CN101647793B - Application of anacardic acid in preparing anti-angiogenic drugs - Google Patents
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- CN101647793B CN101647793B CN200910056246XA CN200910056246A CN101647793B CN 101647793 B CN101647793 B CN 101647793B CN 200910056246X A CN200910056246X A CN 200910056246XA CN 200910056246 A CN200910056246 A CN 200910056246A CN 101647793 B CN101647793 B CN 101647793B
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Abstract
The invention provides an application of anacardic acid in preparing anti-angiogenic drugs. The anti-angiogenic drugs prepared from anacardic acid of the invention can inhibit tumor angiogenesis, arthritis pathological tissue vessel angiogenesis, neovascular eye disease, hemangioma pathological tissue angiogenesis, psoriasis pathological tissue vessel angiogenesis, solid tumor pathological tissue angiogenesis, hemangioma, Kaposi' s sarcoma pathological tissue angiogenesis, leukocythemia, lymphadenoma, myeloma blood cancer and Paget' s disease angiogenesis. The invention also provides the application of a compound containing effective dose of anacardic acid and pharmacy acceptable ingredients in preparing the anti-angiogenic drugs.
Description
Technical field
The present invention relates to a kind of new anti-angiogenic rebirth Chinese herbal medicine monomer anacardic acid and this chemical compound in the application for the treatment of and prevent fields such as relevant diseases of angiogenesis.
Background technology
Angiogenesis is meant that the mature blood endothelial cell of previous tissue Already in forms the process of new filial generation blood vessel in the mode of germinateing or embed by propagation and migration.Angiogenesis all plays a key effect in tens kinds of diseases such as cancer, rheumatoid arthritis, diabetic retinopathy, treating senile maculopathy, leukemia, atherosclerosis, endometritis, psoriasis, leiomyoma of uterus, benign prostatauxe and inflammatory reaction and wound healing.
And cancer is a human big killer, and tumor cell is of a great variety, very easily undergos mutation, and easily develop immunity to drugs, traditional chemotherapy radiotherapy is very big to normal cell injury, discovers, under the supply of nonnutritive composition and oxygen, tumor can only be grown the 2-3 cubic millimeter, in case there is new vessels coupled, tumor will be with the geometrical progression ramp, and tumor vessel also provides the path of transfer simultaneously for tumor cell, therefore, tumor growth all depends on angiogenesis with transfer.Than traditional therapeutic modality, anti-angiogenic rebirth therapy target is due to the capillary endothelium rather than the tumor itself of tumor kitchen range, the vascular endothelial cell inheritance stability, mutation probability is little, be difficult for developing immunity to drugs, and have the broad-spectrum anti-tumor activity, so the continuous development of anti-angiogenic drugs becomes the tempting Therapeutic Method of treatment cancer and other angiogenesis dependence diseases already, the FDA approved multiple anti-angiogenic drugs that gone on the market is treated tumor at present.
Anacardic acid claims anacardic acids again, derive from Folium Ginkgo and Fructus anacardii, anacardic acid is the main antimicrobial component of Semen Ginkgo, multiple gram negative bacteria and positive bacteria all there is inhibitory action, anacardic acid can inhibition of histone the activity of Acetylase, but self activity is subjected to the inhibition of lipoxidase, uncoupling when Hepar Mus mitochondrion oxidative phosphorylation, on the traditional Chinese medical science, that anacardic acid has is antibiotic, expansion, convergence microcirculation improvement, promote the human body metabolism, strengthen the effect of human body life, kidney-tonifying and brain tonic.There is not at present the report of anacardic acid both at home and abroad to angiogenesis effect aspect.
Summary of the invention
The technical problem to be solved in the present invention is to provide the application of a kind of Chinese herbal medicine monomer anacardic acid aspect the preparation anti-angiogenic drugs.
Anacardic acid, Anarcardic Acid, C22H3603, molecular weight 348.5, its structural formula be as the formula (1):
The technical problem to be solved in the present invention is the related application of application, the especially anacardic acid of anacardic acid in preparing anti-angiogenic drugs in suppressing angiogenesis dependence diseases such as cancer and rheumatoid arthritis, psoriasis, diabetic syndrome, atherosclerosis, hemangioma.Can also suppress neonate tumour blood vessel, arthritis pathological changes tissue blood vessel new life, neovascular oculopathy, hemangioma pathological changes tissue blood vessel new life, psoriatic lesions tissue blood vessel new life, solid tumor pathological tissues angiogenesis, hemangioma, Kaposi ' s sarcoma pathological changes tissue blood vessel new life, leukemia, lymphoma, myeloma hematologic cancers, Paget ' s disease angiogenesis.
The technical problem to be solved in the present invention can prepare anti-angiogenic drugs with treatment rheumatoid arthritis, inflammatory arthritis; The neovascular keratopathy, neovascular retinal diseases, neovascular iris disease, neovascular glaucoma, neovascular choroidal diseases, neovascular conjunctiva oculopathy, the new vessels cataract, neovascular vitreous body oculopathy, neovascular optic nerve disease; Diabetic retinopathy, retinal vein occlusion, retinopathy of prematurity, retinal arterial obstruction; Moist old maculopathy; Constitutional or Secondary cases solid tumor; Angiomatosis, hemangioblastoma, optimum blood vessel hyperplasia disease.
The application of compositions in the preparation anti-angiogenic drugs that the technical problem to be solved in the present invention is to provide formula (I) anacardic acid that contains effective dose and pharmacy can accept composition.
The anacardic acid of treatment effective dose and any one adjuvant of pharmaceutically permission can be made pharmaceutical composition according to the present invention, also can add the anti-angiogenic drugs that other and anacardic acid do not have antagonism.Its preparation can be any one dosage form pharmaceutically, includes but not limited to tablet, granule, capsule, pill, oral liquid, injection, liposome etc.
For implementing method of the present invention, anacardic acid can or pass through the administration of implanted reservoir by oral, parenteral, suction-type spraying." parenteral " comprise subcutaneous, Intradermal, intravenous, intramuscular, intraarticular, intra-arterial,
In the synovial cavity, in the breastbone, in the sheath, intralesional and intracranial injection or input technology.
Oral available solid or liquid dosage unit carry out administration as dosage forms such as last agent, powder, tablet, sugar-coat agent, capsule, granule, suspending agent, solution, syrup, drop, sublingual lozenges.
The end agent is The compounds of this invention is worn into suitable fineness and to make.Powder is that The compounds of this invention is worn into suitable fineness, and the pharmaceutical carrier (as carrier, mannitol and so on edibility carbohydrate etc.) with same fineness is mixed and made into then.As required, also can sneak into materials such as correctives, antiseptic, dispersant, coloring agent, spice.
Capsule is to be filled into as in the gelatine capsule shell and make making pulverous last agent and powder as mentioned above or going into the described granular material of tablet part.Also lubricant and fluidizer etc. can be mixed in the powdered substance, in capsule, carry out padding then.If add cosolvent and disintegrating agent etc., as Polyethylene Glycol, sodium carbonate, the drug effect in the time of can improving the capsule picked-up.
The invention discloses the application of Chinese herbal medicine monomer anacardic acid in the preparation anti-angiogenic drugs.Experiment shows, anacardic acid all has the obvious suppression effect in human umbilical vein's endotheliocyte (HUVEC) proliferation experiment, the experiment of human umbilical vein's endothelial cell migration, human umbilical vein's endotheliocyte Boyden cell migration experiment, the experiment of human umbilical vein's endotheliocyte one-tenth pipe, chick chorioallantoic membrane angiogenesis, mice corneal test and mouse-borne tumor test, can be used for preparing the medicine of angiogenesis inhibiting.
Description of drawings
Fig. 1 suppresses Human umbilical vein endothelial cells (HUVEC) propagation for anacardic acid;
Among Fig. 1, so that p＜there were significant differences in 0.05 expression; Wherein,
*Expression p＜0.05;
*Expression p＜0.01;
* *Expression p＜0.001.
Fig. 2 suppresses Human umbilical vein endothelial cells (HUVEC) migration for anacardic acid;
Fig. 3 suppresses the migration of Human umbilical vein endothelial cells (HUVEC) Boyden cell for anacardic acid;
Fig. 4 becomes pipe for anacardic acid suppresses Human umbilical vein endothelial cells (HUVEC);
Fig. 5 forms for anacardic acid suppresses the chick chorioallantoic membrane new vessels;
Fig. 6 forms for anacardic acid suppresses the mice cornea rebirth blood vessel;
Fig. 7 suppresses the nude mice tumor growth for anacardic acid;
Fig. 8 forms for anacardic acid suppresses nude mice tumor blood capillary.
The specific embodiment
Embodiment 1: anacardic acid suppresses Human umbilical vein endothelial cells (HUVEC) propagation
Purpose and principle:
MTS assay is adopted in the endothelial cell proliferation experiment.MTS assay is a kind of assay method that uses colorimetry to measure living cells quantity indirectly.CellTiter
The single solution reagent of Aqueous comprises a kind of tetrazole compound (inner salt; MTS) and an electronics coupled reagent (second sulfur azophenlyene; PES).MTS can be had, and the dehydrogenase effect generates the granule that dissolves in tissue culture medium (TCM) in the metabolic activity cell, and the light absorption value of measuring product at 490nm is directly proportional with the quantity of living cells in the culture.
Method: add Human umbilical vein endothelial cells in 96 orifice plates, matched group and application of sample group are set, matched group adds solvent, the application of sample group adds the anacardic acid contain variable concentrations, hatch 48～72 hours after, add the cell proliferation detectable, hatched 3 hours, and detected absorbance value at the 490nm place with microplate reader.
Result and evaluation: as shown in Figure 1, compare with matched group, the multiplication capacity of Human umbilical vein endothelial cells is suppressed, and illustrates that anacardic acid can suppress the propagation of endotheliocyte.
Embodiment 2: anacardic acid suppresses Human umbilical vein endothelial cells (HUVEC) migration
Purpose and principle: under the effect of vascular endothelial cell growth factor (VEGF), Human umbilical vein endothelial cells can be to the scored area migration that does not have cell.By the endotheliocyte amount of being moved in the cut district in observation, estimate anacardic acid and whether have the ability that suppresses the human microvascular endothelial cell (mvec) migration.
Method: add human microvascular endothelial cell (mvec) in 6 orifice plates, when approximately covering with, use tip standardized cross cut, the cell under drawing with PBS is clean adds VEGF
165And the culture medium that contains different pharmaceutical concentration, it is full to be cultured to group leader VEGF.
Result and evaluation: as shown in Figure 2, examine under a microscope and take pictures, the result shows and compares with matched group that the migration of Human umbilical vein endothelial cells is suppressed, and illustrates that anacardic acid can suppress the migration of human microvascular endothelial cell (mvec).
Embodiment 3: anacardic acid suppresses the migration of Human umbilical vein endothelial cells (HUVEC) Boyden cell
Purpose and principle: the Boyden cell, be used to study leukocytic chemotaxis, this research is separated into two parts based on cell by micropore.Cell places top part, and following part contains chemotactic factor, and under the inducing of chemotactic factor, last confluent monolayer cells can pass the back side that the mocromembrane hole migrates to the bottom of film and is attached to film.Cell can see through poly carbonate filter membrane under the inducing of somatomedin, this experiment can detection of drugs has the influence of resistance transfer ability to endotheliocyte.
Method: with cell bag quilt, abandon gelatin after hatching with gelatin, give a baby a bath on the third day after its birth time with PBS.Add the endotheliocyte culture medium that contains serum and VEGF in outer 24 orifice plates of cell.Insert cell in the cell, add the medicine of equivalent variable concentrations, in incubator, hatch four hours after, abandon culture medium, fix with paraformaldehyde, give a baby a bath on the third day after its birth time with PBS, brazilwood extract dyeing is washed with PBS, dries, microscopically is observed and is taken pictures.
Result and evaluation: as shown in Figure 3, with the matched group ratio, the ability that Human umbilical vein endothelial cells is passed the Boyden cell is suppressed, and illustrates that anacardic acid can suppress the ability of the resistant migration of endotheliocyte.
Embodiment 4: anacardic acid suppresses Human umbilical vein endothelial cells (HUVEC) and becomes pipe
Purpose and principle: Matrigel is the basement membrane extract of the solubility that extracting obtains from murine sarcoma.Be rich in extracellular matrix protein, Human umbilical vein endothelial cells can attach into pipe on Matrigel, can utilize this one-tenth pipe characteristic of Human umbilical vein endothelial cells on Matrigel to study medicine to angiopoietic influence.
Method: Matrigel is taped against on 24 orifice plates, hatches and treat that it solidifies.Every hole adds Human umbilical vein endothelial cells, adds the culture medium of variable concentrations anacardic acid again.Examining under a microscope microtubule after hatching in incubator forms situation and takes pictures.
Result and evaluation: as shown in Figure 4, Human umbilical vein endothelial cells is grown in Matrigel, and individual cells extends in Matrigel, forms tridimensional network.Compare with matched group, endothelium becomes the pipe process to be affected, and three-dimensional net structure is damaged, and illustrates that anacardic acid can suppress the Human umbilical vein endothelial cells microtubule and form.
Embodiment 5: anacardic acid suppresses the chick chorioallantoic membrane new vessels and forms
Purpose and principle: the chick embryo allantois membrane modle is the screening model that comparatively ideal domestic and international screening angiogenesis class medicine is generally acknowledged at present.The carrier that will contain medicine places the avascular area on fertilization chick chorioallantoic membrane surface, can be observed the influence that medicine generates new blood capillary.
Method: the eggshell surface sterilization is placed in the incubator hatched 5 days, in superclean bench, at eggshell blunt end (air chamber end) opening, tear cameral mantle in the sparse place of blood vessel and expose chorioallantoic membrane, add the circular filter paper sheet (5 millimeters of diameters) that contains the variable concentrations anacardic acid, seal, continue to hatch with the adhesive tape of sterilizing, the exposure chorioallantoic membrane of peeling off two days later, microscopically is observed and is taken pictures.
Result and evaluation: as shown in Figure 5, compare with matched group, new blood capillary generates and is suppressed, and illustrates that anacardic acid can suppress the generation of chick chorioallantoic membrane neovascularity.
Embodiment 6: anacardic acid suppresses the mice cornea rebirth blood vessel and forms
Purpose and principle: the mice cornea is an avascular area territory, on the mice cornea, make a pouch, implantation contains the slow-releasing granules of vascular endothelial cell growth factor (VEGF), can induce the blood vessel that is present in Gong Yuan place, angle to grow to the pouch of slow-releasing granules, on slow-releasing granules, add anacardic acid simultaneously, observe these inductive blood vessel areas and whether change.
Method: with the C57/BL6 mouse anesthesia, fixing, in the cornea upper shed, the implantation slow release granule, the blank group only contains solvent, and the VEGF matched group contains vascular endothelial cell growth factor (VEGF) and solvent, test group contains vascular endothelial cell growth factor (VEGF) and anacardic acid, the recovery of test back continues to raise a week, and microscopically is observed and taken pictures.
Result and evaluation: as shown in Figure 6, compare with matched group, new vessels obviously is suppressed, and illustrates that anacardic acid can suppress to be formed by the inductive new vessels of vascular endothelial cell growth factor (VEGF).
Embodiment 7: anacardic acid suppresses the nude mice tumor growth
Purpose and principle: at the mouse bare subcutaneous injection tumor cell, these tumor cells absorb nutrient in the mice body, and propagation forms tumor rapidly, and dosing is handled, and can observe the action effect of medicine to tumor.
Method: at nude mice back subcutaneous injection carcinoma of prostate PC-3 cell, cancer cell multiplication forms tumor, etc. tumor behind certain volume, be divided into matched group and experimental group at random, carry out different disposal, matched group injectable drug every day solvent, experimental group injectable drug every day, measure gross tumor volume every day, inject and carry out tumor after about one month and peel off, take pictures.
Result and evaluation: as shown in Figure 7, compare with matched group, tumor growth obviously is suppressed, and illustrates that anacardic acid can suppress the nude mice tumor growth.
Embodiment 8: anacardic acid suppresses nude mice tumor blood capillary and forms
Purpose and principle: von Willebrand factor vWF can be used for detecting the blood capillary distribution situation in the tissue as the vascular endothelial cell label.
Tumor after method: embodiment 7 peels off is fixed, dehydration, transparent, waxdip, embedding, section, with von Willebrand factor (vWF, VIII related antigen) dyeing, takes pictures after the colour developing, and dark part is a vascular endothelial cell.
Result and evaluation: as shown in Figure 8, compare with matched group, nude mice tumor blood capillary obviously reduces, and illustrates that anacardic acid can suppress nude mice tumor blood capillary and form.
Claims (2)
1. the application of the anacardic acid of formula (I) in preparation inhibition neovascular oculopathy medicine,
Structural formula (I)
Wherein said neovascular oculopathy is neovascular keratopathy, neovascular retinal diseases, neovascular iris disease, neovascular glaucoma, neovascular choroidal diseases, neovascular vitreous body oculopathy, or the neovascular optic nerve disease.
2. application according to claim 1 is characterized in that, contains formula (I) anacardic acid of effective dose and compositions that pharmacy can be accepted composition and suppresses application in the neovascular oculopathy medicine in preparation.
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Effective date of registration: 20160229 Address after: 201100. A2114, building B, building 555, Dongchuan Road, Minhang District, Shanghai Patentee after: BIORAY LABORATORIES Inc. Address before: 200062 Zhongshan North Road, Shanghai, No. 3663 Patentee before: East China Normal University |
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Denomination of invention: Application of lacquer tree acid in the preparation of anti angiogenesis drugs Effective date of registration: 20211228 Granted publication date: 20110629 Pledgee: Minhang Branch of Shanghai Rural Commercial Bank Co.,Ltd. Pledgor: BIORAY LABORATORIES Inc. Registration number: Y2021310000165 |
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Date of cancellation: 20220826 Granted publication date: 20110629 Pledgee: Minhang Branch of Shanghai Rural Commercial Bank Co.,Ltd. Pledgor: BIORAY LABORATORIES Inc. Registration number: Y2021310000165 |