CN106074491A - Dehydrogenation α lapachol is as indoleamine 2, the purposes of 3 dioxygenase 1 inhibitor - Google Patents
Dehydrogenation α lapachol is as indoleamine 2, the purposes of 3 dioxygenase 1 inhibitor Download PDFInfo
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- CN106074491A CN106074491A CN201610410369.9A CN201610410369A CN106074491A CN 106074491 A CN106074491 A CN 106074491A CN 201610410369 A CN201610410369 A CN 201610410369A CN 106074491 A CN106074491 A CN 106074491A
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- Prior art keywords
- ido1
- disease
- lapachol
- dehydrogenation
- inhibitor
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
Abstract
The present invention passes through natural product dehydrogenation α lapachol or its pharmaceutically acceptable salt as indoleamine 2, the purposes of 3 dioxygenases 1 inhibitor (IDO1), dehydrogenation α lapachol is for indoleamine 2, the inhibitory action of 3 dioxygenases 1, IDO1 facilitation in disease development is hindered and/or destroys, thus the disease mediated for treatment IDO1 provides good prospect.
Description
Technical field
The present invention relates to dehydrogenation α-lapachol (dehydro-alpha-lapachone) as indoleamine 2,3-pair of oxygenation
Enzyme-1(IDO1) new application and preparation treatment IDO1 mediation disease in application.
Background technology
Indole amine 2,3-dioxygenase-1 [EC 1.13.11.17] (IDO1) be a kind of at intracellular, monomer containing blood red
Cellulose protein, catalysis l-tryptophan (Trp) catabolism becomes the first step of kynurenine pathway.IDO1 metabolite, N-first
Acyl kynurenin (N-formylkynurenine), is metabolized to other bioactive molecule further.IDO1 has at multiple tissues
Express, including lung, small intestinal, Placenta Hominis, spleen and nervus centralis.IDO1 in many cell types can by inflammatory cytokine (as
Interferon gamma, escherichia coli endotoxin and tumor necrosis factor-alpha etc.) stimulate cause expression.IDO1 also offers carefully at host antigen
Born of the same parents (APC), Monocyte-macrophages and tumor cell are expressed.
IDO1 is as immunosuppressant and a kind of important mechanisms of toleration, anti-at autoimmune disease, transplant rejection
Play an important role in Ying.IDO1, by consuming the concentration of local T rp, suppresses T cell and the activity of NK cell, induces modulability
The formation of T cell.By these mechanism, IDO provides the immunoreation of feedback control.Research find, if IDO ovarian cancer,
High expressed in colorectal cancer and other tumor cells, then tumour patient prognosis is poor, thus it can play the prediction of oncotherapy
Effect.
IDO1 can also work as target spot in kinds of tumors.Such as, swollen in ovarian cancer, colorectal cancer and endometrium
In tumor, IDO1 expression raises.In preclinical model, IDO1 promotes the life of tumor by suppression anti tumor immune response
Long.In these models, micromolecular inhibitor IDO1 can recover immunologic tumor rejection phenomenon and improve Common Chemotherapy medicine
Activity.These data support that IDO1 inhibitor, as new type anticancer medicine, can be combined with existing therapy.Except treatment cancer,
IDO1 inhibitor to other diseases, as sepsis induction hypotension, schizophrenia, Alzheimer's disease and parkinson disease,
Cataract also functions to effect.These find the development interest promoted IDO inhibitor medicine, particularly cancer immunotherapy.?
Widely studied IDO inhibitor is 1-methyl-tryptophan.It is nearest it is demonstrated experimentally that 1-methyl-tryptophan can be with substantial amounts of clinic
Relevant chemotherapy drugs in combination uses, and plays synergism.1-methyl-tryptophan and cyclophosphamide, cisplatin, amycin or Ramulus et folium taxi cuspidatae
The combination of alcohol can cure the mouse breast cancer model of neu induction.
At present, international market has a few class IDO1 inhibitor in clinical experiment, such as Novel IDO 1 inhibitor INCB024360
By Incyte company exploitation treatment late malignant tumour.But, IDO1 inhibitor quantity generally is the most less, and laboratory or
Clinical effectiveness still has much room for improvement.
Summary of the invention
One aspect of the present invention relates to dehydrogenation α-lapachol or its pharmaceutically acceptable salt as a kind of indoleamine 2, and 3-is double
The purposes of oxygenase-1 inhibitor (IDO1).
Another aspect of the present invention provides dehydrogenation α-lapachol or its pharmaceutically acceptable salt in preparation treatment IDO1 mediation
Disease medicine in application.
In some embodiments, the disease of described IDO1 mediation refers to the disease of IDO1 up-regulated, including but do not limit
In, tumor, sepsis induction hypotension, schizophrenia, Alzheimer's disease and parkinson disease and cataract.
In some embodiments, described tumor is selected from ovarian cancer, colorectal cancer and endometrial tumors.Real at some
Executing in mode, described disease does not include tumor.
The structural formula of dehydrogenation α-lapachol is shown below, and existing document shows that it has blood vessel formation against function (WO/
, and toxicity is the lowest (in mice experiment in vivo, does not finds notable poison when up to 100 mg/kg dosage 2012/162627)
Property).Dehydrogenation α-lapachol can be prepared by proper method well known by persons skilled in the art, a kind of exemplary preparation method ginseng
See that Chinese patent application announces CN 105294638 A.
The present invention expects that " pharmaceutically acceptable salt " of dehydrogenation α-lapachol also has identical activity.Generally, this salt
Such as by by these compounds of free acid or alkali form and the suitable alkali of stoichiometric amount or acid in water or organic molten
Prepare in agent or in both mixture.Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are
Preferably.The example of acid-addition salts includes inorganic acid addition salt such as, hydrochlorate, hydrobromate, hydriodate, sulfate, nitre
Hydrochlorate, and organic acid addition salt, such as such as acetate, maleate, fumarate, citrate, oxalates, succinate,
Tartrate, malate, mandelate and tosilate.The example of base addition salts include inorganic salt such as sodium, potassium, calcium,
Ammonium, magnesium, aluminum and lithium salts；And organic base such as ethylenediamine, ethanolamine, N, N-dialkylethanolamines, triethanolamine, glycosamine and alkali
Acidic amino acid salt.
Present invention demonstrates the natural product dehydrogenation α-lapachol inhibitory action for IDO-1, right
IDO1 facilitation in disease development carries out hindering and/or destroying, thus the disease for treatment IDO1 mediation provides
Good prospect.
Accompanying drawing explanation
Fig. 1 is that dehydrogenation α-lapachol is to indole amine 2,3-dioxygenase-1(IDO1) the curve chart of inhibitory action.
Detailed description of the invention
The present invention now will explain in conjunction with following experiment and accompanying drawing further, it should be noted that these experimental examples and accompanying drawing
Should not be construed as limitation of the present invention.
Kynurenin Specification Curve of Increasing
1. the 0.5M kaliumphosphate buffer (pH 6.5) of standard medium (200 μ L): 20 μ L, final concentration of 50 mM；20μL
0.2M ascorbic acid, final concentration of 20 mM；The 0.5mM methylene blue of 4 μ L, final concentration of 10 μMs；The 5mg/ml peroxide of 4 μ L
Change hydrogen enzyme, final concentration of 100 μ g/ml；The dd-H of 132 μ L2O；The kynurenin solution of 20 μ L, final concentration is respectively 0, and 1,
5,7.5,10,25,50,75 and 100 mM.
2. after adding the 1M NaOH solution of 40 μ L, centrifugal culture medium (11,500rpm, 4 ° of C, 15min).
3. the supernatant of 200 μ L is transferred on 96 hole microtitration plates, measures fluorescence intensity (λ ex 360nm, λ em
480nm)。
Quantification of protein
Protein IDO1 content is measured by BCA method.Solution absorption value is measured, subsequently with bovine serum albumin at λ max 570nm
White standard curve (0-2 mg/ml) checks, to obtain protein concentration.
Activity experiment
1. the 0.5M kaliumphosphate buffer (pH 6.5) of standard test culture medium (200 μ L): 20 μ L, final concentration of 50 mM；20
The 0.2M ascorbic acid of μ L, final concentration of 20 mM；The 0.5mM methylene blue of 4 μ L, final concentration of 100 μ g/ml；20 μ L's
2mM L-tryptophan, final concentration of 200 μMs；The dd-H of 112 μ L2O；The IDO1 of 20 μ L, final concentration of 0 to 10 μ g/ml.
2. comparison: with the dd-H of 20 μ L2O substitutes IDO1.
3., after adding the 1M NaOH solution of 40 μ L, 60 ° of C of mixture hatch 15min, with by N-formoxyl kynurenin water
Solve as kynurenin.It is centrifuged culture medium (11,500rpm, 4 ° of C, 15min) subsequently.
4. the supernatant of 200 μ L is transferred on 96 hole microtitration plates, measures fluorescence intensity (λ ex 360nm, λ em
480nm)。
Inhibition test
1. the 0.5M kaliumphosphate buffer (pH 6.5) of standard test culture medium (200 μ L): 20 μ L, final concentration of 50 mM；20
The 0.2M ascorbic acid of μ L, final concentration of 20 mM；The 0.5mM methylene blue of 4 μ L, final concentration of 10 μMs；The 5mg/ml of 4 μ L
Catalase, final concentration of 100 μ g/ml；The dd-H of 112 μ L2O；The 4mM L-tryptophan of 10 μ L, final concentration of 200 μ
M；The 5 μ g/ml IDO1 of 20 μ L and 10 μ l inhibitor (1-methyl-L-tryptophan) solution in DMSO, final concentration is respectively
For 0,0.1,0.5 and 1mM.
2. comparison is (i): with the dd-H of 10 μ L2O substitutes L-Trp.
3. comparison is (ii): with the dd-H of 30 μ L2O substitutes L-Trp and IDO1.
4., after adding the 1M NaOH solution of 40 μ L, 60 ° of C of mixture hatch 15min, with by N-formoxyl kynurenin water
Solve as kynurenin.It is centrifuged culture medium (11,500rpm, 4 ° of C, 15min) subsequently.
5. the supernatant of 200 μ L is transferred on 96 hole microtitration plates, measures fluorescence intensity (λ ex 360nm, λ em
480nm)。
6. calculating suppression ratio with formula (100-(A/Bx100)), wherein A represents the activity of IDO1, B when there is inhibitor
Represent the activity of IDO1 when there is not inhibitor.Result is shown in Fig. 1, and the relevant parameter obtained from figure is shown in Table 1.
The inhibitory action of table 1. dehydrogenation α-lapachol
| Compound name | IC50(uM) | Hillslope | R square |
| Dehydrogenation α-lapachol | 6.509 | -0.5671 | 0.9158 |
Claims (6)
1. dehydrogenation α-lapachol or its pharmaceutically acceptable salt are as the purposes of indole amine 2,3-dioxygenase-1 inhibitor.
2. dehydrogenation α-lapachol or the application in the medicine of the disease of preparation treatment IDO1 mediation of its pharmaceutically acceptable salt.
Application the most according to claim 2, the disease of wherein said IDO1 mediation refers to the disease of IDO1 up-regulated.
4., according to the application described in Claims 2 or 3, the disease of wherein said IDO1 mediation is low selected from tumor, sepsis induction
Blood pressure, schizophrenia, Alzheimer's disease and parkinson disease and cataract.
Application the most according to claim 4, wherein said tumor is selected from swollen in ovarian cancer, colorectal cancer and endometrium
Tumor.
Application the most according to claim 4, wherein said disease does not include tumor.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100076066A1 (en) * | 2007-03-16 | 2010-03-25 | Prendergast George C | Novel IDO Inhibitors and Methods of Use Thereof |
| WO2012162627A1 (en) * | 2011-05-26 | 2012-11-29 | The General Hospital Corporation | Treatment of angiogenic- or vascular-associated diseases |
| WO2015082499A2 (en) * | 2013-12-03 | 2015-06-11 | Iomet Pharma Ltd | Pharmaceutical compound |
| US20150336903A1 (en) * | 2012-11-20 | 2015-11-26 | Vertex Pharmaceuticals Incorporated | Compounds useful as inhibitors of indoleamine 2,3-dioxygenase |
| CN105209449A (en) * | 2013-03-14 | 2015-12-30 | 库拉德夫制药私人有限公司 | Inhibitors of the kynurenine pathway |
-
2016
- 2016-06-13 CN CN201610410369.9A patent/CN106074491A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100076066A1 (en) * | 2007-03-16 | 2010-03-25 | Prendergast George C | Novel IDO Inhibitors and Methods of Use Thereof |
| WO2012162627A1 (en) * | 2011-05-26 | 2012-11-29 | The General Hospital Corporation | Treatment of angiogenic- or vascular-associated diseases |
| US20150336903A1 (en) * | 2012-11-20 | 2015-11-26 | Vertex Pharmaceuticals Incorporated | Compounds useful as inhibitors of indoleamine 2,3-dioxygenase |
| CN105209449A (en) * | 2013-03-14 | 2015-12-30 | 库拉德夫制药私人有限公司 | Inhibitors of the kynurenine pathway |
| WO2015082499A2 (en) * | 2013-12-03 | 2015-06-11 | Iomet Pharma Ltd | Pharmaceutical compound |
Non-Patent Citations (7)
| Title |
|---|
| CHRISTOPHER J. D. AUSTIN等: "The first indoleamine-2,3-dioxygenase-1 (IDO1)inhibitors containing carborane", 《DALTON TRANSACTIONS》 * |
| E. OLIVEIRA SILVA等: "Cytotoxicity of lapachol metabolites produced by probiotics", 《LETTERS IN APPLIED MICROBIOLOGY》 * |
| HOLLE E.FLICK等: "The Tumor-Selective Cytotoxic Agent β-Lapachone is a Potent Inhibitor of IDO1", 《INTERNATIONAL JOURNAL OF TRYPTOPHAN RESEARCH》 * |
| IGOR GARKAVTSEVA等: "Dehydro-α-lapachone, a plant product with antivascular activity", 《PROCEEDINGS OF NATIONAL ACADEMY OF SCIENCE》 * |
| SANJEEV KUMAR等: "Indoleamine 2,3-Dioxygenase Is the Anticancer Target for a Novel Series of Potent Naphthoquinone-Based Inhibitors", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
| 孔令雷等: "IDO抑制剂的研究进展", 《中国药物化学杂志》 * |
| 杨云云等: "新型吲哚胺2,3-二加氧酶抑制剂及其治疗人类疾病的研究 ", 《上海医药》 * |
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