CN103054870A - Use of tryptanthrin compound as indoleamine 2,3-dioxygenase (IDO) inhibitor - Google Patents
Use of tryptanthrin compound as indoleamine 2,3-dioxygenase (IDO) inhibitor Download PDFInfo
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Abstract
The invention belongs to the medicinal field, and concretely relates to a use of a 8-nitrotryptanthrin compound as an IDO inhibitor. The 8-nitrotryptanthrin compound is a reversible IDO inhibitor, has an inhibition constant Ki of 0.054muM, has in-vitro and cell-based median effective inhibition concentrations IC50 of 0.103muM and 1.80*10<-5>muM respectively, and has an inhibition effectiveness obviously better than a present inhibitor 1-methyltryptophan (Ki of 34muM and IC50 of 340muM). 8-nitrotryptanthrin disclosed in the invention can effectively lower the abnormally-increasing IDO activity in a tumor animal model as the IDO inhibitor, and also has tumor treatment effects comprising tumor growth delaying, tumor volume reduction and in-vitro tumor cell killing. 8-nitrotryptanthrin disclosed in the invention has a wide application prospect, and can be used for treating serious diseases having the IDO mediated tryptophan metabolism approach pathology characteristics, such as cancers, the Alzheimer disease, tristimania, cataract and the like as the IDO inhibitor.
Description
Technical field
The invention belongs to field of medicaments, be specifically related to a kind of
The couroupitine A compounds is as the purposes of IDO inhibitor
Background technology
Indoleamine 2, (Indoleamine 2 for the 3-dioxygenase, 3-dioxygenase, IDO) be the enzyme that a kind of cell contains heme, be that but unique catalysis tryptophan metabolism makes it decompose rate-limiting enzyme (MacKenzie, the C. R. et. al. that generates a series of metabolites that comprise quinolinic acid along kynurenine pathway beyond the liver
Current Drug Metabolism,
2007, 8:237-244).
IDO is relevant with a lot of pathological processes.About the research of pregnant mouse model being found the syncytionboph-oblast at female tire interface and antigen presenting cell can synthesize IDO, and the dynamic change that IDO expresses forms consistent with the embryo, if the effect of specific inhibition IDO, then can cause the mice miscarriage, show that IDO can make fetus avoid the repulsion of parent, keep formation (David, the H. M. of the interface immune deviation of female tire; Et al.
Science,
1998, 281:5380).IDO is relevant with the immunologic tolerance of body immune system in this result of study explanation, is a kind of immunomodulating enzyme.It is relevant to its supervision and the immunologic escape phenomenon of killing and wounding that IDO and tumor cell are escaped body immune system.The IDO of discovery various human solid tumor cell (cervical cancer, gastric cancer, colon cancer, melanoma and the cancer of pancreas etc.) high expresseds such as Uyttenhove makes the local T cell proliferation suppressed, thereby the attack (Uyttenhov of mediation tumor cell escape from immune system, C, et al.
Nat Med, 2003, 9:1269-1274).IDO participates in regulating the reaction of T cell.The T cell is responsive especially to tryptophan depletion, and when tryptophan concentration was low, the T cell proliferation will be still in the G1 phase, and IDO can cut off the activation of T cell by the degraded tryptophan.Based on this mechanism, IDO protection fetus avoids parent and repels, and has also mediated the tumour immunity escape.
The kynurenine pathway of tryptophan metabolism is unusual, usually is accompanied by the raising of IDO activity and the rise of quinolinic acid level, with nervous system inflammation and the closely related (Heyes of neurological sexual disorder, M. P., et al., Brain, 1992,115:1249-1273).Directly and indirectly evidence all shows IDO and kynurenine pathway play a significant role (Guillemin, G.J. et al.. Redox Rep 2002,7,199 – 20 in the pathogenesis of Alzheimer (AD); Stone, T.W., et al., J. Alzheimers Dis. 2001,3:355 – 66).Tryptophan concentration in the AD blood samples of patients become with the degree of its cognitive defect negative correlation (Widner B, et al.,
Adv Exp Med Biol 1999, 467:133 – 8), kynurenin concentration is higher than the normal person in the serum, and the degree that raises and level closely related (Baran H, et al., the J. Neural Transm of cognitive defect
1999, 106:165 – 81; Widner B, et al.,
J Neural Transm 2000, 107:343 – 53).IDO content is abundanter than the normal person in the AD brain in patients: IDO and quinolinic acid all have expression in microglia, spider cell and the neuronal cell of AD patient's hippocampus cortical layer, the highest (the Guillemin of content in microglia around senile plaque, the spider cell, G. J. Et al.
Neuropathology and Applied Neurobiology 2005, 31:395 – 404).Beta-amyloyd polypeptide A β (1-42) can activate people's microglia of former culture, induce IDO expression (Guillemin G. J., et al.,
Neuro Report 2003, 14:2311-2315; Walker D. G., et al.,
J. Leukoc. Biol. 2006, 79:596-610).
Interferon gamma can be induced the expression of IDO, and during the continuous activation that high levels of interference element γ stimulates, IDO has reduced the availability of free serum tryptophan.Thereby, also reduced the generation of 5-hydroxy tryptamine.With the generation that these variations that combine help neurological, psychiatric disorders of accumulating such as the Kynurenine metabolism thing with neural activity of quinolinic acid, and be the factor of multiple mood disorders, it also is the related indication factor of some chronic diseases with IDO activation and tryptophan degraded feature, described chronic disease is AD, polytype depression, acquired immune deficiency syndrome (AIDS) (AIDS) and cancer (Schroecksnadel K. for example, et al.
Clin Exp Immunol. 2005, 140 (1): 41 – 45).
The IDO activity also relates to the generation of the nuclear cataract of age-dependent.IDO is first enzyme in the crystalline lens middle-ultraviolet lamp filter biosynthesis, and is rate-limiting enzyme.Ultraviolet filter chemical compound (kynurenin and 3-hydroxykynurenine heteroside) from the tryptophan degraded is modified the protein that is present in people's crystalline lens.The amount of these ultraviolet filter chemical compounds increased with the age, and these ultraviolet filter chemical compounds can cause age-dependent nuclear cataract crystalline lens gradually muddy (Takikawa O,
Et al.,
Exp Eye Res. 2001, 72 (3): 271-7).
The IDO inhibitor can be treated tumor.There are some researches show the IDO inhibitor 1-methyl tryptophan (1-MT) of generally acknowledging at present at the external tumor cell that can strengthen to the immunostimulating sensitivity of T cell, can delay the growth of tumor cell and the antitumous effect of enhancing chemotherapeutics in the animal model in vivo, and almost to all spontaneous tumors (Friberg M that all works
Et al.
Int J Cancer,
2002, 101:151-155).The IDO inhibitor can be treated the disease of pathological characteristics that mood disorders and other have the tryptophan metabolism approach of IDO mediation, comprising: yellow and the autoimmune disease of AIDS, neurodegenerative diseases (Alzheimer, Huntington Chorea and parkinson disease), depression, cataract, age-dependent.
IDO and various diseases pathogenesis are closely related, be proved to be the target of the major diseases such as cancer, Alzheimer, depression, cataract, the IDO inhibitor has broad application prospects as medicine, but do not have so far suitable IDO inhibitor to can be used as the medicine listing, therefore seeking new and effective IDO inhibitor has important theory significance and using value.The research of IDO inhibitor medicaments entered the high speed development stage from about 2000, had had at present two chemical compounds of D-1-MT and INCB023843 to enter clinical second phase test.
Couroupitine A is the indole quinazoline Alkaloid, and its chemical name is indole [2,1-b] quinazoline-6, the l2-diketone.Couroupitine A is a kind of acicular crystal of yellow, mainly be present in Acanthaceous indigo, polygonum tinctorium ait., Isatis indigotica Fort. etc. produce in the blue plants (Honda G,
Et al.
Planta Medica,
1980, 38 (3): 275-276), in addition, also can from the fermentation liquid of microorganism, extract (Hosoe T,
Et a1.
Mycopathologia, 1999, 144 (1): 9-12).In recent years, the home and abroad scholar has carried out part Study to the pharmacology of couroupitine A, that its effect is mainly manifested in is antibiotic, antiinflammatory, antitumor and parasiticide (Oberthur C,
Et al.
Fitoterapia,
2005, 76 (3-4): 324-332; Motoki T,
Et a1.
Biol Pharm Bull,
2005, 28 (2): the aspect such as 260-266).Couroupitine A is a kind of very rare medicine resource, has the potentiality of good research and development new drug.Although can extract couroupitine A from the metabolite of the blue plant of product such as polygonum tinctorium ait., Acanthaceous indigo, Isatis indigotica Fort. and microorganism, separation process is long, extraction ratio is low, be difficult to satisfy the demand of research and clinical application.Only have that weak point consuming time, yield are high by exploring, the easy synthetic approach that is easy to get just can provide more couroupitine A resource, make its further development and application become possibility.
Summary of the invention
The object of the present invention is to provide a kind of 8-nitro couroupitine A as the purposes of IDO (IDO) inhibitor.
The 8-nitro couroupitine A that the present invention proposes is as the purposes of IDO (IDO) inhibitor, and described 8-nitro couroupitine A concrete structure is:
The synthetic of the 8-nitro couroupitine A that the present invention proposes can couroupitine A be raw material, and through nitrated and obtain, its reaction scheme is as follows:
8-nitro couroupitine A of the present invention can make the active effectively downward modulation of the unusual IDO that raises in the animal model for tumour as the IDO inhibitor.
8-nitro couroupitine A of the present invention comprises the lethal effect to tumor cell, to the retarding action of tumor-bearing mice tumor growth in vivo as the application of IDO inhibitor in the treatment tumor.
Among the present invention, 8-nitro couroupitine A prevents and/or treats application in the medicine of disease of pathological characteristics of the tryptophan metabolism disorder with IDO mediation in preparation.
Among the present invention, the disease of the pathological characteristics of described tryptophan metabolism approach with IDO mediation includes but not limited to cancer, Alzheimer, depression.
8-nitro couroupitine A of the present invention is the reversible inhibitor of IDO, and suppressing constant K i is 0.054 μ M, external and cellular level half effective inhibition concentration IC
50Be respectively 0.103 μ M and 1.80 * 10
-5μ M, inhibition effectiveness obviously is better than existing inhibitor 1-methyl tryptophan, and (Ki is 34 μ M, external half effective inhibition concentration IC
50Be 380 μ M).8-nitro couroupitine A of the present invention can be used as highly active Novel IDO inhibitor, be used for having the disease of pathological characteristics of the tryptophan metabolism approach of IDO mediation, comprise the treatment of the major diseases such as cancer, Alzheimer and depression, it has the potentiality of good research and development new drug as rare medicine resource.
The specific embodiment
Followingly further specify the present invention by embodiment, but do not limit the scope of protection of present invention.
The preparation of embodiment 1:8-nitro couroupitine A
Add first the 1ml concentrated sulphuric acid in reaction bulb, the ice bath cooling is lower, adds couroupitine A (248mg, 1mmol) in batches, then drips (0.15ml) concentrated nitric acid, reaction 1h.Reaction is poured in the frozen water after finishing, and drains to get yellow green 8-nitro couroupitine A solid.Productive rate 90%.Characterization data is as follows:
1H NMR (400 MHz, CDCl
3): δ=8.86 (d, 1H), 8.75 (d, 1H), 8.69 (m, 1H), 8.49 (m, 1H), 8.09 (d, 1H), 7.95 (m, 1H), 7.76 (d, 1H).
Embodiment 2:IDO suppresses active Preliminary detection
Structure, Expression in Escherichia coli, extraction and the purification etc. that contain the plasmid of people IDO gene all carry out (Protein Exp Purif, 2000. 19 (1): 22-9) by report methods such as Littlejohn.Chemical compound detects according to the method for introducing the inhibition activity of IDO.With 50 mM kaliumphosphate buffers (pH 6.5), 40 mM vitamin Cs, 400 μ g/ml catalases, 20 μ M methylene blues, substrate L-Trp and testing sample mix, 37 ℃ of insulations of mixed liquor 5 minutes, in above-mentioned mixed liquor, add the IDO enzyme again, reaction was carried out under 37 ℃ 30 minutes, adding 30%(w/v) trichloroacetic acid 200 μ l make reaction terminating, reaction system was 65 ℃ of heating 15 minutes, make it to finish the conversion from the formylkynurenine to the kynurenin, then 12000 rpm centrifugal 10 minutes, get supernatant and equal-volume 2%(w/v) acetic acid solution of p-dimethylaminobenzaldehyde mixes, and kynurenin reacts with it the yellow color of generation and can use microplate reader to observe at 490 nm.
Test result shows: 8-nitro couroupitine A is renderd a service the inhibition of IDO and is better than at present the in the world general IDO inhibitor 1-MT (1-methyl tryptophan, commercially available) of experiment in vivo and vitro.
Whether embodiment 3: be the judgement of reversible inhibition
In the situation of fixing inhibitor concentration, with enzyme and inhibitor reaction and the assaying reaction speed of a series of variable concentrations.To enzyme concentration (ν～[E]) mapping, can determine whether it is reversible inhibitor according to the feature of curve with response speed.
Reaction condition: in the reaction system of 500 μ l, add first 50 mM kaliumphosphate buffers (pH 6.5), 40 mM vitamin Cs, 400 μ g/ml catalases, 20 μ M methylene blues, 300 mM substrate L-Trps or add simultaneously 100 mM inhibitor (8-nitro couroupitine A), 37 ℃ of insulations of mixed liquor 5 minutes, in above-mentioned mixed liquor, add respectively the IDO enzyme of different volumes (for 8-nitro couroupitine A again, the volume that adds enzyme is respectively 0.5,1,2,3,4,5,6,7 μ l), reaction was carried out under 37 ℃ 30 minutes, adding 30%(w/v) trichloroacetic acid 200 μ l make reaction terminating, reaction system was 65 ℃ of heating 15 minutes, make it to finish the conversion from the formylkynurenine to the kynurenin, then 12000 rpm centrifugal 10 minutes, get supernatant and equal-volume 2%(w/v) acetic acid solution of p-dimethylaminobenzaldehyde mixes, and detects 490 nm wavelength readings with microplate reader.
Test result shows: 8-nitro couroupitine A is the reversible inhibitor of IDO.
Embodiment 4:8-nitro couroupitine A inhibitor type is judged and the Ki pH-value determination pH
In the reaction system of 500 μ l, add first 50 mM kaliumphosphate buffers (pH 6.5), 40 mM vitamin Cs, 400 μ g/ml catalases, 20 μ M methylene blues, add respectively 150,200,300 mM substrate L-Trps, under a concentration of substrate, 8-nitro couroupitine A (the 2 μ M that add variable concentrations, 3 μ M, 4 μ M, 5 μ M, 6 μ M, 7 μ M, 8 μ M, 9 μ M, 10 μ M) 37 ℃ of insulations of mixed liquor are 5 minutes, in above-mentioned mixed liquor, add 10 μ l IDO (about 20 nM) again, reaction was carried out under 37 ℃ 30 minutes, add 30% (w/v) trichloroacetic acid, 200 μ l and make reaction terminating, reaction system was 65 ℃ of heating 15 minutes, make it to finish the conversion from the formylkynurenine to the kynurenin, then 12000 rpm centrifugal 10 minutes, get supernatant and equal-volume 2%(w/v) acetic acid solution of p-dimethylaminobenzaldehyde mixes, and detects 490 nm wavelength readings with microplate reader.With the inhibitor type of Dixon graphing method (1/v ~ [I]) judgement 8-nitro couroupitine A, with S/v ~ [I] mapping, the Ki value of the agent that can be inhibited.
Test result shows: 8-nitro couroupitine A is the uncompetitive inhibitor agent of IDO, and the Ki value is 0.054 μ M.The Ki value of 1-MT is 34 μ M.
Embodiment 5: external half effective inhibition concentration IC
50Measure
With 50 mM kaliumphosphate buffers (pH 6.5), 40 mM vitamin Cs, 400 μ g/ml catalases, 20 μ M methylene blues, substrate L-Trp 150 mM and inhibitor mixed.Inhibitor concentration is selected 2 μ M, 4 μ M, and 8 μ M, 10 μ M, 12 μ M, 14 μ M, 37 ℃ of insulations of 16 μ M mixed liquors 5 minutes add the IDO enzyme again in above-mentioned mixed liquor.Reaction was carried out under 37 ℃ 30 minutes, adding 30%(w/v) trichloroacetic acid 200 μ l make reaction terminating, reaction system was 65 ℃ of heating 15 minutes, make it to finish the conversion from the formylkynurenine to the kynurenin, then 12000 rpm rotation is 10 minutes, get 200 μ l supernatants and equal-volume 2%(w/v) acetic acid solution of p-dimethylaminobenzaldehyde mixes, and kynurenin reacts with it the yellow color of generation and can use microplate reader to observe at 490 nm, and acquired results utilizes IC
50Computer calculates.
Test result shows: the external IC of 8-nitro couroupitine A
50Be 0.103 μ M.The IC of 1-MT
50Value is 380 μ M.
Embodiment 6: cellular level half effective inhibition concentration IC
50Measure
Utilize liposome Lipofectamin2000 mediation plasmid pcDNA3.1-hIDO wink to turn HEK 293 cells.It is DMEM in high glucose that the cellular level inhibitor activity is measured HEK 293 cell culture mediums that adopt, and contains 50 U/mL penicillins, 50 U/mL streptomycins, 10% FBS, 37 ℃, 5% CO
2Cultivate.Behind cell transfecting plasmid 24 h, add testing compound, after hatching a period of time, get supernatant in another 96 orifice plate, add 10 μ L 30%(w/v) trichloroacetic acid, make it to finish formylkynurenine to the conversion of kynurenin at 65 ℃ of heating 15 min, then centrifugal 10 min of 12000 rpm, get equal-volume 2%(w/v) acetic acid solution of p-dimethylaminobenzaldehyde mixes colour developing, adopts at last microplate reader to detect light absorption value under 490 nm.
Test result shows: 8-nitro couroupitine A cellular level IC
50Be 1.80 * 10
-5μ M.
Embodiment 7: anti-mice lung cancer effect research
7.1. method
7.1.1. cell line
Mice lewis lung cancer cell Lewis lung carcinoma (LLC) cells is available from American Type Culture Collection.
7.1.2. laboratory animal
Eight age in week the C57BL/6 mice available from Shanghai Slac Experimental Animal Co., Ltd., the quality certification number: SCXK(Shanghai) 2007-0005.
7.1.3. bearing mouse model foundation, grouping and administration
The LLC cell is injected in mice forelimb oxter, every injection 2 * 10
6Begin administration when diameter of tumor reaches 5mm, this experimental cell is divided into 4 groups, 10 every group, is female.Oral sodium carboxymethyl cellulose (0.5% CMC), 200 mg/Kg IDO inhibitor (1-MT, 8-nitro couroupitine A) of giving respectively, 100 mg/Kg intravenous injection cyclophosphamide (CTX) are weekly.Administration continues 14 days.
7.1.4 medicine-feeding test is for the impact of IDO activity in the mice with tumor body
The activity of IDO can reflect that with kynurenin/tryptophan (KYN/TRP) we are respectively organized IDO activity data in the mice serum, and compare with KYN and TRP content in the high performance liquid chromatography test experience mice serum.
After administration finishes, get the serum of respectively organizing mice, 4 ℃ are spent the night, and get supernatant behind centrifugal 15 min of 3000 rpm, and leave standstill 10 min after 5% perchloric acid equal-volume mixes, and centrifugal 10 min of 12000 rpm filter supernatant 4 ℃ of preservations with 0.45 μ m filter.Mobile phase is the acetonitrile of 15 mM acetic acid-sodium acetates and 8%, and detecting wavelength is 225 nm, and chromatographic column is the C18 post.
7.2. result
7.2.1 gross tumor volume computing formula: (width
2* length)/2
| Group | n | Gross tumor volume mm 3 | Tumor weight g |
| The blank group | 10 | 3377.05 | 4.54 |
| The 1-MT group | 10 | 2163.73 | 2.96 |
| 8-nitro couroupitine A group | 10 | 1288.42 | 1.40 |
| The CTX group | 10 | 261.08 | 0.27 |
The IDO inhibitor can effectively dwindle gross tumor volume, reduces tumor weight, and the antitumous effect of 8-nitro couroupitine A is better than 1-MT.
7.2.2 high performance liquid chromatography testing result:
The IDO activity is higher than its excess-three group mice (CTX group, 8-nitro couroupitine A group and 1-MT group) in the blank mouse blood, and the IDO inhibitor can significantly reduce the activity of IDO in the serum, and the action effect of 8-nitro couroupitine A is better than 1-MT.
Embodiment 8: tumor-killing effect research
8.1. method:
8.1.1 cell line and reagent
Human lung carcinoma cell line A549 is available from American Type Culture Collection.
3-[4,5-dimethylthiazol-2-yl]-2,5-diphenylte-trazolium bromide (MTT) is available from sigma.
2. 8.1. MTT experiment
The A549 cell is planted in 96 orifice plates (5 * 10 through the PBS washing
4/ well in 200 μ l). (8-nitro couroupitine A is 1-MT) at 37 ℃ of and 5% CO to add variable concentrations IDO inhibitor
2Hatch adding MTT solution after 24 hours in the incubator, continue to hatch 4 h, then outwell MTT solution; Add behind the 150 μ l DMSO in 37 ° of C for jolting, 10 min.At last, the density in every hole is used SPECTRAmax 250 microplate reader (Molecular Devices, Sunnyvale, CA) detect in 570 nm. cell viability is calculated as follows: (the average light absorption value of the 1 – experimental group/average light absorption value of blank group) * 100%.
8.2. result
8-nitro couroupitine A has powerful lethal effect to the A549 cell, and the A549 cell viability descends 82% under the concentration of 80 μ M, and 1-MT does not does not almost kill and wound effectiveness to A549.
Claims (6)
1. a couroupitine A compounds is characterized in that as the purposes of IDO inhibitor described couroupitine A compounds is 8-nitro couroupitine A.
2. purposes as claimed in claim 1 is characterized in that described 8-nitro couroupitine A has following structural formula:
3. purposes according to claim 1 is characterized in that described 8-nitro couroupitine A is as the application of IDO inhibitor in the treatment tumor.
4. purposes according to claim 3 is characterized in that stating 8-nitro couroupitine A and makes the active effectively downward modulation of unusual high IDO in the animal model for tumour as the IDO inhibitor.
5. purposes according to claim 3 is characterized in that described 8-nitro couroupitine A prevents and/or treats application in the medicine of disease of pathological characteristics of the tryptophan metabolism disorder with IDO mediation in preparation.
6. purposes according to claim 5 is characterized in that the disease of the pathological characteristics of described tryptophan metabolism approach with IDO mediation including but not limited to cancer, Alzheimer, depression.
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| WO2018113624A1 (en) | 2016-12-20 | 2018-06-28 | 深圳微芯生物科技有限责任公司 | Fused imidazole compound having indoleamine 2,3-dioxygenase inhibitory activity |
| US10604529B2 (en) | 2016-12-20 | 2020-03-31 | Shenzhen Chipscreen Biosciences Co., Ltd. | Fused imidazole compound having indoleamine 2,3-dioxygenase inhibitory activity |
| CN115124531A (en) * | 2022-08-09 | 2022-09-30 | 贵州大学 | 4-azatryptanthrin aromatic thioether derivatives, and preparation method and application thereof |
| CN115197227A (en) * | 2022-08-09 | 2022-10-18 | 贵州大学 | Tryptanthrin 1-position or 3-position substituted aromatic thioether derivative, and preparation method and application thereof |
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