CN101606930B - Application of pseudolaric acid B and derivative thereof in preparation of immunity inhibitor - Google Patents
Application of pseudolaric acid B and derivative thereof in preparation of immunity inhibitor Download PDFInfo
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- CN101606930B CN101606930B CN2009100698120A CN200910069812A CN101606930B CN 101606930 B CN101606930 B CN 101606930B CN 2009100698120 A CN2009100698120 A CN 2009100698120A CN 200910069812 A CN200910069812 A CN 200910069812A CN 101606930 B CN101606930 B CN 101606930B
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- acetic acid
- corter pseudolaricis
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Abstract
The invention discloses a pseudolaric acid B and the application of derivative thereof in the preparation of immunity inhibitor. Experiments prove that the pseudolaric acid B and the derivative thereof have excellent immunity inhibiting effect and lower toxicity, so that the pseudolaric acid B and the derivative thereof or pseudolaric acetate and salt of the derivative of the pseudolaric acid B can be taken as medicine for preventing or treating exclusive reaction, autoimmune disease, inflammatory disease, allergic disease and the like which are related to immunity and caused by organ or skin grafting of mammal (especially human beings).
Description
Technical field
The present invention relates to the purposes of corter pseudolaricis acetic acid and derivant thereof, particularly relate to the application in the preparation immunosuppressant of corter pseudolaricis acetic acid and derivant thereof.
Background technology
Pinaceae plant golden larch Pseudolarix amabilis (Nelson) Regd became extinct in succession in glacial epoch of new century more, and the residual minority in China middle and lower reach of Yangtze River only becomes exist only in China now single and belongs to single endemic plant of planting.Owing to the special classification position of golden larch, become the important research object of botanical system.Though the golden larch seeds are rare, its material fragility fractures easily, and economic worth is little, causes rare tree species not treasured, and the situation that the self-employed tree cultivator damages repeatedly occurs.By selecting some typical forest zones to carry out protective development, can allow the lever of market economy prize the enthusiasm that the self-employed tree cultivator cultivates, protects golden larch, have far reaching significance.Cortex Pseudolaricis (" bulletin of Chinese materia medica "), be Cortex Pseudolaricis (" medical material compilation of data "), wattle skin (" middle traditional Chinese medicines are planted will "), pseudolaricis,cortex (" pharmacognosy ") again, dry root bark or near root bark for the pinaceae plant golden larch, the conventional Chinese medicine that records for the Pharmacopoeia of the People's Republic of China, see the supplementary Amplifications of the Compendium of Materia Medica that Qing Dynasty's ZHAO Xue-Min is shown the earliest, " suffering, temperature, poisonous." go into spleen channel, have parasite killing, itching relieving effect.The effective ingredient of Cortex Pseudolaricis is the diterpenoid acid compounds, and the third 2 acid (pseudolaric acid C2) of pseudolaric acid (pseudolaric acid A), corter pseudolaricis acetic acid (pseudolaric acid B), native rose of Sharon propanoic acid (pseudolaricacid C), the native rose of Sharon and pseudolaric acid-β-D-glycoside (pseudolaric acidA-β-D-glucoside) and corter pseudolaricis acetic acid-β-D-glycoside (pseudolaric acid B-β-D-glucoside) is arranged.In recent years get native rose of Sharon butanoic acid and native rose of Sharon valeric acid again.Wherein corter pseudolaricis acetic acid (I) is a main component, and molecular formula is C
23H
28O
8(chemical journal, 1982,40,447).Pharmacological research shows that corter pseudolaricis acetic acid has multiple pharmacotoxicological effects such as antitumor, antifertility, angiogenesis inhibitor, antifungal.
Our studies show that in a large number corter pseudolaricis acetic acid and corter pseudolaricis acetic acid derivant are immunosuppressive activity, but not relevant as yet at present corter pseudolaricis acetic acid and corter pseudolaricis acetic acid derivant are used for clinical treatment as immunosuppressant.
Immunosuppressant is the medicine that a class has immunosuppressive action, can play the effect of these diseases of treatment to a certain extent.All immunosuppressant can be divided into following several substantially: (1) anti-metabolism: azathioprine, methotrexate etc.; (2) alkylating agent class: cyclophosphamide etc.; (3) Adrenocorticosteroids: prednisone, dexamethasone etc.; (4) antibiotics: ciclosporin A (CsA), tacrolimus (FK506), rapamycin etc.; (5) Chinese herbal medicine: Tripterygium glycosides etc.
Clinical immunosuppressive drug commonly used such as azathioprine, cyclophosphamide and methotrexate play a role by restrictive cell activation, propagation at present, can destroy mitosis and cell division, normal cell populations with high turnover rate (as confluent monolayer cells in the medullary cell nuclear gastrointestinal tract) is had serious cytotoxicity side effect, and the serious side effects that these medicines produce comprises lymphopenia, neutrophilic granulocyte minimizing, bone marrow depression, hemorrhagic cystitis, hepar damnification, generation rate of malignant tumour increase, alopecia, gastrointestinal disturbance and sterile etc.
Another kind of immunosuppressive drug Adrenocorticosteroids commonly used, it has the advantage that does not produce the general cytotoxic effect, by preventing or inflammation-inhibiting reaction, cytokine generation and neutrophilic granulocyte, macrophage or lymphocyte activation performance effector function.The representative instance of Adrenocorticosteroids is prednisone and dexamethasone, and it influences carbohydrate and proteinic metabolism and immunologic function.Yet, the specificity of Adrenocorticosteroids shortage effect, and can produce metabolism widely, antiinflammatory and immunization.The typical side effects of this compounds comprises that the infection of organ receptor increases and obstruction wound healing, the dynamic equilibrium of upset blood, carbohydrate and bone metabolism and mineral adjusting, and also rebound phenomenon can occur after the drug withdrawal.
Also having a kind of immunosuppressive drug is to have immunoregulation effect and the general chemical compound that prevents or suppress lymphocyte activation, it is by the effector function or the propagation of blocking-up activating T cell, suppress cytokine and produce, prevent or suppress activation, differentiation or the effector function of platelet, granulocyte, macrophage.Ciclosporin A is the main example of this compounds, can suppress body fluid and cell immune response, is used for rejection and the treatment autoimmune and the inflammatory diseases of organ transplantation.Although its curative effect is proved, yet ciclosporin can cause the immunoreation reduction at exogenous antigen as nonspecific immunosuppressive agent, and tolerance dose can not suppress rejection fully.Therefore, can not stop immunne response fully, also can in many organ receptors, produce serious adverse, and show with the host changes liver, kidney, central nervous system and gastrointestinal are influenced at transplanted tissue.Untoward reaction mainly is that hepatic and/or renal destruction, gingiva tissue hypertrophy, intractable hypertension and infection and malignant tumor sickness rate are increased.
Therefore, need the immunosuppressant of developing safety, effective also energy life-time service badly.
Summary of the invention
The objective of the invention is to overcome deficiency of the prior art, the application in the preparation immunosuppressant of corter pseudolaricis acetic acid and derivant thereof is provided.
Second purpose of the present invention provides the application of salt in the preparation immunosuppressant of corter pseudolaricis acetic acid salt and corter pseudolaricis acetic acid derivant thereof.
Technical scheme of the present invention is summarized as follows:
The application in the preparation immunosuppressant of corter pseudolaricis acetic acid and derivant thereof.
Described corter pseudolaricis acetic acid derivant is six hydrogen corter pseudolaricis acetic acids, deacetylate (R
3)-corter pseudolaricis acetic acid, demethyl (R
2)-corter pseudolaricis acetic acid or deacetylate (R
3) demethyl (R
2)-corter pseudolaricis acetic acid or by the material of code name BP-1, BP-2, BP-3, BP-4, BP-5, BP-6, BP-7, BP-8, BP-9, BP-10, BP-11, BP-12, BP-13, BP-14, BP-15, BP-16, BP-17, BP-18, BP-19, BP-20, BP-21, BP-22 representative;
The structural formula of the material correspondence of described BP-1 to BP-22 representative is:
The application of the salt of corter pseudolaricis acetic acid salt and corter pseudolaricis acetic acid derivant thereof in the preparation immunosuppressant.
Corter pseudolaricis acetic acid salt is potassium salt, sodium salt, ammonium salt, calcium salt, arginine salt, lysinate or piperidinium salt.
The salt of corter pseudolaricis acetic acid derivant is potassium salt, sodium salt, ammonium salt, calcium salt, arginine salt, lysinate or piperidinium salt.
The corter pseudolaricis acetic acid derivant is six hydrogen corter pseudolaricis acetic acids, deacetylate (R
3)-corter pseudolaricis acetic acid, demethyl (R
2)-corter pseudolaricis acetic acid or deacetylate (R
3) demethyl (R
2)-corter pseudolaricis acetic acid or by the material of code name BP-1, BP-2, BP-3, BP-4, BP-5, BP-6, BP-7, BP-8, BP-9, BP-10, BP-11, BP-12, BP-13, BP-14, BP-15, BP-16, BP-17, BP-18, BP-19, BP-20, BP-21, BP-22 representative;
The structural formula of the material correspondence of described BP-1 to BP-22 representative is:
Advantage of the present invention:
Evidence corter pseudolaricis acetic acid and derivant thereof have shown excellent immunosuppressive action, and toxicity is lower, therefore, the salt of corter pseudolaricis acetic acid and derivant thereof or corter pseudolaricis acetic acid salt and corter pseudolaricis acetic acid derivant thereof can be used as the prevention of immune correlated diseases such as rejection that the organ of mammal (especially people) or skin transplantation produce, autoimmune disease, inflammatory diseases, allergic disease or the medicine of treatment.
The specific embodiment
Corter pseudolaricis acetic acid derivant: six hydrogen corter pseudolaricis acetic acids, deacetylate (R
3)-corter pseudolaricis acetic acid, demethyl (R
2)-corter pseudolaricis acetic acid, deacetylate (R
3) demethyl (R
2)-corter pseudolaricis acetic acid, code name BP-1--BP-22 prepare referring to content and the data base of Tsing Hua Tong Fang among China Patent No.: the ZL0013667.X " corter pseudolaricis acetic acid derivant and pharmaceutical composition thereof reach at antineoplastic and antifungal application ":
The present invention can prepare corter pseudolaricis acetic acid salt and derivative salt thereof with known method.
In the following embodiments, carried out in the body and the research and the application of external immunosuppressive activity effect to corter pseudolaricis acetic acid and derivant thereof, the experimental technique of unreceipted actual conditions, usually according to normal condition, or the condition of advising according to manufacturer.Further set forth the present invention below in conjunction with specific embodiment, should understand, these embodiment only are used to illustrate the present invention's usefulness, but not limitation of the present invention, the those of ordinary skill in relevant technologies field, under the situation that does not break away from the spirit and scope of the present invention, can also make various variations and modification, so all technical schemes that are equal to also belong to category of the present invention.
Embodiment 1: the T of mitogenstimulated, bone-marrow-derived lymphocyte propagation
The aseptic mouse spleen of getting grinds the preparation single cell suspension, removes erythrocyte, with the RPMI-1640 culture fluid that contains 10% hyclone (FBS) cell concentration is adjusted to 5 * 10
6/ mL.The cell suspension that in 96 orifice plates, adds 100 μ l/ holes, the sample of 50 μ l/ hole variable concentrations (corter pseudolaricis acetic acid, six hydrogen corter pseudolaricis acetic acids, deacetylate (R
3)-corter pseudolaricis acetic acid, demethyl (R
2)-corter pseudolaricis acetic acid or deacetylate (R
3) demethyl (R
2)-corter pseudolaricis acetic acid, BP-1, BP-3, BP-15, BP-20, BP-2, BP-5, BP-6, BP-7, BP-8, BP-10, BP-11, BP-12, BP-13, BP-14, BP-16, BP-17 BP-18, BP-19) solution, the concanavalin A, Con A (ConA) in 50 μ l/ holes or lipopolysaccharide (LPS), contrast adds the equal-volume culture medium.Behind the mixing in 37 ℃, 5%CO
2Cultivated 48 hours under the condition.Finishing to cultivate preceding 4, adding 5mg/mL MTT solution 100 μ l, measuring at OD 570nm place with microplate reader to 6h.
Table 1 experimental result
Embodiment 2: unidirectional mixed lymphocytes is cultivated
The aseptic BALA/c mouse spleen of getting is made single cell suspension, will be diluted to 1 * 10 with complete RPMI-1640 culture medium as the BALA/c mouse boosting cell of irritation cell
7/ mL, shakes up once every 15min in 37 ℃ of water-bath deactivations therebetween with the ametycin of 50 μ g/mL, and reuse PBS gives a baby a bath on the third day after its birth time, is diluted to 5 * 10 with complete RPMI-1640 culture medium
6/ mL.With the C57BL/6 mouse boosting cell as reacting cells.Get above-mentioned irritation cell and reacting cells mixed liquor 100 μ l/ holes, add the corter pseudolaricis acetic acid 100 μ l/ holes of variable concentrations, negative control adds the equivalent culture medium, and positive control adds 8 * 10
-9M ciclosporin A (CsA).37 ℃, 5%CO
2Condition was cultivated 3 days.Cultivate and finish preceding 12h adding
3H diluent 25 μ l cultivate collecting cell when finishing, and measure radioactivity by liquid scintillation counting and mix, and data are expressed as per minute umber of pulse (cpm).
Table 2 experimental result
Compound c pm
Negative control 15610 ± 117
1 * 10
-7M corter pseudolaricis acetic acid 6904 ± 182
*
1 * 10
-6M corter pseudolaricis acetic acid 5025 ± 138
*
Positive control (CsA) 4832 ± 257
*
*Compare P value＜0.01 with negative control group
Embodiment 3: what cytokine produced inducing and detecting
The aseptic mouse spleen of getting grinds the preparation single cell suspension, removes erythrocyte, with the RPMI-1640 culture fluid that contains 10%FBS cell concentration is adjusted to 5 * 10
6/ mL, cultivation is in 96 orifice plates, every hole 200 μ L, establish 3 multiple holes for every group, cell suspension adds CD 3-resisting monoclonal antibody (anti-CD3) 0.2 μ g/mL), the pharmaceutical intervention group is the corter pseudolaricis acetic acid arginine salt of anti-CD3+ variable concentrations, and negative control adds the equal-volume culture medium, and positive control adds 8 * 10
-9M ciclosporin A (CsA).37 ℃, 5%CO
2Collect supernatant after cultivating 72h under the condition, double-antibody sandwich elisa (ELISA) detects the generation of IFN-γ.Measure absorbance at the OD450nm place with microplate reader, according to the content of the standard curve conversion sample cell factor.
Table 3 experimental result
Compound I FN-γ (ng/mL)
Negative control 0.35 ± 0.02
Anti-CD3 stimulating group 9.2 ± 2.38
1 * 10-7M corter pseudolaricis acetic acid arginine salt 6.78 ± 1.34
*
1 * 10-6M corter pseudolaricis acetic acid arginine salt 2.26 ± 0.17
*
Positive control (CsA) 4.8 ± 1.24
*
*Compare P value＜0.01 with the anti-CD3 group
Embodiment 4: anti-inflammatory activity detects
With 50 of ICR mices, be divided into 5 groups at random, every group 10, be respectively negative control group (external-use substrate), the ointment low concentration group of medicine of the present invention (1% 6 hydrogen corter pseudolaricis acetic acid W/W), middle concentration group (3% 6 hydrogen corter pseudolaricis acetic acid), high concentration group (6% 6 hydrogen corter pseudolaricis acetic acid), positive drug control group (compound recipe Piyanping ointment).Respectively get 0.5 gram, be applied in mice two auricular concha two sides, behind coating 1 hour, dimethylbenzene 0.03ml dripped in mouse right ear shell two sides cause inflammation, after 2 hours, the mice dislocation is put to death, take off circular auricle at left and right sides ear symmetry place respectively with diameter 6mm card punch, analytical balance is weighed, and slide gauge amount thickness, the weight difference of ears and thickness difference are the swelling degree.
Table 4 experimental result
*Compare P value＜0.01 with negative control group
Embodiment 5: delayed hypersensitivity (DTH) animal model
Dinitrofluorobenzene (DNFB) is deployed into the respective concentration solution for standby with acetone and olive oil (4: 1).With the mouse web portion unhairing, the unhairing scope is about 3cm * 3cm size, and 1%DNFB 50 μ l evenly are applied to unhairing position sensitization, and strengthen 1 time with method next day.Evenly be applied to left ear two sides with 0.2%DNFB solution 10ul again behind the 4d and attack (auris dextra is smeared the acetone olive oil solution that equivalent does not have DNCB).Whole mices took off cervical vertebra execution after DNFB was coated with ear 24h.Before attacking 1h and attack the outer respectively ointment (1%BP-20,3%BP-20,6%BP-20) that is coated with basic, normal, high dosage medicine of the present invention of back 12h each once.Attack back 24-48h and detect each index.
Table 5 experimental result
*Compare P value＜0.01 with negative control group
Embodiment 6: the mice Autoimmune Diabetes
Female NOD mices in 6 ages in week (the Autoimmune Diabetes mice can just send out diabetes after 14 ages in week, and overall sickness rate is 60-70%) are divided into test group and matched group immediately with mice.All animals are all freely intake, and measure random plasma glucose weekly one time.Twice intramuscular injection corter pseudolaricis acetic acid sodium 1.5mg/kg weekly, matched group is given the solvent with Isodose.Observation index: body weight, blood glucose, onset diabetes rate (continuous two all blood sugar concentrations greater than 12mmol/L, think mouse invasion).
Table 6 experimental result
*Compare P value＜0.01 with matched group
Embodiment 7: mouse skin is transplanted
Receptor BALA/c (H-2
d) mice anaesthetizes through lumbar injection 0.75% pentobarbital sodium, prone type is fixed on the operating-table, wipes out the hair of 1/3 to 2/3 intersection on the receptor back, removes holostrome skin 1cm * cm behind 75% alcohol disinfecting as transplant bed, the sterile gauze hemostasis by compression is to donor C3H (H-2
k) mice execution, slough the trunk hair, get the abdominal part full thickness skin graft, scrape subcutaneous fat, skin graft is cut into 1cm * cm size as transplanting skin graft, and the wrapping of postoperative sterile gauze is fixing, releasing wrapping in 5 days, observe every day skin color, hardness, whether form a scab, come off, whether obvious inflammatory reaction is arranged around the graft area.A day beginning transplanted in word, reaches 50% to downright bad skin graft area and end as the time-to-live.Begin 2 weeks, 5 intramuscular injection corter pseudolaricis acetic acid ammonium 3mg/kg weekly, keep for 2 times weekly later on.
Table 7 experimental result
The group cutify becomes live time (d)
Transplant matched group 11.6 ± 0.8
Corter pseudolaricis acetic acid ammonium 29.3 ± 2.1
*
*Compare P value＜0.01 with matched group
Embodiment 8: rat arthritis model
The present invention is to use the adjuvant type arthritis model that has similar symptom with human joint's inflammation to arthritic inhibition is active, estimates as index with the suppression ratio of right back pawl swelling.This research uses the female Lewis rat in 8 ages in week as object of study.Rat is divided 5 groups at random: normal group, model group, positive group, medication therapy groups, the right back foot of the rat intradermal injection Freund's complete adjuvant (0.2ml/ only) that jumps brings out arthritis, begin to rats gavaged administration (BP-112.5mg/kg) every day 1 time, continuous 20 days from causing scorching the 8th day; Positive controls gives tripterygium glycosides sheet 6mg/kg, and normal control group and arthritis model group are given normal saline.Use the stereometry device to measure the right sufficient volume of every rat, calculate every group average swelling volume.
Table 8 experimental result
aCompare P value＜0.01 with the normal control group,
bCompare P value＜0.01 with model group
Embodiment 9: the skin irritation test
Select rabbit 4-8 only, female, hero half and half should be established the excipient contrast, adopts the contrast of consubstantiality left and right sides self.Test preceding 24 hours the administration district (back) carry out left and right each 3cm * 3cm depilation.Injured skin should not be tested.Get given the test agent ointment (3%BP-10, W/W) 0.5g directly is applied to a side skin of unhairing, (2.5cm * 2.5cm) and one deck cellophane or analog cover, and reuse adhesive plaster and binder are fixed with two layers of gauze; Opposite side is coated with the excipient contrast.Application time at least 4 hours.After sticking end, remove and tried thing and clean medicine-feeding part with warm water.Multiple dosing should the continuous same division of day and night, in the administration of same position, sticks the time limit generally to be no more than for 4 weeks.Single-dose: remove behind the medicine situations such as 30-60 minute, 24,48h perusal record coating part erythema and edema.Multiple dosing: observe and record erythema, edema, pigmentation, petechia, pachylosis or epidermatic atrophy situation and time of origin and regression time before removing behind the medicine 1 hour at every turn and sticking once more, and erythema and edema are marked.After last sticks, 30-60 minute, 24,48h perusal and write down coating part and have or not situations such as erythema and edema after removing medicine.Reactions such as that the result does not all have is rubescent, dermexanthesis, blister illustrate the ointment nonirritant of this medicine of the present invention, external safety.
Claims (1)
1. the application of six hydrogen corter pseudolaricis acetic acids in the preparation immunosuppressant.
Priority Applications (1)
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|---|---|---|---|
| CN2009100698120A CN101606930B (en) | 2009-07-21 | 2009-07-21 | Application of pseudolaric acid B and derivative thereof in preparation of immunity inhibitor |
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|---|---|---|---|
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| CN102408403B (en) * | 2011-09-26 | 2014-10-22 | 宋云龙 | Pseudolarix acid derivatives as well as preparation method and application thereof |
| CN106138034A (en) * | 2016-06-28 | 2016-11-23 | 中国人民武装警察部队后勤学院 | Corter pseudolaricis acetic acid or derivatives thereof prevents and treats the application in ulcerative colitis medicine in preparation |
| CN113244225B (en) * | 2021-06-16 | 2022-06-28 | 昆明医科大学第一附属医院 | Application of pseudolaric acid B in preparation of antiplatelet drugs |
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2009
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Non-Patent Citations (1)
| Title |
|---|
| Ting Li等.Pseudolaric Acid B Suppresses T Lymphocyte Activation Through Inhibition of NF-kB Signaling Pathway and p38 Phosphorylation.《Journal of Cellular Biochemistry》.2009,第108卷87-95. * |
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