CN102584924A - Application of carbon-21 steride compound - Google Patents
Application of carbon-21 steride compound Download PDFInfo
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Abstract
The invention discloses application of a carbon-21 steride compound STA (stephanthraniline A) in preparation of anti-inflammatory medicines and immunosuppressive agents. The immunosuppressive agents comprise medicines for preventing and treating rejection in organ transplantation, medicines for preventing and treating allergic diseases or medicines for preventing and treating autoimmune diseases. The results of a variety of in-vivo and in-vitro experiments demonstrate that the compound has the effect of T lymphocyte activation suppression and is different from the traditional steride anti-inflammatory medicines in the action mechanism, i.e. the STA acts without virtue of a glucocorticoid receptor.
Description
Technical field
The present invention relates to medical technical field, be specifically related to the purposes of a kind of natural or synthetic carbon-21 steroidal compound S tephanthraniline A (STA).
Background technology
In recent years, the immunosuppressor development has been widely used in control organ transplant rejection, allergic disorder, autoimmune disorder (like rheumatoid arthritis, lupus erythematosus and nephrotic syndrome etc.) and infective inflammation etc. very rapidly.Yet immunosuppressive drug commonly used clinically at present has obvious toxic and side effects mostly.For example, glucocorticosteroid can cause diseases such as osteoporosis, mellitus, glaucoma; Endoxan can cause leukopenia, hemorrhagic cystitis, cardiotoxic and alopecia; The prolonged application azathioprine (Azathioprine, Aza) and mizoribine (Mizoribine MZ) can bring out cancer; Cyclosporin A (Cyclosporine, CsA), tacrolimus (FK506, Tacrolimus), sirolimus (Sirolimus) has renal toxicity, liver toxicity and neurotoxicity, can cause mellitus and hypertension etc.In addition, the therapeutic index of these medicines is little, and the effective blood drug concentration narrow range often causes toxic side effects or increases the probability that treatment is failed because of the dosage discomfort.A series of untoward reaction makes some patients when receiving treatment, and has also tasted varieties of the misery of using immunosuppressor and bringing, and it is complicated more so that worsen that some patient's the state of an illness becomes.Therefore, press for the immunosuppressor that development of new is efficient, toxic side effect is little.
Modern study confirms that the pathogenesis of anti-rejection, allergic disorder and the autoimmune disorder of many inflammatory reactions, organ transplantation is all closely related unusually with the lymphocytic activation of T.First-selected clinically immunosuppressive drug such as CsA and FK506 etc. play a role through suppressing the lymphocytic activation of T.
(Stephanthraniline A is the steroidal compounds that contains 21 carbon atoms on the parent nucleus of chemical structure STA) to the carbon-21 steroidal compound, and its molecular formula (Molecular formula) is: C
31H
43NO
8, molecular weight (Molecular weight) is 557, structural formula is suc as formula shown in the I:
Since its chemical structure is in the news, very few to the research of this compound pharmacologically active aspect, do not appear in the newspapers so far in the application aspect anti-inflammatory and the immunosuppressive drug through suppressing the lymphocytic activation of T about it.
Summary of the invention
The invention provides the new medicinal use of a kind of carbon-21 steroidal compound S TA.
The application of a kind of carbon-21 steroidal compound S TA in preparation anti-inflammatory drug and immunosuppressor, the structural formula of described carbon-21 steroidal compound S TA is:
Described immunosuppressor comprises the medicine of the rejection of prophylactic treatment organ transplantation, the medicine of prophylactic treatment allergic disorder or the medicine of prophylactic treatment autoimmune disorder.
The weight percentage of carbon-21 steroidal compound S TA is 0.1%～99.5% in described anti-inflammatory drug or the immunosuppressor; Further be preferably 0.5%～95%, specifically can comprise carbon-21 steroidal compound S TA and one or more acceptable accessories of treating significant quantity as required.
Described acceptable accessories is meant the pharmaceutical excipient of pharmaceutical field, for example: thinner, weighting agent, tackiness agent, wetting agent, absorption enhancer, tensio-active agent, disintegrating agent, absorption carrier, lubricant etc.Can also add other auxiliary materials such as flavouring agent, sweeting agent etc. in addition.
The formulation of described anti-inflammatory drug or immunosuppressor does not have strict restriction; Can be prepared into various formulations according to the existing method in medicament field (for example makes STA mix with one or more carriers; Be made into required formulation then), modes such as administered through oral, snuffing, rectum, parenteral or percutaneous dosing are applied to the patient who needs this treatment.
STA of the present invention can obtain by extraction separation from natural phant, as can be according to " structure of STA " (Sumio T, Koji H; Hiroshi M.Structure of Stephanthraniline A.Chemical&pharmaceutical bulletin; 1977,25 (10): 2802-2805.) perhaps " separation of C21 steroidal glycoside and structure determination in the wax flower " (Zhang Rusong, Ye Yiping of the record in the literary composition; Li Xiaoyu; Zhang Xiaoying. the separation of C21 steroidal glycoside and structure determination in the wax flower. chemical journal, 2003,12 (61): 1991-1996.) record in the literary composition obtains.
The usage quantity of The compounds of this invention can be according to route of administration, patient age, body weight, the kinds of Diseases adjustment of being treated, and its per daily dose can be 0.01～100mg/kg body weight.Can use by one or many.
The present invention finds that through experimental study STA can present anti-inflammatory and immunosuppressive action through suppressing the lymphocytic activation of T in vivo and in vitro.For example STA can obviously suppress multiple stimulant inductive mouse T lymphocyte propagation such as concanavalin A (Con A), dyers' grapes (PMW), Anti-CD3/CD28 external; Stop its cell fission, suppress Th1, Th2 and Th17 production of cytokines and mRNA and express; Can obviously suppress 2 in vivo, the 4-dinitrofluorobenzene (2,4-dinitrofluorbenzene, DNFB) the induced mice delayed hypersensitivity (delayed-type hypersensitivity response, DTH).The present invention finds that also the effect of STA inhibition T lymphocyte activation does not receive the influence of GR blocker RU486, and is different with traditional steroidal anti-inflammatory drugs thing mechanism of action.
Description of drawings
Fig. 1 is that STA is to the effect of mitogen PMW inducing mouse splenocyte inhibition of proliferation;
Fig. 2 is that STA is to the lymphopoietic restraining effect of Anti-CD3/CD28 inducing mouse T;
Fig. 3 is STA to the splenocyte inhibition of proliferation effect of mitogen Con A inducing mouse and the glucocorticoid receptor antagonists RU486 influence to it;
Fig. 4 is the influence of STA to t lymphocyte subset crowd propagation;
Fig. 5 is STA effect 24 and the influence to the activated T lymphocytes period profile in 48 hours;
Fig. 6 is the influence of different concns STA to the activated T lymphocytes period profile;
Fig. 7 is cytokine secretion and the mRNA expression thereof that STA suppresses activated T lymphocytes;
Fig. 8 is that STA suppresses DNFB inductive DTH reaction;
Wherein, Stimulation Index is a SI, A
570Be the absorbance of 570nm wavelength, the contrast of Control representation model, Blank representes blank; T cell subsets representes the T cell subsets; Ear swelling representes auricle swelling degree, and Saline representes saline water, and a, b, c, f represent significant difference p.
Embodiment
Below further specify the present invention through embodiment.Should be understood that following examples only to be used to the present invention is described and be not used in the scope of the present invention that limits.If do not specialize the conventional means that used technique means is well known to those skilled in the art.
Main agents of using among the embodiment and instrument: carbon-21 steroidal compound S tephanthraniline A (STA) is obtained by inventor's extraction separation from asclepiadaceae wax flower platymiscium wax flower [Stephanotis mucronata (Blanco) Merr.] root; Measured chemical structure through modern Wave Spectrum technology (ir spectra, UV spectrum, mass spectrum, nuclear magnetic resonance spectrum) and chemical degradation method; Measuring its purity through the HPLC-DAD method is more than 98%; According to " separation of C21 steroidal glycoside and structure determination in the wax flower " (Zhang Rusong; Ye Yiping, Li Xiaoyu, Zhang Xiaoying. the separation of C21 steroidal glycoside and structure determination in the wax flower. chemical journal; 2003,12 (61): the method separation of 1991-1996.) putting down in writing in the literary composition obtains; SPF level BALB/c mouse, conformity certification number: SCXK (Shanghai) 2007-0005, in 6 ages in week, 18～22g purchases the Shanghai Experimental Animal Center in the Chinese Academy of Sciences; Antibody is purchased the eBioscience company in the U.S.; Stimulate former Con A and PMW to purchase Sigma company in the U.S.; Mouse cell factor ELISA detection kit is purchased in Wuhan Boster Biological Technology Co., Ltd.; T lymphocyte separator column (Nylon Fiber Column T) is purchased the company in Japanese Wako; The cell cycle damping fluid (Cell cycle staining buffer) is purchased the Bioisystech Co., Ltd in Lian Ke; Bio-Rad 680 type enzyme-linked immunosorbent assay instruments and PTC-200PCR appearance are U.S. Bio-Rad company; FACS Calibur type flow cytometer is a U.S. Becton Dickson company.
The external restraining effect of embodiment 1:STA to the T lymphocyte activation
1.1 experimental technique
1.1.1 mouse boosting cell suspension preparation
The aseptic spleen of getting of mouse adds an amount of Hank ' s liquid and grinds, and filters with 200 order stainless (steel) wires, and centrifugal 5 minutes of 1500rpm abandons supernatant, removes red corpuscle with erythrocyte cracked liquid, adds Hank ' s liquid repeated washing 2 times.Collect splenocyte, add an amount of RPMI 1640 complete culture solution suspendibles, with the numeration of 0.4% (mass percent) trypan blue exclusion method, viable count is no less than 95%.
1.1.2 the T lymphocyte separates
Adopt nylon Mao Zhufa to separate the T cell.Get the nylon hair post vertical fixing of sterilization, be put in the super clean bench, outlet at bottom connects rubber tubing and valve positioner; With Hank ' the s liquid flushing balance columns bed of 37 ℃ of preheatings, regulate the about 3-4mL/min of flow velocity, drain bubble; With the RPMI 1640 complete culture solutions flushing balance columns bed of 37 ℃ of preheatings, when treating nutrient solution near post bed surface, valve-off; Add cell suspension, slow regulated valve, treat that cell suspension immerses the post bed fully after, valve-off is hatched for 37 ℃; 45～60min is hatched and is finished back adding RPMI 1640 complete culture solutions (37 ℃ of preheatings), and slowly regulated valve is controlled flow velocity 3-4ml/min, collecting cell.
1.1.3 mitogen PMW inductive mouse boosting cell proliferative response
In the flat Tissue Culture Plate in 96 holes, every hole adds splenocyte suspension (6 * 10
6Cell/ml) 100 μ l, different concns supplies diluent (1.25～20 μ g/ml) the 50 μ l of reagent thing, and PMW solution (5 μ g/ml) or each 50 μ l of RPMI RPMI-1640, and each concentration repeats 4 holes.Other establishes blank group and cyclosporin A (C
SA, 6.25ng/ml) control group.37 ℃, 5%CO
2Cultivate after 48 hours, mtt assay is measured the OD value.Be calculated as follows SI (SI): SI=and be added with the OD value of a mitogen culture/the be not added with OD value of a mitogen culture.
1.1.4 Anti-CD3/CD28 inductive mouse T lymphocyte proliferative response
In the 96 porocyte culture plates that Anti-CD3 (10 μ g/ml) 100 μ l/ holes encapsulate in advance, every hole adds 5 * 10
6The T lymphocyte suspension 100 μ l of cell/ml concentration and different concns each 50 μ l of STA medicine and Anti-CD28 (2.5 μ g/ml), each concentration repeats 4 holes.Other establishes normal control (being the model contrast), blank and positive drug CsA (6.25ng/ml) and DEXAMETHASONE BP98 (Dexamethasone, Dex) (1ng/ml) contrast.37 ℃, 5% (volume percent) CO
2Cultivate after 48 hours, mtt assay is measured the OD value.
1.1.5 mouse boosting cell proliferative response of mitogen Con A inductive and glucocorticoid receptor antagonists RU486 are to the influence of STA
In 96 porocyte culture plates, add splenocyte suspension 100 μ l, the STA medicine 50 μ l of different concns, Con A (3 μ g/ml), RU486 (1 μ g/ml) or ConA+RU486 mixed solution 50 μ l, multiple 3 holes; Other establishes normal control, blank and positive drug CsA and Dex contrast.37 ℃, 5%CO
2Cultivate 48 back mtt assay and measure the OD value, and calculate SI (SI).
1.1.6 t lymphocyte subset crowd's mensuration
Get the 1ml splenocyte suspension and be inoculated in 24 orifice plates, add the STA of Con A and different concns, each multiple 3 hole, 37 ℃, 5%CO
2Cultivate after 48 hours, collecting cell is made CD3+CD4 and CD3+CD8 mark respectively, after the room temperature lucifuge is hatched 30min, and the washing of PBS damping fluid, flow cytometry analysis detects.
1.1.7 T lymphocytic cell division period measurement
In the 24 porocyte culture plates, the mouse boosting cell of the mouse T lymphocyte of Anti-CD3/CD28 inducing culture and Con A inducing culture is through the medicine STA of different concns effect 24 or after 48 hours, collecting cell; Wash 1 time with the PBS damping fluid; Fixing with 1ml 80% (mass percent) aqueous ethanolic solution-20 ℃, then PBS damping fluid 1ml washes 2 times, again aquation; The centrifugal PBS damping fluid of abandoning adds Cell cycle staining buffer 0.5ml.Flow cytometry analysis detected its period profile of Flowjo software analysis after lucifuge was hatched 30min.
1.1.8 the mensuration that T lymphocytic emiocytosis cytokine and mRNA thereof express
In the 24 porocyte culture plates, the mouse T lymphocyte of Anti-CD3/CD28 inducing culture was through the medicine STA of different concns effect 6 hours, and collecting cell extracts RNA, and the RT-PCR method is analyzed the mRNA expression; Effect 24h or 48 hours collection supernatants, the secretion situation of employing ELISA kit measurement cytokine.
1.2 experimental result
1.2.1 STA is to the effect of mouse T lymphocyte inhibition of proliferation
T lymphocyte and bone-marrow-derived lymphocyte are the topmost immunocytes of body, the propagation of mitogen PMW ability while inducer T lymphocyte and bone-marrow-derived lymphocyte.As can beappreciated from fig. 1, STA and positive control drug CsA all can suppress significantly PMW inductive mouse boosting cell propagation (with drug level be 0 group relatively, the t check,
bP＜0.01,
cP＜0.001 has significant difference).The activation of T cell is mainly by the mediation of the costimulatory molecules (Co-stimulatory molecule) of the first signal T cell surface receptor (TCR) and second signal T cell surface, externally stimulates the T cell to be commonly used to simulate the activation process of T cell with anti-CD3/CD28 monoclonal antibody.As shown in Figure 2, can obviously suppress Anti-CD3/CD28 inductive mouse T lymphocyte propagation more than the STA 5 μ g/ml, and demonstrate concentration dependent; Positive control drug CsA6.25ng/ml and Dex 1ng/ml also all have the obvious suppression effect (with model control group relatively, the t check,
bP＜0.01,
cP＜0.001 has significant difference).Dex is traditional steroidal anti-inflammatory drugs thing glucocorticosteroid; In order to further specify the difference of carbon-21 steroidal compound S TA and traditional steroidal anti-inflammatory drugs thing; But the mitogen ConA with another one specificity inducer T lymphocyte propagation stimulates splenocyte; Further verified STA to the lymphopoietic restraining effect of T, and observed glucocorticoid receptor antagonists RU486 to its active influence, the result is as shown in Figure 3; But STA concentration dependent ground significantly suppresses Con A inductive mouse boosting cell propagation, and positive control drug CsA and Dex also have the effect of utmost point obvious suppression; Glucocorticosteroid antagonist RU486 has tangible antagonistic action to glucocorticosteroid Dex, and to CsA and STA do not have influence (with model control group relatively, the t check,
aP＜0.05,
bP＜0.01,
cP＜0.001; Compare with Con A+Dex group, the t check,
fP＜0.001; Has significant difference).
Above result shows that STA can significantly suppress the lymphocytic propagation of T, and different with traditional steroidal anti-inflammatory drugs thing glucocorticosteroid Dex, and the STA effect does not rely on GR.
1.2.2 STA is to the influence of t lymphocyte subset crowd propagation
Suppress the lymphopoietic effect characteristics of T in order further to observe STA, the t lymphocyte subset crowd to propagation analyzes with flow cytometer, and the result shows that STA mainly suppresses CD3
+CD4
+T lymphocyte subset crowd's propagation (like Fig. 4, compare with model control group, the t check,
cP＜0.001 has significant difference).
1.2.3 STA is to the influence of activated T lymphocyte period profile
With having observed the influence of STA behind Anti-CD3/CD28 and the Con A inducing mouse T lymphocyte activation to its period profile.The result is as shown in Figure 5, and CD3+CD28 can make the T cell cycle distribution take place obviously to change, and 24 hour cells mainly get into the S phase, and getting into G2 phase cell after 48 hours just obviously increases; Medicine STA (15 μ g/ml) can obviously stop cell fission, shows that 24 hours S phases obviously reduced, 48 hours S phases and G2 phase all reduce (with model control group relatively, the t check,
cP＜0.001 has significant difference).To ConA inductive T cell fission, STA appeared too concentration dependent restraining effect (like Fig. 6, with drug level be 0 group relatively, the t check,
bP＜0.01,
cP＜0.001 has significant difference).Above result shows that STA can stop the division of T cell, thereby suppresses its propagation.
1.2.4 suppressing the cytokine secretion and the mRNA thereof of activated T lymphocytes, STA expresses
CD4
+The T cell can be divided into Th1 and Th2 cell according to the difference that cytokine produces, and the former is through main mediated cell immunoreations of cytokine such as secretion of gamma-IFN, and the latter then mainly mediates humoral immune reaction through cytokines such as secretion IL-4, IL-10.Th17 is different and Th1 and the Th2 cell CD4 of newfound in recent years secretion IL-17
+The T cell subsets works in the reaction of mediation autoimmune inflammation.Fail to accept the T cell that useful signal stimulates, in 48 hours, can become fast with dead, and activated T cell can be secreted a large amount of cytokines and proliferation and differentiation.As shown in Figure 7, STA has all shown the dependent restraining effect of significant concn to Anti-CD3/CD28 inductive mouse T lymphocyte factor IL-2, IFN-γ, IL-4 and IL-17 secretion; To its mRNA level also have the obvious suppression effect (with model control group relatively, the t check,
aP＜0.05,
bP＜0.01,
cP＜0.001 has significant difference).But above result shows the activation of STA suppressor T cell, reduces the generation of Th1, Th2 and the Th17 factor.
The interior restraining effect of embodiment 2:STA body to the T lymphocyte activation
The DTH reaction is a kind of immunoreation by the sensitized T cell mediation; It is by the reaction of T cell and antigen-specific and cause with mononuclearcell and soak into and the cytopathy necrosis is the local reaction property inflammation of characteristic; Be gathered in local organization through phagocytic cell and lymphocyte; Cause that local damage and vascular permeability increase, and increase like ear's swelling degree.Therefore we have observed the interior influence to the T lymphocyte activation of STA body with DNFB inductive DTH reaction.
2.1 experimental technique
2.1.1 the preparation of medicine
Medicine STA and positive control CsA are diluted to desired concn after all grinding well with the CMC-Na solution of 0.5% (mass percent).
2.1.2 grouping and processing
Get 50 mouse, belly is shaved hair, smears the acetone sesame oil (1: 1 of 1% (mass percent) DNFB; Volume ratio) after the solution 50 μ l sensitization; Be divided into 5 groups at random, 10 every group, male and female half and half; Each difference of organizing the weight average value is no more than 1g, is respectively: solvent control group, positive control CsA group (20mg/kg), STA group (5,10,20mg/kg).In sensitization administration on the same day, once a day, continuous 6 days.Rechallenge is carried out in 5 days (the 6th day) after the sensitization: i.e. the even acetone sesame oil solution of coating 10 μ l 1% (mass percent) DNFB in ear both sides on a mouse left side, the auris dextra both sides are coated with acetone sesame oil (1: 1, volume ratio) solvent with equivalent as contrast simultaneously.
2.1.3 index observing and mensuration
Disconnected neck is put to death experimental animal behind the rechallenge 24h, cuts left and right sides auricle, lays round auricle with 8mm diameter punch tool in same position.Analytical balance is weighed, and representes the ease auricle swelling degree with the left and right sides ear method of double differences.
2.2 experimental result
As shown in Figure 8, with solvent control group (saline water) relatively, positive control medicine CsA can significantly reduce DNFB inductive mice auricle swelling degree (
aP＜0.05), each dosage of STA (5,10,20mg/kg) also all can significantly reduce auricle swelling degree (
bP＜0.01), shows in the STA body and can significantly suppress the activation of mouse T lymphocyte, and significantly suppress DNFB inductive DTH reaction.
The foregoing description 1 shows with the experiment in vivo and vitro of embodiment 2: different with traditional steroidal anti-inflammatory drugs thing glucocorticosteroid, carbon-21 steroidal compound S TA does not significantly suppress the cell activation of T lymph through its acceptor, present anti-inflammatory and immunosuppressive action.
Tablet:
The preparation method: activeconstituents, lactose and starch are mixed, and water is evenly moistening, and the mixture after moistening sieves and be dry, after sieve, adds Magnesium Stearate, then with the mixture compressing tablet, and every heavy 250mg, active component content 10mg.
Capsule: activeconstituents STA 1.0g
Lactose 18.8g
Magnesium Stearate 0.2g;
Preparing method: activeconstituents, lactose and Magnesium Stearate are mixed, sieve, the hard capsule of packing into, the heavy 200mg of each capsule, active component content 10mg.
Claims (3)
1. the application of carbon-21 steroidal compound S TA in preparation anti-inflammatory drug and immunosuppressor, the structural formula of described carbon-21 steroidal compound S TA is:
2. application according to claim 1 is characterized in that, described immunosuppressor comprises the medicine of the rejection of prophylactic treatment organ transplantation, the medicine of prophylactic treatment allergic disorder or the medicine of prophylactic treatment autoimmune disorder.
3. application according to claim 1 is characterized in that, the weight percentage of carbon-21 steroidal compound S TA is 0.1%～99.5% in described anti-inflammatory drug or the immunosuppressor.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104958304A (en) * | 2015-06-08 | 2015-10-07 | 浙江省医学科学院 | Application of carbon-21 steroid compound STA in preparation of Hedgehog pathway inhibitor and anticancer drugs |
| CN107056855A (en) * | 2017-03-24 | 2017-08-18 | 昆明理工大学 | A kind of 16,17 open loop pregnane glycoside compounds and its application |
| CN107522764A (en) * | 2015-06-12 | 2017-12-29 | 浙江省医学科学院 | A kind of antidepressant compounds |
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| CN1763065A (en) * | 2005-09-15 | 2006-04-26 | 浙江省医学科学院 | A kind of carbon-21 steroidal glycosides with immunosuppressive action |
| US20090297510A1 (en) * | 2008-05-09 | 2009-12-03 | Tong-Jun Lin | Inhibition of calpain reduces allergic inflammation |
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2012
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1763065A (en) * | 2005-09-15 | 2006-04-26 | 浙江省医学科学院 | A kind of carbon-21 steroidal glycosides with immunosuppressive action |
| US20090297510A1 (en) * | 2008-05-09 | 2009-12-03 | Tong-Jun Lin | Inhibition of calpain reduces allergic inflammation |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104958304A (en) * | 2015-06-08 | 2015-10-07 | 浙江省医学科学院 | Application of carbon-21 steroid compound STA in preparation of Hedgehog pathway inhibitor and anticancer drugs |
| CN107522764A (en) * | 2015-06-12 | 2017-12-29 | 浙江省医学科学院 | A kind of antidepressant compounds |
| CN107056855A (en) * | 2017-03-24 | 2017-08-18 | 昆明理工大学 | A kind of 16,17 open loop pregnane glycoside compounds and its application |
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Application publication date: 20120718 |