CN108785318B - Application of phenylpropanoid glycoside compounds in preparation of IDO inhibitor - Google Patents
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Abstract
The invention belongs to the field of medicines or health-care products, and particularly relates to an application of phenylpropanoid glycoside compounds and pharmaceutically acceptable derivatives thereof in preparation of IDO inhibitors. According to the invention, researches show that the inhibitory activity of verbascoside and cistanchid on intracellular IDO is superior to that of a positive control drug 1-methyltryptophan (1-MT) on intracellular IDO, the inhibitory activity of the verbascoside and the cistanchid on intracellular IDO has obvious IDO inhibitory activity, and the verbascoside and the cistanchid can be used for treating cancers, Alzheimer's disease, ankylosing spondylitis, autoimmune diseases, bacterial infection, cataract, mood disorders, depression or anxiety.
Description
Technical Field
The invention belongs to the field of medicines or health-care products, and particularly relates to an application of phenylpropanoid glycoside compounds in preparation of IDO inhibitors.
Background
IDO (indole-2, 3-dioxygenase) is named as indoleamine 2, 3-dioxygenase, is the only rate-limiting enzyme except liver for catalyzing the metabolism of tryptophan along Kynurenine Pathway (KP), and can decompose tryptophan into various metabolites such as L-kynurenine, picolinic acid, quinolinic acid and the like. L-tryptophan, which is an amino acid essential for maintaining cell activation and proliferation in the human body, is also an indispensable component constituting proteins, and its deficiency causes dysfunction of some important cells. Since the discovery in 1967, the mechanism of IDO inhibiting the proliferation of pathogenic microorganisms by degrading tryptophan, the relationship between IDO and neurological diseases has been gradually elucidated; and researches prove that the IDO also participates in the response of regulating T cells and can generate inhibition on the proliferation and activation of the T cells, and the inhibition mediates the immune escape phenomenon of IDO-expressing tumor cells. Therefore, the abnormal increase of the expression or activity of IDO is closely related to the pathogenesis of various diseases, and is an important factor causing various diseases, such as proven tumor, Alzheimer's disease, depression, senile cataract, viral infection such as AIDS, bacterial infection such as Lyme disease and streptococcal infection, and the like (refer to the following documents: research progress of IDO inhibitor, Connaer et al, J.Chem.J.CHIP.Pharma 2009, 19 (2): 147) 154, and CN101429151A, an IDO inhibitor containing (E) -4- (BETA-bromovinyl) phenoxyacyl structure and a preparation method thereof, the publication date of which is 5 months and 13 days in 2009). Therefore, IDO inhibitors are promising therapeutic agents, and attract the attention of numerous scholars.
As a new target, IDO has become a potential cancer immunotherapy target. Screening of highly effective and low toxic IDO inhibitors/antibodies and their use in the treatment of the above diseases have become a common appeal to researchers. In 1978, researchers have investigated the isolation of non-selective competitive IDO inhibitors, but the inhibitory potency was weak. In the early 90 s of the 20 th century, the tryptophan derivative 1-MT (namely indoximod) is synthesized for the first time and is taken as an inhibitor closest to the structure of a substrate tryptophan, so that the attention and interest of people on IDO inhibitors are more extensive. Research and development of IDO inhibitors is still in the early stage of drug development, and only 2 compounds (epacadostat and indoximod) enter phase ii clinic and 1 compound (GDC-0919) enters phase i clinic at present.
The initial work for finding IDO inhibitors was mainly to chemically synthesize IDO and structurally modify IDO using its substrate tryptophan as a template based on the study of structure-activity relationship, and published articles and registered patents cover almost all groups that can be modified, but have little effect. From 2006, scholars at home and abroad try to find high-activity IDO inhibitors with new structural frameworks from natural products, such as: exiguamine A was extracted from the sponge Neopetrosiae xigua by Brastianos et al (Ki value ═ 0.21. mu.M); annulin C (Ki value 0.14. mu.M) was extracted from sea hydroids by Alban Pereir et al; caspari et al found that a commercially available natural product, Brassicanin (Ki value 97.7. mu.M) had moderate activity; chinese patent document CN101843618A discloses: berberine and its derivatives also have IDO inhibiting effect.
Phenylpropanoid glycoside compounds, also known as phenylethanoid glycoside compounds, are a class of natural glycosides containing substituted phenylethyl and cinnamoyl groups, and are widely present in dicotyledonous plants. Since the first phenylpropanoid glycoside compound was isolated in 1963, the number of such compounds isolated has increased. With the continuous and deep research on the compounds, pharmacodynamic experiments show that the phenylpropanoid glycoside compounds have wide and obvious biological activities, such as: has antibacterial, antiinflammatory, antitumor, antiviral, antioxidant, hepatoprotective, and base repairing effects.
At present, no report is available about the application of phenylpropanoid glycoside compounds in preparing IDO inhibitors.
Disclosure of Invention
Therefore, the invention aims to solve the technical problem that phenylpropanoid glycoside compounds are not used for preparing IDO inhibitors in the prior art, thereby providing the application of the phenylpropanoid glycoside compounds in preparing IDO inhibitors.
In order to solve the technical problems, the invention is realized by the following technical scheme:
the invention provides an application of phenylpropanoid glycoside compounds and pharmaceutically acceptable derivatives thereof in preparing IDO inhibitors;
the IDO inhibitors are useful for the treatment of cancer, alzheimer's disease, ankylosing spondylitis, autoimmune diseases, bacterial infections, cataracts, mood disorders, depression or anxiety disorders; the pharmaceutically acceptable derivative is selected from a salt, ester, prodrug or solvate;
the phenylpropanoid glycoside compound has the following structure:
wherein R is1、R2Independently of one another, from-H or-CH3。
The invention also provides the application of the phenylpropanoid glycoside compounds and the pharmaceutically acceptable derivatives thereof in preparing medicines for treating diseases with pathological characteristics of IDO mediated tryptophan metabolic pathway;
the disease is cancer, Alzheimer's disease, ankylosing spondylitis, autoimmune disease, bacterial infection, cataract, mood disorder, depression or anxiety; the pharmaceutically acceptable derivative is selected from a salt, ester, prodrug or solvate;
the phenylpropanoid glycoside compound has the following structure:
wherein R is1、R2Independently of one another, from-H or-CH3。
Preferably, in the above use, the phenylpropanoid glycoside compound is:
preferably, the above uses do not include the following technical solutions:
use of verbascoside and pharmaceutically acceptable derivatives thereof in the preparation of an IDO inhibitor for the treatment of cancer, autoimmune diseases, alzheimer's disease or depression;
use of cistanoside D and pharmaceutically acceptable derivatives thereof in the preparation of IDO inhibitors for the treatment of cancer.
Preferably, the above uses do not include the following technical solutions:
use of verbascoside and pharmaceutically acceptable derivatives thereof in the manufacture of a medicament for the treatment of a disease characterized by the pathology of the IDO-mediated tryptophan metabolic pathway, said disease being cancer, autoimmune disease, alzheimer's disease or depression;
use of cistanoside D and pharmaceutically acceptable derivatives thereof in the preparation of a medicament for the treatment of a disease characterized by the IDO-mediated tryptophan metabolic pathway pathology, said disease being cancer.
Preferably, in the application, the phenylpropanoid glycoside compounds and the pharmaceutically acceptable derivatives thereof are prepared into clinically acceptable tablets, capsules, powder, mixtures, pills, granules, syrups, emplastrums, suppositories, aerosols, ointments or injections by adding conventional auxiliary materials according to a conventional process.
The conventional auxiliary materials are as follows: fillers, disintegrants, lubricants, suspending agents, binders, sweeteners, flavoring agents, preservatives, bases, and the like. The filler comprises: starch, pregelatinized starch, lactose, mannitol, chitin, microcrystalline cellulose, sucrose, etc.; the disintegrating agent comprises: starch, pregelatinized starch, microcrystalline cellulose, sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone, low-substituted hydroxypropylcellulose, cross-linked sodium carboxymethyl cellulose, etc.; the lubricant comprises: magnesium stearate, sodium lauryl sulfate, talc, silica, and the like; the suspending agent comprises: polyvinylpyrrolidone, microcrystalline cellulose, sucrose, agar, hydroxypropyl methylcellulose, and the like; the adhesive comprises starch slurry, polyvinylpyrrolidone, hydroxypropyl methylcellulose, etc.; the sweetener comprises: saccharin sodium, aspartame, sucrose, sodium cyclamate, glycyrrhetinic acid, and the like; the flavoring agent comprises: sweeteners and various essences; the preservative comprises: parabens, benzoic acid, sodium benzoate, sorbic acid and its salts, benzalkonium bromide, chloroacetidine acetate, eucalyptus oil, etc.; the matrix comprises: PEG6000, PEG4000, insect wax, etc.
The technical scheme of the invention has the following advantages:
according to the invention, researches show that the inhibitory activity of verbascoside and cistanchid on intracellular IDO is superior to that of a positive control drug 1-methyltryptophan (1-MT) on intracellular IDO, the inhibitory activity of the verbascoside and the cistanchid on intracellular IDO has obvious IDO inhibitory activity, and the verbascoside and the cistanchid can be used for treating cancers, Alzheimer's disease, ankylosing spondylitis, autoimmune diseases, bacterial infection, cataract, mood disorders, depression or anxiety.
Detailed Description
In the following examples and experimental examples of the present invention, verbascoside can be obtained by purchase, can be prepared according to the method of the present invention in example 1, and can be prepared according to the existing literature; cistanoside D can be prepared according to the method of the invention in example 1, and can also be prepared according to the existing literature.
Example 1Preparation of verbascoside and cistanoside D
Taking dry succulent stem of Cistanchis herba (Cistanchis herba Ma), adding 10 times of ethanol water solution with volume concentration of 75% by weight, heating and reflux extracting for 2 times, 1 st time for 2 hr, 2 nd time for 1 hr, mixing extractive solutions, and concentrating under reduced pressure to obtain Cistanchis herba extract;
suspending the cistanche extract in water with the weight of 1 time, extracting for 2 times by taking n-butyl alcohol as an extractant, collecting organic phases of extract liquor, and then concentrating under reduced pressure to obtain an extract of n-butyl alcohol extraction parts of the cistanche;
purifying the extract of n-butanol extract part of herba cistanches by AB-8 macroporous resin column chromatography (diameter of macroporous resin column is 8cm, column volume is 3.5L), performing gradient elution with water as mobile phase A and ethanol as mobile phase B according to the following procedures (flow rate of gradient elution is 3 BV/h): firstly, using A: b volume ratio is 100%: elution of 3BV with 0% mobile phase, then a: b volume ratio is 80%: 20% of the mobile phase eluted 4BV, then A: b volume ratio is 60%: 40% of the mobile phase eluted 4BV, then A: b volume ratio is 40%: 60% of the mobile phase eluted 4BV, then A: b volume ratio is 5%: and (3) eluting 95% of mobile phase to regenerate the macroporous resin, and respectively collecting the mobile phase A: b volume ratio is 80%: 20%, A: b volume ratio is 60%: concentrating 40% of the eluate under reduced pressure to obtain herba cistanches ethanol elution part extract-1 and herba cistanches ethanol elution part extract-2;
the ethanol elution part extract-1 of the cistanche deserticola is subjected to liquid phase separation and purification by C18 reverse phase of Agilent SD-1, water is taken as a mobile phase C, methanol is taken as a mobile phase D, and gradient elution is carried out according to the following procedures: firstly, using C: d volume ratio is 90%: 10% of the mobile phase was eluted and then eluted with C: d volume ratio is 80%: 20% of the mobile phase was eluted and then eluted with C: d volume ratio is 70%: 30% of the mobile phase was eluted, then C: d volume ratio is 60%: 40% of the mobile phase was eluted and then eluted with C: d volume ratio is 50%: eluting 50% of the mobile phase, detecting by TLC or HPLC-MS, and collecting the mobile phase C: d volume ratio is 70%: concentrating 30% eluate under reduced pressure, and drying to obtain cistanoside D (HPLC purity is not less than 95%);
the ethanol elution part extract-2 of the cistanche deserticola is subjected to liquid phase separation and purification by C18 reverse phase of Agilent SD-1, water is taken as a mobile phase C, methanol is taken as a mobile phase D, and gradient elution is carried out according to the following procedures: firstly, using C: d volume ratio is 80%: 20% of the mobile phase was eluted and then eluted with C: d volume ratio is 75%: 25% of the mobile phase was eluted and then eluted with C: d volume ratio is 55%: 45% of the mobile phase was eluted and then eluted with C: d volume ratio is 40%: eluting 60% of the mobile phase, detecting by TLC or HPLC-MS, and collecting the mobile phase C: d volume ratio is 55%: 45% of the eluent is then decompressed, concentrated and dried to obtain the verbascoside (the HPLC purity is more than or equal to 95%).
Respectively passing the compounds prepared above through1H-NMR、13The structure was confirmed by C-NMR and HPLC-MS, respectively, by comparison with those in the prior art (chemical composition study of cistanche, J.Pharmaol., 2011, 46(14), 1053-1H-NMR、13Comparing C-NMR and HPLC-MS, and finding that the prepared compounds are cistanoside D and verbascoside respectively.
Experimental example 1Study on inhibitory Activity of verbascoside and cistanoside D on IDO
1. Purpose of experiment
HEK293 cells are transfected by the plasmid pcDNA3.1-IDO to enable the HEK293 cells to highly express IDO, and then the inhibitory activity of verbascoside and cistanoside D on IDO at the cell level is respectively determined.
2. Experimental methods
HEK293 cells were seeded at 2.5X104 cells/well in 96-well plates, cultured in DMEM medium (containing 10% fetal bovine serum, 50U/mL penicillin and 50mg/mL streptomycin), conditioned at 37 ℃ with 95% humidity and 5% CO2Cultured in an incubator. After 24h of culture, pcDNA3.1-hIDO plasmid transfection was mediated by liposome Lipofectamin 2000 and divided into positive control group and experimental group 1-2. The positive control group uses 1-methyl tryptophan (1-MT) as a test sample, and the experimental groups 1-2 respectively use acteoside and cistanchid prepared in example 1 as test samples.
After 24h of transfection, each group was added separately toThe test sample is incubated. Incubating for 5h, collecting 140 μ L supernatant, adding 10 μ L30% (w/v) trichloroacetic acid into another 96-well plate, heating at 65 deg.C for 15min, centrifuging at 12000rpm for 10min, mixing with 2% (w/v) p-dimethylaminobenzaldehyde acetic acid solution, developing, detecting absorbance at 492nm with enzyme reader, and determining activity by IC50The values are represented.
3. Results of the experiment
The results of specific experiments on the inhibitory activity of IDO for each group are shown in table 1.
Table 1 results of specific experiments on the inhibitory activity of IDO at the cellular level for each group
| Group of | IC50(μM) |
| Positive control group | 17.8 |
| Experimental group 1 group | 13.8 |
| Experimental group 2 groups | 15.5 |
As can be seen from Table 1: (1) the inhibition activity of the experimental group 1-2 on the IDO in the cells is better than that of the positive control group on the IDO in the cells, and the inhibition activity of the IDO is obvious;
(2) the inhibitory activity of the experimental groups 1-2 on IDO in cells is equivalent, which shows that R of phenylpropanoid glycosides1、R2The difference in substituents has no significant effect on the inhibitory activity.
4. Conclusion of the experiment
The inhibitory activity of cistanoside D and verbascoside on the IDO in the cells is better than that of the positive control medicament 1-methyltryptophan (1-MT) on the IDO in the cells, and the inhibitory activity of the cistanoside D and the verbascoside on the IDO in the cells is obvious.
Experimental example 2Therapeutic effect of phenylpropanoid glycoside compounds on ankylosing spondylitis
1. Purpose of experiment
A mouse ankylosing spondylitis model is established by a proteoglycan immunization method, then mullein glucoside and cistanchid are irrigated, the levels of inflammatory marker serum TNF-alpha and NF-k B receptor activating factor ligand (RANKL) are detected by an ELISA method, the serum IDO activity (Kyn/Trp) is detected, and the curative effect of the phenylpropanoid glycosides compound on ankylosing spondylitis is verified.
2. Experimental methods
2.1 Experimental animals
Healthy male BALB/c mice 32, weighing (18. + -.2) g, aged 4-5 weeks, were purchased from Shanghaisley.
2.2 test drugs
Verbascoside and cistanoside D prepared in example 1 were used as test drugs.
2.3 Experimental grouping and modeling
After 1 week of adaptive feeding, 8 of the mice were used as blank control groups. Taking the rest 24 mice, establishing a ankylosing spondylitis model by a proteoglycan immunization method, injecting 0.15mL (75 mug + Freund's adjuvant) of proteoglycan emulsion into the abdominal cavity of the mice, strengthening the immunity 7 days after the first immunization, injecting 0.15mL of emulsion into the abdominal cavity, and molding for 21 days; after the molding is successful, the molding is divided into 3 groups: experimental groups 1-2 and model control groups. Experimental groups 1-2 groups were administered with verbascoside and cistanoside D prepared in example 1 by intragastric administration 1 time daily at a dose of 0.2g/10 g. The model control group and the blank control group were both administered with the same amount of physiological saline for intragastric administration. Each group was administered for 60 days, and orbital bleeds were taken on day 61.
2.4 inflammatory factor assay
ELISA is adopted to detect the levels of serum TNF-alpha and RANKL in the peripheral blood of animals, and the operation is carried out according to the kit instruction.
2.5IDO Activity assay
And (3) simultaneously detecting the Trp concentration and the Kyn concentration in the serum of the mouse by utilizing a high performance liquid chromatography technology. Because IDO catalyzes the metabolism of substrate Trp to produce product Kyn, the Kyn/Trp ratio reflects IDO activity.
The serum was left overnight at 4 ℃ and centrifuged at 3000rpm for 15 min. Collecting supernatant, adding 5% perchloric acid solution with the same volume, and mixing in a vortex mixer for 0.5-1 min. Standing at room temperature for 10-15min to fully precipitate proteins in serum, centrifuging at 12000rpm for 10min, taking supernatant, adding 1/2 volumes of methanol (chromatographic purity), oscillating on a cyclone analyzer for 5min, centrifuging at 12000rpm for 10min, filtering the supernatant with a 0.45 μm filter, loading, and detecting kynurenine/tryptophan (Kyn/Trp) ratio in serum, thereby reflecting the change of IDO activity. Chromatographic conditions are as follows: c18 column (250 mm. times.4.6 mm, 5 μm); mobile phase: 15mmol/L sodium acetate-acetic acid solution (containing 7% volume fraction of acetonitrile, pH 3.5); flow rate: 1 mL/min; detection wavelength: 225 nm; sample introduction amount: 20 mu L of the solution; the column temperature was 25 ℃.
2.6 statistical treatment
The analysis is carried out by SPSS22.0 statistical software, and the average value plus or minus standard deviation is used for measuring data
Indicating, and checking a line t; counting data are expressed in percentage, and performing X2 test; p < 0.05 indicates that the difference is statistically significant.
3. Results of the experiment
The results of the experiments are shown in Table 2.
TABLE 2 serum TNF-alpha and RANKL levels and inhibition of IDO activity in groups of mice
#Compared with a blank control group, P is less than 0.05,*p is less than 0.05 compared with the model control group
As can be seen from Table 2, (1) the serum TNF-alpha and RANKL levels of the model control group mice are obviously increased, which indicates that the ankylosing spondylitis model is successfully modeled; (2) serum TNF-alpha and RANKL levels of mice in experimental groups 1-2 are obviously reduced (P is less than 0.05), and IDO activity is obviously reduced (P is less than 0.05); this indicates that acteoside and cistanoside D prepared in example 1 have therapeutic effects on ankylosing spondylitis by inhibiting IDO activity.
4. Conclusion of the experiment
The verbascoside and the cistanoside D can obviously reduce the serum TNF-alpha and RANKL levels of a ankylosing spondylitis model and have obvious inhibiting effect on the activity of IDO; acteoside and cistanoside D have remarkable therapeutic effect on ankylosing spondylitis.
Experimental example 3Therapeutic action of phenylpropanoid glycosides on streptococcal infection
1. Purpose of experiment
The inhibition rate of the mice infected by streptococcus is detected by gavage verbascoside and cistanchid D of the mice infected by streptococcus, and the treatment effect of the mice infected by streptococcus is verified.
2. Experimental methods
2.1 Experimental animals
40 healthy male Kunming mice, weighing (18 + -2) g and aged 4-5 weeks, were purchased from Shanghai Slek.
2.2 test drugs
Verbascoside and cistanoside D prepared in example 1 were used as test drugs.
2.3 Experimental grouping and modeling
The streptococcus hemolyticus CMCC (B)32171 standard strain is inoculated to a rabbit blood agar plate, and after streaking, a single colony with obvious hemolytic rings is obtained by culture. A single colony was inoculated in THY medium (containing 5% calf serum) and amplified overnight at OD600nm ═ 0.6 (about 10)9CFU/ml), and stored at 4 ℃ for further use. THY medium (tryptone per liter)20 g, yeast extract 3 g, beef extract 5 g, sodium chloride 2g, glucose 4 g, sodium carbonate 2.5 g, disodium hydrogen phosphate 0.4 g, pH adjusted to 7.4. Solid medium: adding 1.5% agar powder, sterilizing with high pressure steam for 30min, and storing at 4 deg.C).
10 mice were used as a blank control group. The remaining 30 mice were divided equally into 3 groups: experimental groups 1-2 and model control groups, 10 mice per group. Experimental groups 1-2 groups were administered with verbascoside and cistanoside D prepared in example 1, respectively, by intragastric administration at a dose of 80mg/kg each time. The model control group and the blank control group were both administered with the same amount of physiological saline for intragastric administration. After the experimental group 1-2 and the model control group were gavaged for 1h, the tail vein was injected with OD600nm ═ 0.6 streptococcus pyogenes 322171PBS solution at the injection dose: 0.4ml of the bacterial suspension/10 g of mouse was administered 1 time at 24h intervals, and observed 1 time at 6h intervals, and the death status of the mice at 6h, 12h, 24h and 48h was recorded.
3. Results of the experiment
The effect of different time on the death of streptococcal infected mice in each group is shown in table 3.
TABLE 3 Effect of different time on the death of mice infected with Streptococcus (n ═ 10)
As can be seen from table 3, (1) after 48 hours of administration, the survival rates of the mice in the experimental groups 1-2 were 70% and 70%, respectively, while the survival rate of the mice in the model control group was only 20%; this indicates that the verbascoside and cistanoside D prepared in example 1 can significantly improve the survival rate of mice infected with streptococcus, and have significant therapeutic effect on streptococcus infection.
4. Conclusion of the experiment
Acteoside and cistanoside D have significant therapeutic effect on streptococcal infection.
It should be understood that the above examples are only for clarity of illustration and are not intended to limit the embodiments. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. And obvious variations or modifications therefrom are within the scope of the invention.
Claims (2)
1. Use of cistanoside D and pharmaceutically acceptable derivatives thereof in the preparation of medicaments for treating ankylosing spondylitis or streptococcal infection, wherein the pharmaceutically acceptable derivatives are selected from salts.
2. The use according to claim 1, wherein the cistanoside D and the pharmaceutically acceptable derivatives thereof are prepared into clinically acceptable tablets, capsules, powders, mixtures, pills, granules, syrups, emplastrums, suppositories, aerosols, ointments or injections by adding conventional adjuvants according to a conventional process.
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