CN105193795A - Application of two halogen-phenol compounds to effect of promoting angiogenesis - Google Patents
Application of two halogen-phenol compounds to effect of promoting angiogenesis Download PDFInfo
- Publication number
- CN105193795A CN105193795A CN201510602045.0A CN201510602045A CN105193795A CN 105193795 A CN105193795 A CN 105193795A CN 201510602045 A CN201510602045 A CN 201510602045A CN 105193795 A CN105193795 A CN 105193795A
- Authority
- CN
- China
- Prior art keywords
- compounds
- medicine
- halogen
- effect
- angiogenesis
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 0 CC=CN(CC(C=CC(Br)=C=C1)=C1C(c1cc(O)c(*)cc1SC)=O)C(*)=* Chemical compound CC=CN(CC(C=CC(Br)=C=C1)=C1C(c1cc(O)c(*)cc1SC)=O)C(*)=* 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention relates to two halogen-phenol compounds, namely 2, 4', 5'-trihydroxy-5, 2'-dibromo benzophenone and 2',5-dibromo-2-(2-phenyl imidazole-1-group) methyl-4',5'-dihydroxy benaophenonel, and novel pharmacological application of medicine compositions of the two compounds in the effect of promoting angiogenesis. According to the application of the two halogen-phenol compounds, the angiogenesis promotion effect of the two halogen-phenol compounds is defined, and the compounds have the specific effects that the length of a damaged internode blood vessel of a zebra fish can be remarkably increased, and the zebra fish suffering from vascular injury can be protected. The compounds can be used independently or in combination with other pharmaceutic adjuvant ingredients acceptable to pharmacy for preparing medicine having the angiogenesis promotion function, and potential application prospects in prevention and treatment of ischemic heart disease, apoplexy, muscle atrophy, far-end limb necrosis and the like are achieved.
Description
Technical field
The invention belongs to halophenol compound novelty teabag field, be specifically related to two kinds of halophenol compounds and the application of pharmaceutical composition in angiogenesispromoting effect thereof, the application specifically in the disease such as ischemic heart desease, apoplexy, amyotrophy, distal limb necrosis that prevention and therapy is relevant to angiogenesispromoting effect.
Background technology
It is active that halophenol compound has the multi-biologicals such as antioxidation, antimicrobial, antitumor, antithrombotic, antiinflammatory, alpha-glucosaccharase enzyme level, Protein-tyrosine-phosphatase (PTPIB) suppression, biological refusing to eat.For solving the limitation of its biogenetic derivation; applicant's design and synthesis various new halophenol compound in early stage, find this compounds have protect vascular endothelial cell, atherosclerosis significantly, pharmacological action that myocardial damage that protection ischemia-reperfusion causes etc. is relevant to cardiovascular disease.
Brachydanio rerio, as a kind of animal model, plays an important role, is widely used in each process of medicament research and development simultaneously in the research in the multidisciplinary fields such as toxicology, hereditism, auxology.Because Brachydanio rerio and mankind's related gene and signal path have high homology, it is made to have great potentiality in new medicament screen field.Embryo and the larva of Brachydanio rerio are transparent, are easy to observe disease development and medicine to the detailed process of disease effect at body.It is worth noting compared with small-sized mammalian, Brachydanio rerio nearly all blood vessel in growth course realize visual, non-invasively can produce some vascular morphologies and hemodynamic parameter, this advantage is the research means of the promotion angiogenesis function described in the application.In addition, Brachydanio rerio individuality is little, growth promoter rapid, micromolecule permeability is strong, can reduce the demand of given the test agent.
A kind ofly have in the pharmaceutical procedures of prevention and therapy and angiogenesispromoting effect relevant disease safely and effectively in exploitation, cell growth factor subclass medicine has played important function.But very important is that biopharmaceutical macromolecular drug often faces problems such as obtaining difficulty, instability, bioavailability is low, administration is inconvenient, and compliance is low.Therefore obtain a kind of small-molecule drug with promotion angiogenesis function, more selection of clinical will be provided for multiple ischemic diseases.
Summary of the invention
The object of the present invention is to provide two kinds of halophenol compounds 2,4', 5'-trihydroxy-5,2'-dibromobenzo-phenone (i.e. LM49) and pharmaceutical composition thereof and 2', the bromo-2-(2-phenylimidazole of 5-bis--1-base) methyl-4', the new pharmacological effect purposes of 5'-dihydroxy benaophenonel (i.e. LW38a) and pharmaceutical composition thereof, the application specifically in angiogenesispromoting effect.Wherein, the structure of 2,4', 5'-trihydroxy-5,2'-dibromobenzo-phenone is:
; The bromo-2-(2-phenylimidazole of 2', 5-bis--1-base) structure of methyl-4', 5'-dihydroxy benaophenonel is:
.
Another object of the present invention is to provide a kind of heart relevant to promoting angiogenesis for prevention and therapy, the medicine of the ischemic diseases of brain and extremity, this medicine is with halophenol compound 2, 4', 5'-trihydroxy-5, 2'-dibromobenzo-phenone or 2', the bromo-2-(2-phenylimidazole of 5-bis--1-base) methyl-4', 5'-dihydroxy benaophenonel is active component, and this medicine also with one or more pharmaceutically acceptable pharmaceutic adjuvant become assignment system to use, this medicine can require to make injection according to difference, tablet, pill agent or capsule, to more rapid and better playing clinical drug effect.This medicine specifically can be used for the diseases such as prevention and therapy ischemic heart desease, apoplexy, amyotrophy, distal limb necrosis, or as studying the instrument medicine of these diseases.
In the present invention 2,4', 5'-trihydroxy-5,2'-dibromobenzo-phenone and the bromo-2-(2-phenylimidazole of 2', 5-bis--1-base) methyl-4', 5'-dihydroxy benaophenonel two kinds of halophenol compounds have good angiogenesispromoting effect, prove that it has low toxicity by toxicity test simultaneously, the advantages such as side effect is little, and can industrialization synthesize, cheap.Therefore, halophenol compound 2,4', 5'-trihydroxy-5,2'-dibromobenzo-phenone and 2', the bromo-2-(2-phenylimidazole of 5-bis--1-base) methyl-4', 5'-dihydroxy benaophenonel can use separately or with pharmaceutically acceptable pharmaceutic adjuvant composition jointly, with for the preparation of prevention and therapy and the medicine of ischemic diseases promoting the relevant heart, brain and the extremity of angiogenesis, thus be that the disease that clinical treatment is relevant to promoting angiogenesis provides new measure, for clinical application opens new direction.
The transgenic zebrafish of the present invention by two kinds of halophenol compound effects are damaged in tyrosine kinase inhibitor PTK787 induction of vascular; specify that it has the effect promoting that Brachydanio rerio intersegmental blood vessel generates; be embodied in: the length that significantly can increase Brachydanio rerio damaged intersegmental blood vessel, has protective effect to the Brachydanio rerio of blood vessel injury.
Accompanying drawing explanation
Fig. 1 is the impact (n=7) of halophenol compound 2,4', 5'-trihydroxy-5,2'-dibromobenzo-phenone on Brachydanio rerio intersegmental blood vessel length.
Fig. 2 is the bromo-2-(2-phenylimidazole of halophenol compound 2', 5-bis--1-base) methyl-4', 5'-dihydroxy benaophenonel is on the impact (n=10) of Brachydanio rerio intersegmental blood vessel length.
Fig. 3 is the impact (× 4, ruler units: 200 μm) that in table 1, each group is grown Brachydanio rerio ISV.
In figure: A-blank, B-model group, C-LM49(2 μ g/ml), D-LM49(1 μ g/ml), E-LM49(0.5 μ g/ml), F-LW38a(100 μ g/ml), G-LW38a(50 μ g/ml), H-LW38a(25 μ g/ml).
Detailed description of the invention
In order to explain the flesh and blood of pharmacological use of the present invention better, be further elaborated below by way of specific embodiment, but embodiment does not do any restriction to the present invention.
Embodiment: halophenol compound 2,4', 5'-trihydroxy-5,2'-dibromobenzo-phenone and the bromo-2-(2-phenylimidazole of 2', 5-bis--1-base) methyl-4', 5'-dihydroxy benaophenonel is to the effect of the transgenic zebrafish that PTK787 induction of vascular damages.
One, experimental technique
1, the preparation of zebrafish embryo
Choose healthy sexually matured raun, each one of milter puts into fish jar, and two fishes are separated, spend the night.Baffle plate removes by morning next day, and female milter lays eggs (small rice grain size, transparence).Move into after germ cell is carried out disinfection in zebrafish embryo cultivation water, control light at 28 DEG C and cultivate
2, sample solution preparation
PTK787, LM49, LW38a dimethyl sulfoxide (DMSO) is mixed with respectively the mother solution of 0.5g/L, 20g/L, 100g/L.
3, sample is on the impact of transgenic zebrafish angiogenesis
After development of fertilized ova 24h, pronase e (PronaseE) solution of 1g/L is used to slough its egg membrane.Experiment is divided into (50 μ g/ml), LW38a low (25 μ g/ml) administration group in (1 μ g/ml) in blank group, model group, LM49 high (2 μ g/ml), LM49, LM49 low (0.5 μ g/ml), LW38a high (100 μ g/ml), LW38a.In 24 orifice plates, each administration group adds LM49 or LW38a sample liquid and the PTK787 solution of certain volume, and add to 2mL with cultivation water, PTK787 concentration is made to be 0.4 μ g/mL, sample LM49 final concentration is respectively 2 μ g/ml, 1 μ g/ml, 0.5 μ g/ml, sample LW38a final concentration is respectively 100 μ g/ml, 50 μ g/ml, 25 μ g/ml, blank group adds the cultivation water 2mL containing 0.2%DMSO, model group adds PTK787 solution and cultivates water to 2mL, makes PTK787 final concentration be 0.4 μ g/mL.Under stereomicroscope, select normal zebrafish embryo, move in 24 well culture plates, every hole is about 8-10 piece.Then culture plate is added a cover, be placed in constant temperature illumination box (28 DEG C) and allow embryo continue to grow.
4, result is observed and process
When development of fertilized ova 48h, gather image with fluorescence microscope Brachydanio rerio, and with Image-proplus software measurement Brachydanio rerio intersegmental blood vessel (intersegmentalvessels, ISVs) length, adopt SPSS13.0 analysis design mothod data, each administration group carries out two independent samples t test with model group respectively, respectively organizes new vessels difference.
Two, experimental result
Result shows: intersegmental blood vessel (ISVs) region of blank group is complete, intact connection dorsal aorta (DA) and back notochord blood vessel (DLAVs).And significantly disappearance appears in model group ISVs, angiogenesis receives suppression.Intersegmental blood vessel length is calculated, within the scope of test dose, the each administration group of LM49 and LW38a and model group comparing difference all have statistical significance (* * P<0.01, * P<0.05), and the effect enhancing promoting intersegmental blood vessel growth is increased with dosage.Illustrate that it has protective effect to the blood vessel of PTK787 damage, can angiogenesis be promoted.
Table 1LM49 and LW38a is on the impact of transgenic zebrafish intersegmental blood vessel length
Note: compare with model group,
*p<0.05,
*p<0.01
Three, experiment conclusion: as shown in Figure 1, 2, two kinds of halophenol compounds 2,4', 5'-trihydroxy-5,2'-dibromobenzo-phenone and 2', the bromo-2-(2-phenylimidazole of 5-bis--1-base) methyl-4', 5'-dihydroxy benaophenonel has the effect clearly promoting that the transgenic zebrafish intersegmental blood vessel of PTK787 induction of vascular damage generates; As shown in Figure 3, the each group of impact (× 4 that Brachydanio rerio ISV is grown, ruler units: 200 μm), wherein, A is blank, B is model group, C is LM49(2 μ g/ml), D is LM49(1 μ g/ml), E is LM49(0.5 μ g/ml), F is LW38a(100 μ g/ml), G is LW38a(50 μ g/ml), H is LW38a(25 μ g/ml).
Claims (4)
1. halophenol compound 2,4', 5'-trihydroxy-5,2'-dibromobenzo-phenone and the bromo-2-(2-phenylimidazole of 2', 5-bis--1-base) application of methyl-4', 5'-dihydroxy benaophenonel in angiogenesispromoting effect.
2. one kind for prevention and therapy and the medicine of ischemic diseases promoting the relevant heart, brain and the extremity of angiogenesis, it is characterized in that: the active component of described medicine is halophenol compound 2,4', 5'-trihydroxy-5,2'-dibromobenzo-phenone or 2', the bromo-2-(2-phenylimidazole of 5-bis--1-base) methyl-4', 5'-dihydroxy benaophenonel.
3. the medicine of the ischemic diseases of the heart, brain and the extremity relevant to promoting angiogenesis for prevention and therapy according to claim 2, is characterized in that: this medicine can contain one or more pharmaceutically acceptable pharmaceutic adjuvant compositions.
4. the medicine of the ischemic diseases of the heart, brain and the extremity relevant to promoting angiogenesis for prevention and therapy according to Claims 2 or 3, is characterized in that: described medicine is solid dispersion, injection, tablet, pill agent or capsule.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510602045.0A CN105193795B (en) | 2015-09-21 | 2015-09-21 | Application of two kinds of halophenol compounds in terms of angiogenesispromoting effect |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510602045.0A CN105193795B (en) | 2015-09-21 | 2015-09-21 | Application of two kinds of halophenol compounds in terms of angiogenesispromoting effect |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105193795A true CN105193795A (en) | 2015-12-30 |
| CN105193795B CN105193795B (en) | 2018-10-02 |
Family
ID=54941990
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510602045.0A Expired - Fee Related CN105193795B (en) | 2015-09-21 | 2015-09-21 | Application of two kinds of halophenol compounds in terms of angiogenesispromoting effect |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105193795B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105816446A (en) * | 2016-04-29 | 2016-08-03 | 山西医科大学 | Application of two halophenol compounds in preparation of medicines of resisting type II diabetic nephropathy |
| WO2017186141A1 (en) * | 2016-04-29 | 2017-11-02 | 山西医科大学 | Use of benzophenone compound in pharmaceuticals |
| CN117085005A (en) * | 2023-10-08 | 2023-11-21 | 山东省科学院生物研究所 | Application of 5-hydroxymethyl-2-furancarboxylic acid in preparation of angiogenesis-promoting related products |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101602657A (en) * | 2009-07-16 | 2009-12-16 | 李青山 | Halogenated hydroxyl arone compounds and its production and use |
| CN102423308A (en) * | 2011-09-30 | 2012-04-25 | 山西医科大学 | Two bromophenol compounds and application of pharmaceutically-acceptable salts of two bromophenol compounds in preparation of protection drug |
| CN102451177A (en) * | 2010-10-22 | 2012-05-16 | 石药集团恩必普药业有限公司 | Application of butylphthalide or derivatives thereof in preparation of medicaments for promoting angiogenesis |
| CN102499135A (en) * | 2011-10-25 | 2012-06-20 | 澳门大学 | Zebra fish vascular injury model for screening vascular injury resisting medicament as well as building method and application thereof |
| CN103156829A (en) * | 2012-12-24 | 2013-06-19 | 山西医科大学 | Application of polyhydroxy bromo-benzophenone compound and derivatives thereof in treatment and prevention of atherosclerosis |
-
2015
- 2015-09-21 CN CN201510602045.0A patent/CN105193795B/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101602657A (en) * | 2009-07-16 | 2009-12-16 | 李青山 | Halogenated hydroxyl arone compounds and its production and use |
| CN102451177A (en) * | 2010-10-22 | 2012-05-16 | 石药集团恩必普药业有限公司 | Application of butylphthalide or derivatives thereof in preparation of medicaments for promoting angiogenesis |
| CN102423308A (en) * | 2011-09-30 | 2012-04-25 | 山西医科大学 | Two bromophenol compounds and application of pharmaceutically-acceptable salts of two bromophenol compounds in preparation of protection drug |
| CN102499135A (en) * | 2011-10-25 | 2012-06-20 | 澳门大学 | Zebra fish vascular injury model for screening vascular injury resisting medicament as well as building method and application thereof |
| CN103156829A (en) * | 2012-12-24 | 2013-06-19 | 山西医科大学 | Application of polyhydroxy bromo-benzophenone compound and derivatives thereof in treatment and prevention of atherosclerosis |
Non-Patent Citations (2)
| Title |
|---|
| SILVIA GOBBI ET AL.: "Imidazolylmethylbenzophenones as Highly Potent Aromatase Inhibitors", 《J. MED. CHEM.》 * |
| 赵万一等: "新型卤酚类化合物的合成及其体外抗氧化活性", 《中国药物化学杂志》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105816446A (en) * | 2016-04-29 | 2016-08-03 | 山西医科大学 | Application of two halophenol compounds in preparation of medicines of resisting type II diabetic nephropathy |
| WO2017186141A1 (en) * | 2016-04-29 | 2017-11-02 | 山西医科大学 | Use of benzophenone compound in pharmaceuticals |
| CN117085005A (en) * | 2023-10-08 | 2023-11-21 | 山东省科学院生物研究所 | Application of 5-hydroxymethyl-2-furancarboxylic acid in preparation of angiogenesis-promoting related products |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105193795B (en) | 2018-10-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104510747B (en) | A kind of new medicine use of iridoid glycoside | |
| CN102631405A (en) | Compound apigenin nanoemulsion antihypertensive drug | |
| CN105193795A (en) | Application of two halogen-phenol compounds to effect of promoting angiogenesis | |
| CN101619089B (en) | Anticancer drug CL168, synthesis method and application thereof | |
| Abdullah et al. | Bioreactor-grown exo-and endo-β-glucan from Malaysian Ganoderma lucidum: An in vitro and in vivo study for potential antidiabetic treatment | |
| CN107158008B (en) | A kind of pharmaceutical composition for treating myocardial infarction | |
| CN102964405A (en) | Application of dchydrodiisoeugenol capable of prompting angiogenesis | |
| CN106389329B (en) | A kind of Dipyridamole Orally taken emulsion drug delivery system and preparation method thereof | |
| WO2015190872A1 (en) | Pharmaceutical composition containing spirulina maxima extract as active ingredient for treating and preventing obesity | |
| CN109985059A (en) | Dendrobium polysaccharide Reproductive Damage after preparing cancer chemotherapy restores the application in drug | |
| CN104415135A (en) | Use of hydroxyl polymethoxylated flavonoid compound and/or derivative thereof | |
| CN110575450B (en) | Application of 2, 5-furandimethanol in preparation of antitumor drugs | |
| CN102440987B (en) | Drug compound of apigenin, apigenin-like derivants, artemisinin and artemisinin-like derivants and application thereof | |
| TW202139995A (en) | Use of ovatodiolide against sars-cov-2 | |
| CN111544440A (en) | Application of diosmin and composition in preparation of anti-obesity product | |
| CN115252630B (en) | Application of phellodendron ketone in preparing medicine for preventing, improving or treating non-alcoholic fatty liver disease | |
| CN105853402B (en) | A kind of purposes of terpene complex ester | |
| CN115025072B (en) | Application of squalene in preparation of medicines for treating renal ischemia reperfusion injury | |
| CN107875147B (en) | Application of peucedanum praeruptorum dunn E in preparing drug for protecting liver injury | |
| CN109106711A (en) | Bicyclic alcohols and its pharmaceutical usable derivatives are used to prevent or the purposes of medicine physical property hepatic injury | |
| CN103169693A (en) | Application of wogonin derivant in preparation of drug for treating liver cancer | |
| CN107693509A (en) | SB FI 26 are preparing the application in treating breast cancer medicines | |
| CN106727495B (en) | A kind of flavanone compound is preparing the application in myocardial preservation drug | |
| CN104069062B (en) | Hilicidum injection for preventing and treating ischemic cardiovascular and cerebrovascular diseases as well as preparation method and application thereof | |
| CN105816545A (en) | Application of rose flower polysaccharides in preparation of cytotoxicity-independent antitumor drugs |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20181002 Termination date: 20190921 |