CN101781283A - Thioredoxin reductase inhibiter compounds and preparation method and application thereof - Google Patents
Thioredoxin reductase inhibiter compounds and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses thioredoxin reductase inhibiter compounds, which have antitumor activity, particularly have growth inhibition activity for solid tumor, wherein the solid tumor is thyroid cancer, prostatic cancer, colon cancer, rectal cancer, melanoma, liver cancer, lung cancer, gastric cancer, carcinoma submaxilary gland, nasopharyngeal darcinoma or breast cancer.
Description
Technical field
The present invention relates to a kind of novel organic selenium compounds, particularly a kind of thioredoxin reductase inhibiter compounds and preparation method thereof and its application.
Background technology
Thioredoxin system comprises thioredoxin reductase (Thioredoxin reductase, TrxR), Trx (thioredoxin, Trx) and Reduced nicotinamide-adenine dinucleotide (nicotinamide adeninedinucleotide phosphate, NADPH).Research shows, Trx (Trx) system and cancer in close relations: 1) Trx and TrxR are the significant thing of cancer: TrxR expression amount in tumour cell is 10 times of healthy tissues.Turunen etc. have studied Trx and TrxR at the intravital expression of patient with breast cancer by the method for immunohistochemical methods, and the result is that Trx and the positive rate of TrxR in patient's tenuigenin are respectively 67% and 59%, and the positive rate in nucleus is 55% and 6%.And Trx is male patient with breast cancer's cancer cell multiplication in nucleus and tenuigenin very fast, and the course of disease is very short.Lincoln etc. adopt immunocytochemical method to measure location and the expression of TrxR in the former hair-cream gland cancer of people, thyroid carcinoma, prostate cancer, colorectal carcinoma and malignant melanoma, the result shows, the tumour overexpression TrxR that invasiveness is strong, and proliferative ability is strong, apoptosis rate is low, metastatic capacity is high.The tumour cell TrxR1 gene knockout that people such as Yoo MH finish experiment showed, that TrxR1 is absolutely necessary in tumour cell; 2) the Trx system participates in the different steps of tumor development, and shows characteristics such as overexpression, promotion tumor proliferation, expressing promoting survival signal and the short survival course of startup in tumour cell.Therefore, the expression of inhibition TrxR has important effect to suppressing links such as tumor growth and transfer.
CN1166651C, CN1281593C, CN1242999C, CN1280279A, CN1704408A, CN1704409A, CN1704410A, CN1853627A and CN1990475A disclose " having the two or different selenazoles substitution compound of sugared phenylpropyl alcohol of anti-inflammatory and antitumor action R-" respectively, " immunomodulatory of benzisoxa selenazoles derivative and biotherapy effect ", " benzisoxa selenazoles derivative and application thereof ", " two benzisoxa sulfinpyrazone compounds and synthetic and application thereof ", " different selenazoles ketone compounds and its title complex and application thereof ", " have anti-fibrosis and suppress active compound of gelatinase and application thereof ", " Benzisoelenazolone derivative and preparation method thereof and application ", " bibenziisosehenazoleethane ethane cyclodextrin or cyclodextrin derivant clathrate and preparation method thereof and its purposes ", " replace benzisoxa selenazoles ketone compounds and uses thereof ".The disclosed content of these applications or patent is all as the application's reference.
Summary of the invention
The object of the present invention is to provide a kind of thioredoxin reductase inhibiter compounds, described compound has following I-X structure:
Another object of the present invention is to provide a kind of active pharmaceutical composition of inhibition thioredoxin reductase (TrxR) that has, form with pharmaceutically acceptable carrier by any or its combination of Compound I-X.
Another object of the present invention is to provide a kind of pharmaceutical composition, form with pharmaceutically acceptable carrier by any or its combination of Compound I-X with anti-tumor activity.
Further, Compound I-X in the composition: the weight ratio of auxiliary material is 0.001-99: 1-99, is preferably 0.001-90: 1-95, more preferably 0.001-80: 1-90 most preferably is 0.001-70: 1-85.
Further, the weight percentage of Compound I-X is 1-99% in the composition, is preferably 5-95%, also is preferably 10-90%, and more preferably 15-85% most preferably is 20-80%.
Composition of the present invention can be various formulation well known in the art.Be suitable for formulation of the present invention and can be oral preparations, external preparation or injection, be preferably oral preparations or injection.Described oral preparations is selected from inclusion preparation, dispersion agent, oral liquid, tablet, capsule, granule, dripping pill, pill, powder, syrup, mixture, distillate medicinal water, suspension agent, effervescent, paste, suspension, emulsion or medicinal tea; Be preferably inclusion preparation or dispersion agent; Preferred described suspension agent is selected from does outstanding agent or suspension; Described external preparation is selected from gelifying agent, paste, emplastrum, plaster, creme, ointment, liniment, lotion, suppository, basting agent or coagulates paste; Described injection is selected from injection (injection liquid), transfusion or freeze-dried powder etc.Can adopt preparation technique means well known in the art to prepare composition of the present invention.
Described pharmaceutically acceptable carrier is well known usual excipients or the auxiliary material that is used to prepare above-mentioned preparation, and vehicle that oral preparations or external preparation are commonly used or auxiliary material include but are not limited to weighting agent (claim not only thinner), lubricant (but also claiming glidant or antitack agent), dispersion agent, wetting agent, tackiness agent, conditioning agent, solubilizing agent, oxidation inhibitor, fungistat, emulsifying agent, correctives or reodorant etc.Tackiness agent, for example syrup, gum arabic, gelatin, sorbyl alcohol, tragacanth, Mierocrystalline cellulose and derivative thereof, gelatine size, syrup, starch slurry or polyvinylpyrrolidone, preferred derivatived cellulose is Microcrystalline Cellulose, Xylo-Mucine, ethyl cellulose or HPMC; Weighting agent, for example lactose, Icing Sugar, dextrin, starch and derivative thereof, Mierocrystalline cellulose and derivative thereof, inorganic calcium salt, sorbyl alcohol or glycine, preferred inorganic calcium salt is calcium sulfate, calcium phosphate, secondary calcium phosphate or precipitated calcium carbonate; Lubricant, for example micropowder silica gel, Magnesium Stearate, talcum powder, aluminium hydroxide, boric acid, hydrogenated vegetable oil or polyoxyethylene glycol; Disintegrating agent, for example starch and derivative thereof, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone or Microcrystalline Cellulose, preferred starch derivative is sodium starch glycolate, Explotab, pregelatinized Starch, modified starch, hydroxypropylated starch or W-Gum; Wetting agent, for example sodium lauryl sulphate, water or alcohol etc.
Vehicle or auxiliary material that described injection is commonly used include but are not limited to: oxidation inhibitor, for example S-WAT, sodium bisulfite and Sodium Pyrosulfite; Fungistat, for example 0.5% phenol, 0.3% cresols, 0.5% trichloro-butyl alcohol; Acid-base modifier, for example hydrochloric acid, Citric Acid, potassium hydroxide, sodium hydroxide, Sodium Citrate and buffer reagent phosphoric acid salt and damping fluid thereof; Emulsifying agent, for example Tween-80, do not have that sour sorb is smooth, Pu Luonike F-68, lecithin, fabaceous lecithin; Solubilizing agent, for example tween-80, bile, glycerine etc.
In addition, also activeconstituents can be mixed by its preparation requirement with pharmaceutically acceptable slow controlled release carrier, again according to the preparation method of sustained-release preparation well known in the art, as adding the retarding agent dressing or with making micropill after the active principle microcapsulesization again, as sustained release pellet or controlled release micro pill; Described slow controlled release carrier includes but are not limited to oil agent, hydrophilic colloid or the dressing retarding agent etc. of mixing, described oil any or its combination that agent is selected from glyceryl monostearate, hydrogenated castor oil, Dormant oils, polysiloxane or dimethyl siloxane of mixing; Described hydrophilic colloid is selected from any or its combination of Xylo-Mucine, hydroxypropylcellulose, Vltra tears, PVP, gum arabic, tragcanth or carbopol; Described dressing retarding agent is selected from any or its combination of ethyl cellulose (EC), HPMC (HMPC), polyvinylpyrrolidone (PVP), cellulose acetate-phthalate (CAP), acrylic resin.
Another object of the present invention is to provide Compound I-X or its composition to have application in inhibition thioredoxin reductase (TrxR) active medicine in preparation.
Another object of the present invention is to provide Compound I-X or its composition to have application in the anti-tumor activity medicine in preparation, described tumour comprises solid tumor or leukemia, be preferably solid tumor, described solid tumor is selected from thyroid carcinoma, prostate cancer, colorectal carcinoma, the rectum cancer, melanoma, liver cancer, lung cancer, colorectal carcinoma, cancer of the stomach, carcinoma of submaxilary gland, nasopharyngeal carcinoma or mammary cancer, is preferably colorectal carcinoma, cancer of the stomach, carcinoma of submaxilary gland.
The dosage that Compound I of the present invention and II are used for the treatment of tumour is about the 0.05-250mg/Kg body weight, is preferably the 0.5-200mg/Kg body weight, and more preferably the 2-100mg/Kg body weight most preferably is the 5-80mg/Kg body weight.The actual dosage of Compound I and II can suitably be adjusted according to factors such as patient's the state of an illness, physique, body weight, age, sexes.
Embodiment
Specify the present invention below with reference to embodiment, embodiments of the invention only are used to technical scheme of the present invention is described, and non-limiting essence of the present invention.
Embodiment 1The preparation of compound VI
Synthetic route:
Synthesis step:
1) with the 2-hydroxyl-1 of 0.1mmol, the 3-propylene diamine is dissolved in the methylene dichloride of 20ml, drips the triethylamine of 0.2mmol, stirs;
2) the selenium chlorine with 0.1mmol is dissolved in the methylene dichloride of 10ml, at normal temperatures it is added drop-wise to 1 then) go on foot in the reaction solution of gained, until separating out solid.
MS-FAB(m/z)：453。
Embodiment 2The preparation of compound VI I
Synthetic route:
Synthesis step:
2.1 two selenium two (5-hydroxyl) phenylformic acid (calling " intermediate 4 " in the following text) is synthetic
2.1.1 two sodium selenide preparations
With open method among the CN1166651C.
2.1.25-the preparation of hydroxyl-2 benzaminic acid diazonium salt
1) under cryosel bath condition, in beaker, add the two sodium selenides of 2.8 grams, add 6ml hydrochloric acid and 24ml water again;
2) get 1.6 gram Sodium Nitrites and put into beaker, add 6ml water and few ice cubes again;
3) with 2) step gained reaction solution is added drop-wise to 1) in the step gained reaction solution, fully reaction, promptly.
2.1.3 the preparation of intermediate 4
1) under ice bath and PH＞9 conditions, 2.1.2 is made diazonium salt be added drop-wise to two sodium selenides that 2.1.1 makes, room temperature condition is reaction 2h down;
2) with hydrochloric acid: water=be added drop-wise to 1 at 1: 1) in the step gained reaction solution, drip till the PH=2, suction filtration, drying, solid;
3) under the condition of boiling, with 2) to pour concentration into be in 11.67% the aqueous sodium carbonate to step gained solid, dissolving back suction filtration, filtrate;
4) with hydrochloric acid: water=be added drop-wise to 3 at 1: 1) in the step gained filtrate, drip till its PH=2, suction filtration, drying, promptly.
2.2 intermediate 5 is synthetic
1) get 20ml methyl alcohol and 2ml water places flask, put into 0.8g potassium hydroxide, make its fusing, melt;
2) under oil bath (80 ℃) condition, 1) go on foot adding 0.8g intermediate 4 in the gained melt, reaction 0.5h adds the 1.2ml. methyl iodide, behind the reaction backflow 16h, adds hcl acidifying and Jia Shui, and the adding ethyl acetate extraction is got upper organic phase;
3) 2) add anhydrous sodium sulfate drying in the step gained organic phase, be spin-dried for oily mater, through straight empty dry, solid.
2.3 5-methoxyl group-2 selenium chloro-benzoyl chloride (calling " intermediate 6 " in the following text) is synthetic
Get 0.6g intermediate 5 in flask, add 1 DMF and 5ml thionyl chloride, behind the back flow reaction 3h, thionyl chloride is reclaimed in underpressure distillation, adds the 30ml sherwood oil, and the 0.5h that refluxes again gets petroleum ether layer, be spin-dried for petroleum ether layer after, it is standby to add methylene dichloride.
2.4 compound VI I's is synthetic
Get an amount of intermediate 6 and place round-bottomed flask, splash into the dichloromethane solution of quadrol, the triethylamine of dropping and quadrol equivalent stirs 2h under the normal temperature again, and suction filtration gets solid.
MS-FAB(m/z)：483。
Embodiment 3The preparation of compound VIII
Synthetic route:
3.1 2-'s (2-hydroxyl)-benzisoxa selenazoles-3-(2H)-ketone (calling " intermediate 1 " in the following text) is synthetic
Get 1g selenium chloro-benzoyl chloride and be dissolved in the 10ml methylene dichloride, slowly drip in the dichloromethane solution that is dissolved with thanomin, drip back room temperature reaction 2h fully, suction filtration, drying, promptly.
3.2 2-'s (2-chlorine)-benzisoxa selenazoles-3-(2H)-ketone (calling " intermediate 2 " in the following text) is synthetic
Method 1: get 1g intermediate 1 in round-bottomed flask, add the 7ml thionyl chloride, behind the backflow 8h, thionyl chloride is reclaimed in underpressure distillation, adds ethanol again and is spin-dried for, and reclaims thionyl chloride as far as possible.Then, inject water and extracted with diethyl ether, get the ether layer; Be spin-dried for the ether layer, drying, promptly.
Method 2: get 0.6g two chloroethylamine hydrochlorides and 0.6g sodium hydroxide, it is dissolved in the mixing solutions of methylene dichloride and water; Selenium chloro-benzoyl chloride dichloromethane solution (1g/10ml) is slowly dripped in aforementioned mixing solutions, room temperature reaction 3h, backflow 24h promptly gets product.
3.3 2-'s (2-amino)-benzisoxa selenazoles-3-(2H)-ketone (calling " intermediate 3 " in the following text) is synthetic
1) get the 0.21g Hexamine, it joined in 95% the hot ethanol of 10 times of weight, add the 0.25g sodium iodide again, slowly add 0.40g intermediate 2, reaction 4h, suction filtration, solid;
2) with diluted hydrochloric acid dissolution 1) step gained solid, suction filtration gets the aqueous solution;
3) 2) go on foot adding sodium hydroxide saturated solution in the obtained aqueous solution, suction filtration, promptly.
Intermediate 4-6's is synthetic with embodiment 3.
3.4 the preparation of compound VIII
1) intermediate 3 with 0.1mmol is dissolved in the methylene dichloride of 20ml, is added dropwise to the 0.2mmol triethylamine, stirs;
2) intermediate 6 with 0.1mmol is dissolved in the methylene dichloride of 10ml, under the normal temperature it is added drop-wise to 1) go on foot in the reaction solution of gained, until separating out solid, promptly.
MS-FAB(m/z)：453。
Embodiment 4The preparation of Compound I X
Synthetic route:
Synthesis step:
1) in methylene dichloride, add the selenium chloro-benzoyl chloride and the para-amino benzoic acid of equimolar amount, and the triethylamine of qdx, reaction 3h, suction filtration, drying gets white solid;
2) in the 20ml diacetyl oxide, add 1) step gained solid 0.1mol, backflow 12h, the reclaim under reduced pressure diacetyl oxide obtains the oily solid, add isopropyl ether reflux extraction three times after, combining extraction liquid in 4 ℃ of preservations, is separated out solid next day;
3) in methylene dichloride, add 2 of equivalent '-deoxidation-2 ' 2 '-difluocytosine hydrochloride and triethylamine, stirring at normal temperature 3h collects the insoluble white solid of separating out, 2 '-deoxidation-2 ' 2 '-difluocytosine;
4) in DMF, 2 of adding equivalent '-deoxidation-2 ' 2 '-difluocytosine hydrochloride and 2) step reaction gained solid, stirring at normal temperature is spin-dried for DMF behind the 24h, add water, separates out solid product, promptly.
MS-FAB(m/z)：564。
Embodiment 5The preparation of compounds X
Synthetic route:
Synthesis step:
1) in an amount of methylene dichloride, add 2 of equivalent '-deoxidation-2 ' 2 '-difluocytosine hydrochloride and triethylamine, stirring at normal temperature 3h collects the solid of separating out, promptly get the acidifying 2 that desalts '-deoxidation-2 ' 2 '-difluocytosine;
2) in the 20ml methylene dichloride, 2 of adding equimolar amount (0.1mmol) '-deoxidation-2 ' 2 '-difluocytosine and selenium chloro-benzoyl chloride, reaction 3h is spin-dried for solvent, adds 50ml water again, stirs, and separates out solid, promptly.
MS-FAB(m/z)：445。
Embodiment 6The external inhibition activity of Compound I-X to thioredoxin reductase (TrxR)
Adopt the external inhibition activity of DTNB reduction method research Compound I-VI to thioredoxin reductase (TrxR).
6.1 experiment material: DTNB, the TrxR (0.34mg/mL storing solution) that purifying extracts, NADPH is available from Sigma company.
6.2 test principle
It is yellow that the reduzate TNB of DTNB is, and at 412nm uv-absorbing arranged, and can be used for monitoring enzymatic reaction speed, with the enzyme activity of reflection TrxR.
6.3 test work solution preparation
6.3.1TrxR the preparation of working fluid: it is the TrxR storing solution of 0.34mg/mL that precision is measured 175 μ L concentration, and it is diluted to 500 μ L, and it is mixed with concentration is 0.119mg/mL TrxR working fluid;
6.3.2NADPH the preparation of working fluid: precision takes by weighing 5mg NADPH, and it is dissolved in the 12mL potassium phosphate buffer, and it is mixed with the working fluid that concentration is 0.5mM;
6.3.3DTNB the preparation of working fluid: precision takes by weighing 25mgDTNB, and it is dissolved among the DMSO of 63mL, it is mixed with concentration is the 1mM working fluid;
6.3.4 the preparation of potassiumphosphate buffer system: the EDTA of the bovine serum albumin (BSA) of 0.2mg/mL and 1mM is joined in the potassium phosphate buffer of PH7.4 (dipotassium hydrogen phosphate/potassium primary phosphate), promptly.
6.4 testing sequence
Trx (Trx) system is in the presence of NADPH, and the reaction of the disulfide bond reduction of catalysis Regular Insulin is opened the disulfide linkage of Regular Insulin, and Regular Insulin is cracked into two strands, and its catalyzed reaction is as follows:
Trx-(SH)
2+ Regular Insulin → Trx-S
2+Regular Insulin-H
2
NADPH has responsive absorbancy peak under 340nm, and the consumption of NADPH represented the speed of enzymatic reaction, can reflect enzyme activity by detecting the speed that the 340nm absorbancy descends.
Reaction system: in the micro-cuvette of 0.5ml, add Regular Insulin, NADPH, Trx and testing sample successively, postreaction damping fluid (0.1mol/L potassiumphosphate/2mmol/L EDTA) is to cumulative volume 0.5ml, the concentration of each composition is in the gained reaction system: Regular Insulin 130 μ mol/L, NADPH 0.4mmol/L, Trx4 μ mol/L and testing sample, it is inserted in the ultraviolet spectrophotometer, and the continuous detecting reaction system changes in the absorbancy at 340nm place.Calculate enzyme activity according to following calculation formula.
Activity unit is defined as: 1U=Δ A340nm/min*1000, and the TR activity is in U/L in the sample, and the result is referring to table 1.
Embodiment 7The anti tumor activity in vitro research of Compound I-X
Adopt the external inhibition activity of mtt assay research Compound I-IX to breast cancer cell (MCF-7).
Get that to be in logarithmic phase concentration be 5 * 10
4The MCF-7 cell of individual/ml, be inoculated in 96 orifice plates, 180 μ l/ holes treat that every hole, adherent back adds 20 μ l concentration and is respectively 0 μ M/ml, 5 μ M/ml, 10 μ M/ml, 20 μ M/ml, 50 μ M/ml, the medicine of 100 μ M/ml, MTT (20 μ l/ hole) respectively at 24h, 48h, 72h adding 5mg/ml puts into CO
2After incubator was cultivated 3～4h, 3000r/min was centrifugal, abandons supernatant, treated that air-dry back adds the acidifying Virahol, surveys the OD value at microplate reader 570nm place.
Cell survival rate %=(the blank group of dosing cell OD-OD)/(the blank group of control cells OD-OD) * 100;
Cell killing rate %=1-cell survival rate %, the result is referring to table 1.
The external inhibition activity of table 1 Compound I-X to thioredoxin reductase (TrxR) and tumour cell (MCF-7)
| Compound number | Inhibition activity (IC50/ μ M) to TrxR | Inhibition activity (IC50/ μ M) to MCF-7 |
| ??I | ??0.35 | ??4.54 |
| ??II | ??0.84 | ??5.49 |
| ??III | ??0.94 | ??6.03 |
| ??IV | ??0.98 | ??11.72 |
| ??V | ??0.88 | ??9.77 |
| ??VI | ??0.5 | ??20.78 |
| ??VII | ??0.63 | ??20.48 |
| ??VIII | ??4.23 | ??30.04 |
| Compound number | Inhibition activity (IC50/ μ M) to TrxR | Inhibition activity (IC50/ μ M) to MCF-7 |
| ??IX | ??0.03 | ??2.13 |
| ??X | ??9.285 | ??＞50 |
Brief summary: except that the X compound, Compound I-IX is very obvious to the inhibition activity of thioredoxin reductase (TrxR), simultaneously, Compound I-IX also shows effective restraining effect to the MCF-7 tumour, tentatively infer thus, Compound I-IX is to having certain dependency between the restraining effect of thioredoxin reductase and its antitumor action.
Claims (10)
1. thioredoxin reductase inhibiter compounds, described compound has following I-X structure:
2. one kind has the active pharmaceutical composition of inhibition thioredoxin reductase (TrxR), is made up of with pharmaceutically acceptable carrier any or its combination of the described Compound I-X of claim 1.
3. the pharmaceutical composition with anti-tumor activity is made up of with pharmaceutically acceptable carrier any or its combination of the described Compound I-X of claim 1.
4. according to claim 2 or 3 described pharmaceutical compositions, Compound I-X in the composition: the weight ratio of auxiliary material is 0.001-99: 1-99.
5. according to claim 2 or 3 described pharmaceutical compositions, the weight percentage of Compound I-X is 1-99% in the composition.
6. according to each described pharmaceutical composition of claim 2-5, the formulation of described composition is selected from oral preparations, external preparation, injection or its sustained-release preparation.
7. described Compound I-X of claim 1 and/or claim 2, each described composition of 4-6 have application in inhibition thioredoxin reductase (TrxR) active medicine in preparation.
8. each described composition of described Compound I-X of claim 1 and/or claim 3-6 has application in the anti-tumor activity medicine in preparation.
9. application according to claim 8, described tumour comprises solid tumor or leukemia.
10. application according to claim 9, described solid tumor is selected from thyroid carcinoma, prostate cancer, colorectal carcinoma, the rectum cancer, melanoma, liver cancer, lung cancer, colorectal carcinoma, cancer of the stomach, carcinoma of submaxilary gland, nasopharyngeal carcinoma or mammary cancer.
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