CN109806259A - Application of the proto-berberine compounds with TDO selective inhibitory activity in pharmacy - Google Patents
Application of the proto-berberine compounds with TDO selective inhibitory activity in pharmacy Download PDFInfo
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- CN109806259A CN109806259A CN201910151795.9A CN201910151795A CN109806259A CN 109806259 A CN109806259 A CN 109806259A CN 201910151795 A CN201910151795 A CN 201910151795A CN 109806259 A CN109806259 A CN 109806259A
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Abstract
The invention discloses a kind of proto-berberine compounds to prepare TDO inhibitor or treat or prevent the application in the disease mediated drug of TDO in preparation.Enzyme activity inhibition assay result of the present invention is shown: compound tetrahydro epiberberine and cheilanthifolin Cheilanthifolin tryptophan 2,3- dioxygenase has inhibiting effect, it can be used for preparing TDO inhibitor, the drug or derivative of the disease that preparation treatment or prevention TDO are mediated.Liver cancer, the glioblastoma that the disease that TDO is mediated generally refers to TDO expression up-regulation or activity is remarkably reinforced, celiothelioma, head and neck cancer, non-small cell lung cancer, bladder cancer, the tumours such as breast cancer perhaps metabolic disturbance diseases or the autoimmune disease such as depression, organ-graft refection, neuropathy illness, obesity.
Description
Technical field
The invention belongs to technical field of pharmaceuticals, and in particular to a kind of proto-berberine compounds, especially four hydrogen meter barberries
Alkali and cheilanthifolin Cheilanthifolin are preparing TDO inhibitor or are treating or preventing the disease mediated drug of TDO in preparation
In application.
Background technique
Tryptophan 2,3- dioxygenase TDO and indoleamine 2,3-dioxygenase IDO are as kynurenine metabolism pathway process
Middle first step rate-limiting enzyme, catalysis essential amino acids tryptophan generate N- formylkynurenine.95% tryptophan passes through this approach
Metabolism, 5% tryptophan is through other by way of being converted into serotonin.TDO is mainly expressed in liver, and physiological function is mainly wrapped
Include kynurenin concentration level in regulator control system tryptophan levels and liver.In vitro and in vivo experiments confirm that TDO is promoting to swell
It plays a significant role in oncocyte survival and transition process.Late often detect that kynurenin concentration increases in cancer patient
It is improved with kynurenin/tryptophan ratio, these parameters and tumour poorer prognosis are obviously related.
It recent studies have shown that TDO/IDO as inflammation regulatory factor, promotes inflammatory reaction in metabolic process, cause immune escape
Ease and tissue new vascular generation, promote metastases development.Mono-selectivity IDO inhibitor improves immune as immune metabolism adjuvant
The curative effect for the treatment of has entered clinical trial, and inhibitor rebuilds immunosurveillance and passivation new vascular generation, in tumor microenvironment
It assists and non-inhibited immune response form, tumour cell is removed, as immunization therapy, radiotherapy, chemotherapy or combined immunization therapy
Strong adjuvant, play a significant role.IDO inhibitor, which represents a kind of research more, thoroughly and clinically to be confirmed effectively
Tumour immunity inhibits access.
TDO is expressed in kinds of tumor cells and surrounding microenvironment.According to statistics, in the tumour cell of 104 kinds of separate sources
In system, 36 kinds of tumor cells expression TDO (Pilotte, Larrieu et al.2012).Therefore, it for the inhibitor of the enzyme, mentions
The validity of high immunotherapy of tumors copes with the anti-epidemic system of body, and T cell is helped preferably to attack tumour.It is female in people's colloid
In cytoma, TDO continuous expression, endogenic ligand of the kynurenine metabolites of generation as aryl hydrocarbon receptor Ahr promotes
The survival and migration of tumour cell reduce anti tumor immune response, support TDO-Kyn-Ahr access theory.Gene knockout or
The Immune Sensibility of stimulation of the mouse for endotaxin induction can be improved in TDO inhibitor, and side confirms that TDO is inhibiting inflammation
The important function played in reaction and maintenance vivo immunization balance.
In conclusion TDO is the potential important target spot of the metabolic disturbance diseases such as immunotherapy of tumors and obesity treatment, suppression
Preparation can be used as immunization therapy (PD-1, PD-L1 inhibitor), radiotherapy, chemotherapy or combined immunization therapy strong adjuvant,
It plays a significant role, has wide application prospect.
So far, it has no in the prior art and relates to proto-berberine compounds of the present invention in preparation TDO inhibitor, system
The standby report for treating or preventing the application in the disease mediated drug of TDO.
Summary of the invention
Of the invention is to provide at present proto-berberine compounds or its pharmaceutically acceptable carrier in preparation TDO
Inhibitor, preparation treat or prevent the application in the disease mediated drug of TDO.
In order to realize above-mentioned purpose of the invention, the present invention provides the following technical solutions:
Proto-berberine compounds shown in Formulas I are preparing the application in TDO inhibitor,
Wherein, R1, R2, R3, R4Can be same or different, it can be hydrogen, methoxyl group (- MeO), hydroxyl, (methylenedioxy)
Base.
Proto-berberine compounds shown in Formulas I treat or prevent the application in the disease mediated drug of TDO in preparation,
Wherein substituent group is defined as above.
Proto-berberine compounds tetrahydro epiberberine and/or cheilanthifolin shown in following structural formula
Cheilanthifolin is preparing TDO inhibitor or is treating or preventing the application in the disease mediated drug of TDO in preparation,
Application as mentioned, wherein the disease that the TDO is mediated refers to TDO activity or expression relevant tryptophan generation
Relevant tumor disease, metabolic disturbance diseases, nerve is remarkably reinforced in disease, TDO expression up-regulation or the activity for thanking to disorder feature
Systemic disease, autoimmune disease.
Application as mentioned, wherein the disease that the TDO is mediated refers to lung cancer, glioblastoma, celiothelioma, neck
Cancer, non-small cell lung cancer, bladder cancer, kidney, breast cancer is fat, depression, organ-graft refection, cataract.
The present invention provides proto-berberine compounds tetrahydro epiberberine and cheilanthifolin Cheilanthifolin are independent
Or combine application of other tumour immunotherapies in the disease that TDO is mediated.
In some embodiments, the disease that TDO is mediated refers to the related disease of TDO expression up-regulation or function enhancing, packet
Include but be not limited to lung cancer, glioblastoma, celiothelioma, head and neck cancer, non-small cell lung cancer, bladder cancer, the tumours such as breast cancer with
And the metabolic disturbance diseases such as obesity.
Specific embodiment
In order to more fully understand technology contents of the invention, combined with specific embodiments below to technical solution of the present invention
It is further introduced and illustrates.
Embodiment 1
The preparation of compound tetrahydro epiberberine and cheilanthifolin Cheilanthifolin:
Dry sinomenium acutum (Sinomeniumacutum (Thunb.) Rehd.et Wils.) 10kg, after crushed at room temperature
3 times (30L × 3) are extracted with methanol, are impregnated every time for 24 hours.Combined extract, after organic solvent is recycled in vacuum distillation, with 3% salt
Acid adjusts pH value to 1~2, then is extracted with ethyl acetate 3 times.Water phase ammonium hydroxide tune pH value to 9~10, chloroform are extracted 3 times, are concentrated to give
Total alkali 144g.By this total alkali through alkali alumina (100-200 mesh, 2kg), petroleum ether-acetone (7:1-1:1), chloroform-methanol
(100:1-1:1) gradient elution obtains three components (Fr1-Fr3) through combining data detection.MCI column is pressed in component 3 (26g) warp, with 10
~100% methanol/water gradient elution obtains 7 incremental subfractions (Fr2.1-Fr2.7) of polarity through combining data detection.Component 2.3
(400mg) obtains compound tetrahydro epiberberine (10mg) and cheilanthifolin through silica gel column chromatography (petroleum ether-ethyl acetate, 8:2)
Cheilanthifolin(13mg)。
Compound tetrahydro epiberberine: white powder, ESIMS m/z 340 [M+H]+,C20H21NO4。1H NMR
(600MHz,CDCl3): δH6.71 (1H, s, H-1), 6.67 (1H, d, J=8.0Hz, H-11), 6.63 (1H, d, J=8.0Hz,
), H-12 6.60 (1H, s, H-4), 5.94 (1H, d, J=1.3Hz, HA-OCH2), O 5.91 (1H, d, J=1.3Hz, HB-
OCH2), O 4.08 (1H, d, J=15.3Hz, H-8A),3.87(3H,s,2-OCH3),3.85(3H,s,3-OCH3),3.58(1H,
Dd, J=11.3,2.5Hz, H-14), 3.53 (1H, d, J=15.2Hz, H-8B), 3.26 (1H, dd, J=15.9,3.4Hz, H-
13A),3.14(2H,m,H-5A,6A), 2.80 (1H, dd, J=15.5,11.7Hz, H-13B),2.64(2H,m,H-5B,6B)；13C
NMR(100MHz,CDCl3):δc 106.7(C-1),147.5(C-2),147.4(C-3),111.3(C-4),126.7(C-4a),
29.0(C-5),51.3(C-6),52.9(C-8),116.8(C-8a),143.2(C-9),145.0(C-10),108.5(C-11),
121.0(C-12),128.5(C-12a),36.3(C-13),59.4(C-14),129.5(C-14a),55.8(OMe),56.0
(OMe),101.1(O-CH2-O)。
Compound cheilanthifolin Cheilanthifolin: white powder, ESIMS m/z 326 [M+H]+,C19H19NO4。1H
NMR(600MHz,CDCl3):δH6.79 (1H, s, H-4), 6.66 (1H, d, J=8.0Hz, H-11), 6.62 (1H, d, J=
8.0Hz, H-12), 6.58 (1H, s, H-1), 5.93 (1H, d, J=1.4Hz, HA-OCH2), O 5.90 (1H, d, J=1.4Hz, HB-
OCH2), O 4.08 (1H, d, J=15.2Hz, H-8A),3.85(3H,s,3-OCH3), 3.56 (1H, dd, J=11.4,1.8Hz, H-
14), 3.52 (1H, d, J=15.2Hz, H-8B), 3.24 (1H, dd, J=16.0,3.5Hz, H-13A),3.13(2H,m,H-6),
2.79 (1H, dd, J=15.5,11.8Hz, H-13B),2.63(2H,m,H-5)；13C NMR(100MHz,CDCl3):δc 111.3
(C-1),143.9(C-2),145.1(C-3),110.6(C-4),125.9(C-4a),29.0(C-5),51.4(C-6),52.9
(C-8),116.7(C-8a),144.9(C-9),143.2(C-10),106.7(C-11),121.0(C-12),128.5(C-
12a),36.1(C-13),59.3(C-14),130.2(C-14a),55.8(OMe),101.0(O-CH2-O)。
Embodiment 2
Experimental method:
The protein example of 1.1TDO prepares
The gene cloning of source of people TDO, protein expression purification process bibliography (Meng, Wu et al.2014).Source of people
The gene cloning of IDO, protein expression purification process bibliography (Nelp, Kates et al.2018).It is with document report
Standard is slightly adjusted according to experiment condition.
The concentration mensuration of protein
It is reference with bovine serum protein standard curve, protein is detected by BCA Protein Assay Kit
Concentration.In each detection process, detected simultaneously using different diluted concentrations, it is ensured that the error during Concentration Testing.
1.2 activity experiment
Reaction system is 200uL, wherein the 0.5M kaliumphosphate buffer (pH 6.5) of 20uL, the 0.2M Vitamin C of 40uL
Acid, the methylene blue of the 0.5mM of 8uL, the catalase of the 5mg/ml of 8uL, the L-Trp of 15uL, the ddH of 120uL2O。
The final concentration of each component is respectively as follows: 50mM kaliumphosphate buffer (pH6.5), 40mM ascorbic acid, 200ug/ml catalase,
20uM methylene blue, 300uM substrate L-Trp and sample to be tested mixing.
By 37 DEG C of preheating 5min of above-mentioned mixed liquor, IDO1 the TDO protein of various concentration, final concentration of 0- is added
0.3uM.Above-mentioned reaction system is incubated for 30 minutes at 37 DEG C, the trichlorine that mother liquid concentration is 30% (w/v) is added after enzymatic reaction
Acetic acid terminates reaction to final concentration of 9%.Mixture 65 DEG C heat 15 minutes, be allowed to complete from N- formylkynurenine to
The conversion of kynurenin.After reaction solution is cooling, mixed liquor is centrifuged 10min (revolving speed 12000rpm).Supernatant is taken to be transferred to
In 96 orifice plates, mixes with the acetic acid solution of the p- dimethylaminobenzaldehyde of 2% (w/v) of same volume, read with microplate reader
490nm light absorption value.
1.3 Inhibition test
According to above-mentioned activity experiment, the best effort concentration of protein IDO or TDO that acquisition Inhibition test need to use, one
As for 0.1uM or so.Continue subsequent zymetology Inhibition test using this protein concentration.
Reaction system is 200uL, wherein the 0.5M kaliumphosphate buffer (pH 6.5) of 20uL, the 0.2M Vitamin C of 40uL
Acid, the methylene blue of the 0.5mM of 8uL, the catalase of the 5mg/ml of 8uL, the L-Trp of 15uL, the ddH of 120uL2O with
And the untested compound (compound 1-16) of various concentration.The final concentration of each reactive component is consistent with above-mentioned activity experiment, DMSO
Ultimate density control within 2%.
Blank control I: with 15uL ddH2O replaces 15uL L-Trp
Blank control II: with the ddH of same volume2O replaces IDO TDO recombinant protein
Negative control III: with the ddH of same volume2O replaces untested compound, i.e. untested compound concentration is 0
Positive control IV: during each Inhibition test, using 1- methyl-L-tryptophan small molecule as positive control.
The concentration of 1- methyl-L-tryptophan is respectively 0,0.1,0.2,0.3,0.4,0.6,0.8 and 1mM
By 37 DEG C of preheating 5min of above-mentioned mixed liquor, IDO1 TDO recombinant protein, final concentration of 0.1uM is added.It will be upper
It states reaction system to be incubated for 30 minutes at 37 DEG C, trichloroacetic acid is added after enzymatic reaction and is terminated to final concentration of 9% (w/v) and reacts.
Mixture heats 15 minutes at 65 DEG C, cools down later, is centrifuged 10min (revolving speed 12000rpm).Supernatant is taken to be transferred to 96 holes micro-
It measures in titer plate, mixes with the acetic acid solution of the p- dimethylaminobenzaldehyde of 2% (w/v) of same volume, read with microplate reader
490nm dog light absorption value.
By 490nm light absorption value initial data, inhibition of the compound various concentration point to IDO/TDO enzymatic activity is calculated, is adopted
Non linear fit analysis is carried out to inhibiting rate data with GraphPad Prism software and obtains the half-inhibitory concentration IC of compound50
Value.
2. experimental result:
The enzyme of compound tetrahydro epiberberine of the embodiment of the present invention and cheilanthifolin Cheilanthifolin to IDO and TDO
It learns inhibitory activity to be measured by above method, experimental result IC50Value is as shown in appendix 1.Tetrahydro epiberberine as the result is shown
There is obvious inhibitory activity to TDO enzyme with cheilanthifolin Cheilanthifolin, to IDO enzyme without obvious inhibitory activity.
Zymetology inhibitory activity of the table 1- proto-berberine compounds for TDO
Embodiment 3:
Tablet: by the resulting compound 10mg of embodiment 1, being added lactose 180mg, and the auxiliary materials such as starch 55mg are uniformly mixed,
And particle and drying are made after being soaked with water, tabletting after magnesium stearate 5mg is mixed is added, every nearly weighs 250mg.
Embodiment 4:
Ampulla: the resulting compound 2mg of embodiment 1, sodium chloride 10mg are dissolved in suitable water for injection, mistake
Acquired solution is filtered, is aseptically fitted into ampoule bottle.
Embodiment 5:
Injection is freeze-dried: by embodiment 1 resulting compound 10mg, sodium bicarbonate 2mg, mannitol 252mg.
Preparation method: sodium bicarbonate, mannitol are dissolved in water for injection, and add active carbon adsorption 30min depyrogenation, mistake
Deactivation carbon is filtered out, compound or its salt is added in filtrate, ultrasonic treatment makes to dissolve, and adjusting PH with 1N hydrochloric acid is 5.0-7.0,
Miillpore filter filtration, add water for injection, dispense, freeze-drying, top plug, roll lid to get.
Embodiment 6:
Capsule: by embodiment 1 resulting compound 10mg, lactose 187mg, magnesium stearate 3mg；Preparation method: will change
It closes object or its salt and cosolvent mixes, sieving uniformly mixes, and obtained mixture is packed into hard gelatin capsule, each capsule weight
200mg, active component content 10mg.
Claims (6)
1. proto-berberine compounds shown in Formulas I are preparing the application in TDO inhibitor,
Wherein, R1, R2, R3, R4Can be same or different, it can be hydrogen, methoxyl group (- MeO), hydroxyl, methylene-dioxy.
2. proto-berberine compounds shown in claim 1 Formulas I treat or prevent in the disease mediated drug of TDO in preparation
Application, wherein substituent group is defined as above.
3. proto-berberine compounds tetrahydro epiberberine and/or cheilanthifolin shown in following structural formula
Cheilanthifolin is preparing TDO inhibitor or is treating or preventing the application in the disease mediated drug of TDO in preparation,
4. application of the proto-berberine compounds as described in claims 1 or 2 or 3 in pharmacy, it is characterised in that described
The disease that mediates of TDO refer to the disease of TDO activity or the relevant tryptophan metabolism disorder feature of expression, TDO expression up-regulation
Or relevant tumor disease, metabolic disturbance diseases, the nervous system disease, autoimmune disease is remarkably reinforced in activity.
5. application of the proto-berberine compounds as described in claims 1 or 2 or 3 in pharmacy, it is characterised in that described
The disease that mediates of TDO refer to lung cancer, glioblastoma, celiothelioma, head and neck cancer, non-small cell lung cancer, bladder cancer, kidney,
Breast cancer, fat, depression, organ-graft refection, cataract.
6. application of the proto-berberine compounds as described in claims 1 or 2 or 3 in pharmacy, it is characterised in that described
Using referring to that proto-berberine compounds tetrahydro epiberberine and cheilanthifolin Cheilanthifolin combine other tumour immunities
Application of the therapy in the drug of the preparation treatment TDO disease mediated.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112979640A (en) * | 2019-12-12 | 2021-06-18 | 中国医学科学院药物研究所 | Alkaloid dimer compound and application thereof in preparation of PD-1/PD-L1 pathway inhibitor |
| CN116375644A (en) * | 2023-03-14 | 2023-07-04 | 中国科学院昆明植物研究所 | Aporphine alkaloid compound and preparation method and application thereof |
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2019
- 2019-02-28 CN CN201910151795.9A patent/CN109806259A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103622958A (en) * | 2012-08-25 | 2014-03-12 | 北京以岭药业有限公司 | Application of tetrahydroproberberine compounds to prepare antidepressants |
Non-Patent Citations (1)
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| SOK-SIYA BUN等: "Cytotoxic Activity of Alkaloids Isolated from Stephania rotunda In vitro cytotoxic activity of cepharanthine", 《PHYTOTHER. RES.》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112979640A (en) * | 2019-12-12 | 2021-06-18 | 中国医学科学院药物研究所 | Alkaloid dimer compound and application thereof in preparation of PD-1/PD-L1 pathway inhibitor |
| CN112979640B (en) * | 2019-12-12 | 2022-07-19 | 中国医学科学院药物研究所 | Alkaloid dimer compound and application thereof in preparation of PD-1/PD-L1 pathway inhibitor |
| CN116375644A (en) * | 2023-03-14 | 2023-07-04 | 中国科学院昆明植物研究所 | Aporphine alkaloid compound and preparation method and application thereof |
| CN116375644B (en) * | 2023-03-14 | 2024-01-16 | 中国科学院昆明植物研究所 | Aporphine alkaloid compound and preparation method and application thereof |
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