target quadrant, and the compound of structure shown in formula I~IV has good
The effect of good improvement dementia symptom.And test display, the effect of the improvement dementia symptom of the compound of structure shown in Formulas I~IV
Fruit is significantly better than rutaecarpin.
In some embodiments, the oxa- rutaecarpin derivative improve dementia symptom dosage be 1.6mg/kg weight/
It.
In some embodiments, the drug is the drug of low bio-toxicity.
The present invention is studies have shown that the compound that concentration is structure shown in Formulas I~IV of 5 μ g/mL has no cell activity
It is obvious to inhibit, and have the function of certain promotion cell activity, the compound of structure shown in formula I~IV has low life
The characteristics of object toxicity.The cell is human neuroblastoma cells shy5y or human liver cancer cell hepG2.And identical test item
Under part, rutaecarpin produces apparent inhibiting effect to cell activity.
The present invention also provides a kind of drugs for improving dementia symptom, including oxa- rutaecarpin derivative.
In drug provided by the invention, the oxa- rutaecarpin derivative is the compound of structure shown in Formulas I~IV：
In the embodiment of the present invention, the drug is injection or oral preparation.
The dosage form of the oral preparation is tablet, capsule, capsule and pill, oral solutions, pill, granule or oral scattered
Agent.
In some embodiments, the solvent of the injection is the PBS solution containing 20vol%PEG.
The present invention provides the antioxidations of oxa- rutaecarpin derivative, and it is dull-witted in preparation improvement to provide it
Application in the drug of symptom.Experiment shows the antioxidant activity of oxa- rutaecarpin derivative and improves dull-witted effect all
It is significantly better than rutaecarpin, and reduces cytotoxicity.
Detailed description of the invention
Fig. 1 shows 4 kinds of oxa- rutaecarpin derivative cytotoxicity analysis；Wherein, Fig. 1-a shows to SH-Y5Y cell activity
Influence；Fig. 1-b shows the influence to HepG2 cell activity；
Fig. 2 shows the antioxidation of 4 kinds of oxa- rutaecarpin derivatives；
Fig. 3 shows that 4 kinds of oxa- rutaecarpin derivatives improve the cognitive behavior of dementia mice；Wherein, Fig. 3-a shows to target
The influence of quadrant residence time；Fig. 3-b shows the influence to target quadrant traversing times.
Specific embodiment
The present invention provides the purposes of oxa- rutaecarpin derivative, those skilled in the art can use for reference present disclosure,
It is suitably modified realization of process parameters.In particular, it should be pointed out that all similar substitutions and modifications carry out those skilled in the art
Say it is it will be apparent that they are considered as being included in the present invention.Method and application of the invention has passed through preferred embodiment
Be described, related personnel obviously can not depart from the content of present invention, in spirit and scope to methods herein and application into
Row change or appropriate changes and combinations, carry out implementation and application the technology of the present invention.
The test material that the present invention uses is all common commercially available product, can all be bought in market.
Formulas I~IV compound is synthesized using carboline and substituted septichen as raw material according to the method in document
(Chem Comm,2016,52(87):12869-12872)。
Below with reference to embodiment, the present invention is further explained：
Embodiment 1：4 kinds of oxa- rutaecarpin derivatives reduce cytotoxicity than rutaecarpin
Human neuroblastoma cells shy5y and human liver cancer cell hepG2 are seeded in respectively in 96 orifice plates, every hole 1
Ten thousand cells.Cell culture is stayed overnight.Formulas I~IV oxa- rutaecarpin derivative is separately added into the cell of overnight incubation,
Final concentration of 5 μ g/ml, it is (each by positive control of the rutaecarpin of comparable sodium solvent DMSO is added as negative control
6 repetitions of drug).Cell continues culture 48 hours, how much living cells is analyzed with CCK-8kit, as a result such as Fig. 1.As the result is shown：
Relative to rutaecarpin, Formulas I~IV compound reduces 77%, 67%, 87% and to the cytotoxicity of shy5y respectively
110%；250%, 210%, 170% and 260% is reduced respectively to the cytotoxicity of hepG2, p<0.05.
Embodiment 2：4 kinds of oxa- rutaecarpin derivatives enhance antioxidant activity than rutaecarpin
Human neuroblastoma cells shy5y is seeded in 96 orifice plates, 10,000, every hole cell.Cell culture is stayed overnight.?
4 kinds of oxa- rutaecarpin derivatives, final concentration of 0.05 μ g/ml, solvent is added are separately added into the cell of overnight incubation
DMSO is negative control, using the rutaecarpin of comparable sodium as positive control (6 repetitions of each drug).Cell continues culture 3
After hour, hydrogen peroxide is added to 200um/ml, using PBS as H in every hole2O2Negative control, continue culture 24 hours, CCK-
It is how many (Fig. 2) that 8kit analyzes living cells.The results show that four kinds of derivatives are all to the cell activity under hydrogen peroxide effect with good
Good protective effect, illustrates that four kinds of derivatives all have good antioxidant activity.It is compared with rutaecarpin, Formulas I~IV chemical combination
Object has increased separately 50%, 40%, 30% and 50% to the antioxidant activity of shy5y, p<0.05.
Embodiment 3：Therapeutic effect of 4 kinds of oxa- rutaecarpin derivatives to transgenosis dementia mice
The female APP/PS1 double transgenic Model of Dementia mouse at 4 monthly ages and it is divided into 7 with the other wild-type mice of the age same sex
Group, every group 7, respectively wild control group, model control group, rutaecarpin treatment group, 49 treatment group of derivative, derivative
51 treatment groups, 58 treatment group of derivative, 60 treatment group of derivative.Rutaecarpin and 4 kinds of oxa- rutaecarpin derivative difference are molten
Solution, by the dosage of 1.6mg/kg body weight/day, is injected intraperitoneally in 20%PEG/PBS solution, 5 times a week, continuous 4 weeks.It is wild
Control and model comparison give the solvent of equal volume.It is discontinued after a week, carries out water maze laboratory, training 5 according to a conventional method
It, the spatial memory capacity (Fig. 3) of the 6th day detection mouse.The result shows that rutaecarpin and 4 kinds of oxa- rutaecarpin derivatives
The mouse for the treatment of is all apparently higher than vehicle control group, and 4 kinds of oxa- rutaecarpin derivatives in the residence time of target quadrant
Effect it is more stronger than rutaecarpin；The mouse of rutaecarpin and 4 kinds of oxa- rutaecarpin derivatives for treatment is passing through target quadrant
Number be all apparently higher than vehicle control group, 4 kinds of oxa- rutaecarpin derivative effects are more stronger than rutaecarpin or fair,
The significant effect of the compound experimental group of middle giving construction I or formula IV is better than the effect of other experimental groups, p<0.05.
The above is only the preferred embodiment of the present invention, it is noted that those skilled in the art are come
It says, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications should also regard
For protection scope of the present invention.
Claims (9)
1. oxa- rutaecarpin derivative is preparing the application in oxidation resistant preparation.
2. application according to claim 1, which is characterized in that the oxa- rutaecarpin derivative is shown in Formulas I~IV
The compound of structure：
3. application of the oxa- rutaecarpin derivative in the drug that preparation improves dementia symptom.
4. application according to claim 3, which is characterized in that the oxa- rutaecarpin derivative is shown in Formulas I~IV
The compound of structure：
5. a kind of drug for improving dementia symptom, which is characterized in that including oxa- rutaecarpin derivative.
6. drug according to claim 5, which is characterized in that the oxa- rutaecarpin derivative is shown in Formulas I~IV
The compound of structure：
7. drug according to claim 5 or 6, which is characterized in that the drug is injection or oral preparation.
8. drug according to claim 7, which is characterized in that the dosage form of the oral preparation is tablet, capsule, capsule and pill
Agent, oral solutions, pill, granule or oral powder.
9. drug according to claim 7, which is characterized in that the solvent of the injection is to contain 20vol%PEG's
PBS solution.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810601573.8A CN108853113B (en) | 2018-06-12 | 2018-06-12 | Application of oxaevodiamine derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810601573.8A CN108853113B (en) | 2018-06-12 | 2018-06-12 | Application of oxaevodiamine derivative |
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| Publication Number | Publication Date |
|---|---|
| CN108853113A true CN108853113A (en) | 2018-11-23 |
| CN108853113B CN108853113B (en) | 2021-08-10 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810601573.8A Active CN108853113B (en) | 2018-06-12 | 2018-06-12 | Application of oxaevodiamine derivative |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110483550A (en) * | 2019-09-04 | 2019-11-22 | 南华大学 | One kind derivative of rutaecarpin containing trimethoxyphenyl and its application |
| CN115381835A (en) * | 2022-08-29 | 2022-11-25 | 上海大学 | Application of evodiamine derivative in preventing or treating postmenopausal osteoporosis |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103992336A (en) * | 2014-05-19 | 2014-08-20 | 中国人民解放军第二军医大学 | Oxa- or thio-evodiamine anti-tumor derivatives and preparation method thereof |
-
2018
- 2018-06-12 CN CN201810601573.8A patent/CN108853113B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103992336A (en) * | 2014-05-19 | 2014-08-20 | 中国人民解放军第二军医大学 | Oxa- or thio-evodiamine anti-tumor derivatives and preparation method thereof |
Non-Patent Citations (4)
| Title |
|---|
| LE SHI, ET AL.: "Evodiamine exerts anti-tumor effects against hepatocellularcarcinoma through inhibiting β-catenin-mediated angiogenesis", 《TUMOR BIOL.》 * |
| 张兆旺: "《中药药剂学》", 31 January 2003 * |
| 王君伟: "吴茱萸生物碱的提取、纯化、结构及抗氧化性能的研究", 《华中农业大学硕士学位论文》 * |
| 袁树民: "吴茱萸碱对APPswe/PS△E9转基因阿尔茨海默病小鼠模型的治疗作用及机理研究", 《中国医学科学院北京协和医学院博士学位论文》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110483550A (en) * | 2019-09-04 | 2019-11-22 | 南华大学 | One kind derivative of rutaecarpin containing trimethoxyphenyl and its application |
| CN115381835A (en) * | 2022-08-29 | 2022-11-25 | 上海大学 | Application of evodiamine derivative in preventing or treating postmenopausal osteoporosis |
| CN115381835B (en) * | 2022-08-29 | 2023-12-22 | 上海大学 | Application of evodiamine derivative in preventing or treating postmenopausal osteoporosis |
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| Publication number | Publication date |
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| CN108853113B (en) | 2021-08-10 |
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