CN105294660A - 3R, 6S-3, 6-disubstituted piperazine-2, 5-diketone, preparation therefor and application thereof - Google Patents

3R, 6S-3, 6-disubstituted piperazine-2, 5-diketone, preparation therefor and application thereof Download PDF

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CN105294660A
CN105294660A CN201410260127.7A CN201410260127A CN105294660A CN 105294660 A CN105294660 A CN 105294660A CN 201410260127 A CN201410260127 A CN 201410260127A CN 105294660 A CN105294660 A CN 105294660A
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diketone
ethyl
piperazine
indoles
amino
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CN105294660B (en
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彭师奇
赵明
王玉记
吴建辉
王枫
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Capital Medical University
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Abstract

The present invention discloses (3R, 6S)-3-(4-butylamino)-6-(indole-3-ethyl)-piperazine-2, 5-diketone, a preparation method therefor and effects thereof for inhibiting invasion and migration of tumor cells, and further discloses effects thereof, such as, haemostasis, anti-inflammation and the like. The 3R, 6S-3, 6-disubstituted piperazine-2, 5-diketone provided by the present invention belongs to the filed of biomedicine.

Description

(3R, 6S)-3,6-disubstituted piperazine-2,5-diketone, its preparations and applicatio
Technical field
The present invention relates to small molecules u-PA inhibitor shown in structural formula below, relate to it preparation method and as the application of u-PA inhibitor in Tumor suppression invasion and attack and migration, hemostasis and anti-inflammatory.The invention belongs to biomedicine field.
Background technology
Plasminogen activating system system is by plasminogen activator (Pas), and Plasminogen activation inhibitor (PAIs) and extracellular plasminogen activator receptor (PAR) form.Plasminogen activating system system relates to cell migration, vasculogenesis, wound healing, fetal development, a series of processes such as tumour cell diffusion and transfer.Tissue-type plasminogen activator (t-PA) and urokinase type plasminogen activator (u-PA) two kinds of plasminogen activators are mainly contained in mammalian body.
Urokinase type plasminogen activator (u-PA) is a kind of serine protease extracted from people's urine or nephrocyte tissue culture medium, belong to double chain urokinase type Plasminogen Activator (tcu-PA), molecular weight is 55000 or 33000, is the activator of exogenous fibrolysis system.U-PA can arginine (560)-α-amino-isovaleric acid (561) peptide bond of By Direct Pyrolysis Profibrinolysin, makes the strand Profibrinolysin of non-activity change activated double-strand plasmin into.
In tumor tissues, u-PA plasminogen activation is converted into plasmin, and plasmin directly or indirectly causes extracellular matrix degradation, causes the infiltration of tumour cell further, transfer and vasculogenesis, promotes the propagation of tumour.In blood circulation, u-PA participates in by plasminogen activation the balance regulating intravascular coagulation-fibrinolytic, plays an important role to suppression thrombus.
In inflammatory response process, u-PA is by being combined with the u-PAR on inflammatory cell surface, participate in the penetrating power regulating inflammatory cell to blood vessel and tissue, promote that inflammatory cell moves to inflammation part, promote the release of inflammatory reaction and inflammatory factor, and the release of inflammatory factor can induce u-PA to express rising.
Because the enzymic activity of u-PA is applied in the cross of tumour-fibrinolytic-inflammation complexity, so the activity affecting u-PA can affect complicated cross.That is, the u-PA inhibitor inventing outstanding activity is significant at tumour-thrombus-inflammation cross for suppression u-PA.This meaning is embodied in more than 70% cancer patient and dies from metastasis of cancer; There is the cancer of late stage patient of about 10% to occur bleeding, such as, occur almost unpredictable nose, pharynx, lung or massive gastrointestinal bleeding; Extract the hemorrhage of tumor operation generation, also worsen the prognosis of patient.For this situation, the present invention proposes (3R, 6S)-3-(4-fourth is amino)-6-(indoles-3-ethyl)-piperazine-2,5-diketone, its preparation and therapeutic action.
Before this, it is u-PA inhibitor (structure is shown in Fig. 1) that contriver once reported that the diketopiperazine of structure below comprised CIPPC, has outstanding styptic activity.Under 1nmol/kg dosage, CIPPC significantly can reduce the mouse mouse tail bleeding time [33,34].Unfortunately, under 10nmol/kg dosage, CIPPC can promote that thrombus generates.Thrombus is that tumour is important and close disease, is the important factor causing tumour dead.What CIPPC can promote thrombus to generate act as tumour patient brings new threat.Under contrast, (3R, 6S)-3-(4-fourth is amino)-6-(indoles-3-ethyl)-piperazine-2, the beyond thought advantage of 5-diketone is, except the same with CIPPC have outstanding styptic activity except, also have inhibition tumor cell invasion and m etastasis, the concurrent inflammatory effect of Tumor suppression, can not thrombosis be caused simultaneously.
Summary of the invention
First content of the present invention is to provide u-PA inhibitor (3R, 6S)-3-(4-fourth is amino)-6-(indoles-3-ethyl)-piperazine-2, the 5-diketone of structural formula below;
Second content of the present invention is to provide the preparation method of (3R, 6S)-3-(4-fourth is amino)-6-(indoles-3-ethyl)-piperazine-2,5-diketone, and the method comprises four reactions steps below:
(1) under DCC and HOBt exists, D-Trp-OBzl is L-Boc-Lys (Z)-L-Trp-OBzl with L-Boc-Lys (Z) condensation in anhydrous tetrahydro furan;
(2) in hydrogenchloride-ethyl acetate solution, L-Boc-Lys (Z)-D-Trp-OBzl sloughs Boc and generates L-Lys (Z)-L-Trp-OBzl;
(3) at ethyl acetate and 5%NaHCO 3there is lower L-Lys (Z)-D-Trp-OBzl and generate (3S, 6S)-3-(4-fourth aminobenzyl)-6-(indoles-3-ethyl)-piperazine-2,5-diketone;
(4) at Pd/C and H 2under existence, (3R in methyl alcohol, 6S)-3-(4-fourth aminobenzyl)-6-(indoles-3-ethyl)-piperazine-2,5-bis-reactive ketone generates (3R, 6S)-3-(4-fourth is amino)-6-(indoles-3-ethyl)-piperazine-2,5-diketone.
Four reactions steps above can describe by the synthetic route of Fig. 2.
3rd content of the present invention evaluates small molecules u-PA inhibitor (3R, 6S) the effect of-3-(4-fourth is amino)-6-(indoles-3-ethyl)-piperazine-2,5-diketone in inhibition tumor cell Infiltration and metastasis and in hemostasis and anti-inflammatory etc.
Accompanying drawing explanation
The structure of u-PA inhibitor diketopiperazine CIPPC of Fig. 1 contriver's report before this.
Fig. 2 synthesizes the route 1.i of (3R, 6S)-3-(4-fourth is amino)-6-(indoles-3-ethyl)-piperazine-2,5-diketone) DCC, HOBt, NMM, THF; Ii) HCl/EA (4N); Iii) EA, 5%NaHCO 3(3a) orEA, TEA, 80 DEG C (3b, 3c); Iv) CH 3oH, Pd/C, H 2.
Fig. 3 (3R, 6S)-3-(4-fourth is amino)-6-(indoles-3-ethyl)-piperazine-2,5-diketone is in vitro on the impact of UK plasminogen activation vigor.Wherein 1 human plasminogen (PLG) being classified as single component, 2 are classified as hatching altogether of UK and PLG; 3 be classified as 100 μ g (3R, 6S)-3-(4-fourth amino)-6-(indoles-3-ethyl)-piperazine-2,5-diketone and 5 μ LUK (400U/mL) and 5 μ LPLG (5mg/mL) hatch component altogether; 4 be classified as 50 μ g (3R, 6S)-3-(4-fourth amino)-6-(indoles-3-ethyl)-piperazine-2,5-diketone and 5 μ LUK (400U/mL) and 5 μ LPLG (5mg/mL) hatch component altogether; 5 be classified as 10 μ g (3R, 6S)-3-(4-fourth amino)-6-(indoles-3-ethyl)-piperazine-2,5-diketone and 5 μ LUK (400U/mL) and 5 μ LPLG (5mg/mL) hatch component altogether; 6 be the EACA of 500 μ g and 5 μ LUK (400U/mL) with 5 μ LPLG (5mg/mL) hatch component altogether; 7 be the EACA of 250 μ g and 5 μ LUK (400U/mL) with 5 μ LPLG (5mg/mL) hatch component altogether.
Embodiment
In order to set forth the present invention further, provide a series of embodiment below.These embodiments are illustrative completely, and they are only used for being specifically described the present invention, not should be understood to limitation of the present invention.
Embodiment 1 prepares L-Boc-Lys (Z)-D-Trp-OBzl (1)
1.9g (5.0mmol) L-Boc-Lys (Z) is suspended in 20mL anhydrous tetrahydro furan, in solution, 0.675g (5.0mmol) HOBt is added under stirring at room temperature, ice bath adds 1.133g (5.5mmol) DCC under stirring, obtain reaction solution I, stir 30 minutes under ice bath.1.47g (5.0mmol) D-Trp-OBzl is suspended in 20mL anhydrous tetrahydro furan, then adds NMM gradually, regulate pH to 8-9, obtain reaction solution II.Reaction solution II is added in reaction solution I, first under ice bath, stir 1h, then in stirring at room temperature, TLC monitoring disappears to raw material point.Aftertreatment: filtration under diminished pressure removing DCU, filtrate reduced in volume is removed tetrahydrofuran (THF), and residue 150mL acetic acid ethyl dissolution, is placed in 250mL separating funnel by the solution obtained, uses 5%KHSO successively 4the aqueous solution is washed and is respectively washed 3 times, ethyl acetate layer anhydrous Na with the saturated NaCl aqueous solution 2sO 4dry 30min, filtration under diminished pressure, filtrate reduced in volume is to dry, and the yellow foaming material obtained, through purification by silica gel column chromatography (CH 2cl 2: CH 3oH=100: 1 ~ 20: 1), obtaining 2.722g (83%) title compound, is colorless solid.ESI-MS(m/e)：657[M+H] +。
Embodiment 2 prepares L-Lys (Z)-D-Trp-OBzl (2)
Sterling 2.62g (4mmol) L-Boc-Lys (Z)-D-Trp-OBzl (1) is placed in 100mL eggplant bottle, ice bath stirs the lower slow 30mL4N hydrogenchloride-ethyl acetate solution that drips in reaction flask, add drying tube, ice bath stirs lower reaction TLC monitoring raw material point disappearance after 4 hours, termination reaction.Aftertreatment: under stirring with water pump by reaction solution decompressing and extracting, again use water pump decompressing and extracting after adding acetic acid ethyl dissolution, in triplicate; Leave standstill after adding the abundant suspendible of anhydrous diethyl ether, pour out ether, drain product, in triplicate, obtaining 2.08g (94.5%) title compound, is pale yellow powder.ESI-MS(m/e)：557[M+H] +。
Embodiment 3 prepares (3R, 6S)-3-(4-fourth aminobenzyl)-6-(indoles-3-ethyl)-piperazine-2,5-diketone (3)
By 1.83g (3.29mmol) compound L-Lys (Z)-D-Trp-OBzl (2) with 80mL acetic acid ethyl dissolution, adjust pH to 9 with triethylamine, oil bath 80 DEG C reaction 6 hours, TLC shows raw material point and substantially disappears.Aftertreatment: reaction solution is directly used silica gel mixed sample, purification by silica gel column chromatography (CH 2cl 2: CH 3oH=100: 1-20: 1), obtaining 0.913g (62%) title compound, is colorless solid.ESI-MS(m/e)：449[M+H] +. (c＝0.5，CH 3OH). 1HNMR(300MHz，DMSO-d6)：δ/ppm＝10.89(s，1H)，8.03(s，1H)，7.85(s，1H)，7.56(d，J＝9.0Hz，1H)，7.35(m，6H)，7.19(t，J＝6.0Hz，1H)，7.05(m，2H)，6.95(t，J＝6.0Hz，1H)，4.99(s，2H)，4.07(s，1H)，3.25(dd，J＝3.0Hz，J＝15.0Hz，1H)，3.09(dd，J＝3.0Hz，J＝15.0Hz，1H)，2.99(s，1H)，2.91(q，J＝6.0Hz，2H)，1.48(m，2H)，1.24(m，2H)，1.16(m，2H)。
Embodiment 4 prepares (3R, 6S)-3-(4-fourth is amino)-6-(indoles-3-ethyl)-piperazine-2,5-diketone (4)
By 0.108g (0.24mmol) compound (3S, 6R)-3-(4-fourth aminobenzyl)-6-(indoles-3-ethyl)-piperazine-2,5-diketone (3) is placed in 50mL reaction flask, add 10mL dissolve with methanol, in solution, add 20mgPd/C, pass into H 2, stirring at room temperature reacts 48 hours, and TLC shows the basic disappearance of raw material, and elimination Pd/C, concentrating under reduced pressure obtains 42mg (55.5%) title compound, is colourless powder.ESI-MS(m/e)：315[M+H] +.Mp183-185℃.IR(KBr)：3223，2926，2862，1670，1456，1327，1099，742cm -1. (c＝0.28，CH 3OH). 1HNMR(300MHz，DMSO-d6)：δ/ppm＝10.92(s，1H)，8.04(s，1H)，7.88(s，1H)，7.56(d，J＝9.0Hz，1H)，7.31(d，J＝9.0Hz，1H)，7.06(s，1H)，7.04(t，J＝9Hz，1H)，6.94(t，J＝9Hz，1H)，4.07(s，1H)，3.26(dd，J＝3Hz，J＝12Hz，1H)，3.02(dd，J＝6.0Hz，J＝15Hz，1H)，2.98(m，2H)，2.44(m，2H)，1.21(m，2H)，1.09(m，2H). 13CNMR(200MHz，DMSO-d 6)：δ/ppm＝168.00，167.57，135.79，127.48，124.43，120.72，118.68，118.27，111.03，108.30，55.28，53.10，32.62，31.51，28.79，20.69.Elem.Anal：C 17H 22N 4O 2.C，64.95；H，7.05；N，17.82。
Experimental example 1 measures (3R, 6S)-3-(4-fourth is amino)-6-(indoles-3-ethyl)-piperazine-2,5-diketone to the impact of urokinase (UK) activity
1) main agents and instrument
Reagent: SDS-PAGE gel electrophoresis agents useful for same and hexosamine (EACA) are commercial reagent;
Human plasminogen (PLG) and urokinase (UK) available from Sigma.
Instrument: Vertial electrophorestic tank Mini-PRORENTetraSystem (BIO-RAD);
Electrophoresis apparatus PowerPac (BIO-RAD);
Scanner Scanmaker8700 (MICROTEK).
2) preparation of solution
The preparation of PLG solution: take PLG5mg, is placed in 15mL centrifuge tube, adds 1mL physiological saline solution and namely obtains PLG solution, and concentration is 5mg/mL; Packing, often pipe 0.1mL ,-20 DEG C of preservations are stand-by;
The preparation of UK solution: by whole bottle UK (100,000U) with 10mL physiological saline solution, obtain mother liquor; Get 0.1mL mother liquor with normal saline dilution to 2.5mL, obtain UK solution, concentration is 400U/mL; Packing, often pipe 0.1mL ,-20 DEG C of preservations are stand-by;
The preparation of EACA solution: take 50mg compound, with 1mL physiological saline solution, obtains mother liquor 1, and concentration is 50mg/mL; Get 0.5mL mother liquor 1, with normal saline dilution to 1mL, obtain solution 2, concentration is 25mg/mL;
(3R, 6S)-3-(4-fourth is amino)-6-(indoles-3-ethyl)-piperazine-2, the preparation of 5-diketone solution: take 5mg (3R, 6S)-3-(4-fourth is amino)-6-(indoles-3-ethyl)-piperazine-2,5-diketone, with 1mL physiological saline solution, concentration is 5mg/mL;-20 DEG C of preservations are stand-by.
3) preparation of sample
Get 5 μ LUK (400U/mL) solution; Packing, often pipe 0.1mL, be placed in 0.5mL centrifuge tube, add 10 μ L physiological saline or (3R wherein respectively again, 6S)-3-(4-fourth is amino)-6-(indoles-3-ethyl)-piperazine-2,5-diketone solution, hatches 15 minutes for 37 DEG C; In each centrifuge tube, add 5 μ LPLG solution respectively again, hatch 15 minutes for 37 DEG C; After hatching end, then in each centrifuge tube, add 5 μ L5 × SDS electrophoresis sample-loading buffers respectively, by the sex change 5 minutes in 100 DEG C of water-baths of each centrifuge tube after mixing, the SDS-PAGE gel electrophoresis with 12% after quick ice bath cooling is separated.
4) SDS-PAGE gel electrophoresis
Reagent prepares:
30% deposit sol solution: acrylamide (Acr) 29.0g, methylene bisacrylamide (Bis) 1.0g, adds ultrapure water (up-H after mixing 2o), 37 DEG C of dissolvings, be settled to 100mL, brown bottle is stored in room temperature;
1.5MTris-HCl (pH8.0): Tris18.17g adds up-H 2o dissolves, and concentrated hydrochloric acid adjusts pH to 8.0, is settled to 100mL;
1MTris-HCl (pH6.8): Tris12.11g adds up-H 2o dissolves, and concentrated hydrochloric acid adjusts pH to 6.8, is settled to 100mL;
12%SDS: electrophoresis level SDS12.0g adds up-H 2o is in 68 DEG C of hydrotropies, and concentrated hydrochloric acid is adjusted to pH7.2, is settled to 100mL;
10% ammonium persulphate (AP): 100mgAP adds up-H 2o1mL;
Coomassie brilliant blue staining fluid: methanol-water-acetic acid=45mL+45mL+10mL, adds 100mg Xylene Brilliant Cyanine G solid, is mixed with staining fluid;
Destainer: methanol-water-acetic acid=10mL+90mL+10mL, is mixed with destainer.
Operation steps:
Adopt rectilinear electrophoresis chamber device
(1) preparation of polyacrylamide gel
1. the preparation of separation gel (12%):
Ultrapure water 4.0mL
30% deposit sol solution 3.3mL
1.5MTris-HCl2.5mL
12％SDS0.1mL
10％AP0.1mL
Get the above-mentioned mixed solution of 1mL, add TEMED (N, N, N ', N '-Tetramethyl Ethylene Diamine) 10 μ L back covers, more than add TEMED4 μ L, pour into after mixing between sheet glass, with water seal top, note liquid level is put down, gel is polymerized completely needs about 60min.
2. the preparation of concentrated glue (4%):
Ultrapure water 1.4mL
30% deposit sol solution 0.33mL
1MTris-HCl0.25mL
12％SDS0.02mL
10％AP0.02mL
TEMED2μL
Gone by water on separation gel, add above-mentioned mixed solution, insert between sheet glass immediately by comb, polymerization needs about 30min completely.
(2) sample preparation: 5 × SDS sample-loading buffer sample being added respective amount, 100 DEG C of heating 3-5min make protein denaturation, take out, fast cooling.
(3) loading: the sample after process is added in sample pool, and adds 20 μ L Protein Marker product and compare.
(4) electrophoresis: add 1 × electrophoretic buffer in electrophoresis chamber, connect power supply, negative pole is upper, positive pole under, during electrophoresis, concentrated glue voltage 80V, 30min, separation gel voltage 100V walk to electrophoresis chamber lower end to electrophoresis to bromjophenol blue and stop (about needing 1.5h).
(5) dye: taken out from sheet glass by glue, Coomassie brilliant blue staining fluid dyes, in shaking table (60RPM) room temperature 10min.
(6) decolour: glue is taken out from staining fluid, puts into destainer, spend the night in the decolouring of shaking table (60RPM) room temperature.
(7) by the glue scanner scanning after decolouring, observations.
5) the results are shown in Figure 3, (3R, 6S)-3-(4-fourth is amino)-6-(indoles-3-ethyl)-piperazine-2,5-diketone concentration dependant ground suppresses UK to be hydrolyzed the activity of human plasminogen.Illustrate that it is the inhibitor of UK.
Experimental example 2 measures (3R, 6S)-3-(4-fourth is amino)-6-(indoles-3-ethyl)-piperazine-2,5-diketone to the impact of HCCLM3 cell invasion ability
1) given the test agent
The DMEM substratum of (3R, 6S)-3-(4-fourth is amino)-6-(indoles-3-ethyl)-piperazine-2,5-diketone containing 0.1%DMSO is mixed with 50 μMs of concentration;
The DMEM substratum of RGDS containing 0.1%DMSO is mixed with 100 μMs of concentration.
2) cell strain
HCCLM3 (high-transfer human liver cancer cell), purchased from ATCC.
3) key instrument and consumptive material
Super clean bench: VS-1300-U clean bench, SuZhou Antai Air Tech Co., Ltd.;
Cell incubation case: INC153, memmer company;
Microscope: Zeiss company;
The Transwell cell in 8.0 μm of apertures, 12 porocyte culture plate and 25cm 2culturing bottle: ComingCostar company.
4) main agents
DMEM culture medium dry powder: Gibco company;
PBS damping fluid: containing NaCl8.2g, KCl0.2g, Na in every 1L solution 2hPO 4h 2o1.56g, KH 2pO 40.2g, pH value 7.4;
Foetal calf serum: Hyclone company;
0.25% trypsin solution: Hyclone company;
Penicillin, Streptomycin sulphate: Zhongnuo Pharmaceutical (Shijiazhuang) Co., Ltd., Shiyao Group;
DMSO (dimethyl sulfoxide (DMSO)): Hyclone company;
Matrigel (matrigel): BD company;
Viola crystallina dye liquor: green skies company.
5) evaluation method
Bag is by matrigel: spent the night by the frozen matrigel4 in-20 DEG C of refrigerators DEG C, liquefy; Get 720 μ L plasma-free DMEM medium, add 180 μ LMatrigel, mixing, room on the polycarbonate membrane being added to Transwell cell, 100 μ L/; Put into 37 DEG C, 5%CO 2in incubator, hatch 5h;
Aquation basilar membrane: absorb residual liquid in cell, every hole adds the DMEM substratum of 50 μ L, 37 DEG C, 5%CO 230min is hatched in incubator;
Inoculating cell: digestion HCCLM3 cell, plasma-free DMEM medium washes 3 times, and counting, be made into cell suspension, density is 5 × 10 5individual/mL; Every hole adds 100 μ L cell suspensions, and add 25 μ L (3R, 6S)-3-(4-fourth is amino)-6-(indoles-3-ethyl)-piperazine-2,5-diketone simultaneously and make final concentration be 10 μMs, RGDS final concentration is 20 μMs; Lower room adds the DMEM substratum containing 10%FBS of 600 μ L, at 37 DEG C, 5%CO 2cultivate 48 hours in incubator;
Violet staining: the cell wiping matrigel and upper indoor with cotton swab; With the paraformaldehyde fixed cell 30min of 4%, absorb stationary liquid, wash 3 times with PBS; With the Viola crystallina dye liquor dyeing 30min of 0.1%, absorb staining fluid, wash 3 times with PBS;
Counting: choose 9 roughly the same visuals field at each cell and observe, take pictures, counting; Experimental data statistics all adopt t inspection and variance analysis, cell count with ( individual) represent.
6) the results are shown in Table 1, (3R, 6S)-3-(4-fourth is amino)-6-(indoles-3-ethyl)-piperazine-2,5-diketone can suppress HCCLM3 cell invasion effectively.
Table 1. (3R, 6S)-3-(4-fourth is amino)-6-(indoles-3-ethyl)-piperazine-2,5-diketone is on the impact of HCCLM3 cell invasion ability a
A) n=3; B) with physiological saline ratio, P < 0.05.
Experimental example 3 evaluates (3R, 6S)-3-(4-fourth is amino)-6-(indoles-3-ethyl)-piperazine-2,5-diketone to the impact of HCCLM3 cell migration ability
1) given the test agent
The DMEM substratum of compound 4 containing 0.1%DMSO is mixed with 50 μMs of concentration;
The DMEM substratum of RGDS containing 0.1%DMSO is mixed with 100 μMs of concentration.
2) cell strain
HCCLM3 (high-transfer human liver cancer cell).
3) key instrument and consumptive material
Super clean bench: VS-1300-U clean bench, SuZhou Antai Air Tech Co., Ltd.;
Cell incubation case: INC153, memmer company;
Microscope: Zeiss company;
The Transwell cell in 8.0 μm of apertures, 12 porocyte culture plate and 25cm 2culturing bottle: CorningCostar company.
4) main agents
DMEM culture medium dry powder: Gibco company;
PBS damping fluid: containing NaCl8.2g, KCl0.2g, Na in every 1L solution 2hPO 4h 2o1.56g, KH 2pO 40.2g, pH value 7.4;
Foetal calf serum: Hyclone company;
0.25% trypsin solution: Hyclone company;
Penicillin, Streptomycin sulphate: Zhongnuo Pharmaceutical (Shijiazhuang) Co., Ltd., Shiyao Group;
DMSO (dimethyl sulfoxide (DMSO)): Hyclone company;
Viola crystallina dye liquor: green skies company.
5) evaluation method
Inoculating cell: digestion HCCLM3 cell, plasma-free DMEM medium washes 3 times, and counting, be made into cell suspension, density is 2 × 10 6individual/mL; Every hole adds 100 μ L cell suspensions, and add 25 μ L (3R, 6S)-3-(4-fourth is amino)-6-(indoles-3-ethyl)-piperazine-2,5-diketone simultaneously and make final concentration be 10 μMs, RGDS final concentration is 20 μMs; Lower room adds the DMEM substratum containing 10%FBS of 600 μ L, at 37 DEG C, 5%CO 2cultivate 6 hours in incubator;
Violet staining: the cell wiping matrigel and upper indoor with cotton swab; With the paraformaldehyde fixed cell 30min of 4%, absorb stationary liquid, wash 3 times with PBS; With the Viola crystallina dye liquor dyeing 30min of 0.1%, absorb staining fluid, wash 3 times with PBS;
Counting: choose 9 roughly the same visuals field at each cell and observe, take pictures, counting; Experimental data statistics all adopt t inspection and variance analysis, cell count with ( individual) represent.
6) the results are shown in Table 2, (3R, 6S)-3-(4-fourth is amino)-6-(indoles-3-ethyl)-piperazine-2,5-diketone can suppress HCCLM3 cell migration effectively.
Table 2. compound 4 is on the impact of HCCLM3 cell migration ability a
A) n=3; B) with physiological saline than P < 0.05.
Experimental example 4 evaluates (3R, 6S)-3-(4-fourth is amino)-6-(indoles-3-ethyl)-piperazine-2,5-diketone to the impact in ICR mouse mouse tail bleeding time
1) experiment material
Test-compound: (3R, 6S)-3-(4-fourth is amino)-6-(indoles-3-ethyl)-piperazine-2,5-diketone;
Positive control is 6-aminocaprolc acid (EACA); Negative control is physiological saline (NS);
Laboratory animal: ICR male mice (cleaning grade), body weight 18-22g, is provided by Beijing Vital River Experimental Animals Technology Co., Ltd.; Every 10 mouse one group, blank and each one group of positive control;
Solvent: physiological saline.
2) Pharmaceutical formulations
Weigh Compound 4 according to quantity, adds physiological saline to desired concn; 6-aminocaprolc acid (EACA) is normal saline solution.
3) dosage and administering mode
Dosage: EACA is 1.96mmol/kg; (3S, 6S)-3-(4-fourth is amino)-6-(indoles-3-ethyl)-piperazine-2,5-diketone is 0.05 μm of ol/kg; According to Mouse Weight, every 10g is to 0.1mL liquid or physiological saline; Gastric infusion.
4) foundation of animal model
ICR male mice 70, body weight 18-22g, is divided into compound group, EACA group and blank group at random, often organizes 10.Each group of according to dosage gastric infusion.Administration is after 30 minutes, mouse is loaded in stationary installation, make outside its tail is exposed to, with milimeter scale Measurement accuracy, making marks apart from mouse tail end 3mm place, cut by profit and go out quick shearing at mouse tail end mark, when blood can overflow voluntarily, start timing, every 30 seconds, wipe incision position drop of blood gently away with filter paper, until blood stops naturally, without till blood when namely filter paper is inhaled.
5) statistical method
This experimental data statistics all adopt t inspection and variance analysis, the bleeding time with ( s) represent.
6) the results are shown in Table 3, (3R lower than the dosage of positive control EACA 3920 times time, 6S)-3-(4-fourth is amino)-6-(indoles-3-ethyl)-piperazine-2,5-diketone still shortens the mouse bleeding time effectively, illustrates that it can stop blooding effectively.
Table 3. (3R, 6S)-3-(4-fourth is amino)-6-(indoles-3-ethyl)-piperazine-2,5-diketone is on the impact in ICR mouse mouse tail bleeding time a
A) n=10; B) with physiological saline than P < 0.05; C) with physiological saline than P < 0.01; D) with physiological saline than P > 0.05.
Experimental example 5 measures the impact that (3R, 6S)-3-(4-fourth is amino)-6-(indoles-3-ethyl)-piperazine-2,5-diketone generates rat carotid artery thrombus
1) experiment material
Test-compound: (3R, 6S)-3-(4-fourth is amino)-6-(indoles-3-ethyl)-piperazine-2,5-diketone;
Positive control is acetylsalicylic acid (Aspirin); Negative control is physiological saline (NS);
Laboratory animal: SD male rat (cleaning grade), body weight 180-220g, is provided by Beijing Vital River Experimental Animals Technology Co., Ltd.; Every 10 rats one group, blank and each one group of positive control;
Solvent: physiological saline.
2) Pharmaceutical formulations
Take (3R, 6S)-3-(4-fourth is amino)-6-(indoles-3-ethyl)-piperazine-2,5-diketone according to quantity, add physiological saline successively to desired concn; Acetylsalicylic acid is normal saline solution.
3) dosage and administering mode
Dosage: acetylsalicylic acid is 50 μm of ol/kg; (3S, 6S)-3-(4-fourth is amino)-6-(indoles-3-ethyl)-piperazine-2,5-diketone is 0.05 μm of ol/kg; According to rat body weight, every 100g is to 0.3mL liquid or physiological saline; Gastric infusion.
4) foundation of animal model
SD male rat 70, body weight 180-220g, is divided into compound group, acetylsalicylic acid group and blank group at random, often organizes 10.Each group of according to dosage gastric infusion.Administration is after 30 minutes, and each group rat, with 10% chloral hydrate anesthesia, is isolated arteria carotis communis and the total vein of neck, causes rat artery thrombus model with rat carotid artery-venous cannula bypass circuit tuft method; Circulate 15 minutes, take out the strap bolt silk thread in bypass tube, wipe the floating blood in surface away, claim strap bolt silk thread weight in wet base, after deducting silk thread weight, obtain thrombosed weight in wet base, record data.
5) statistical method
This experimental data statistics all adopt t inspection and variance analysis, wet weight of thrombus with ( mg) represent.
6) the results are shown in Table 4, under 0.05 μm of ol/kg dosage, (3S, 6S)-3-(4-fourth is amino)-6-(indoles-3-ethyl)-piperazine-2,5-diketone does not promote the effect of mouse thrombosis, does not namely have thrombosis risk.
Table 4. (3R, 6S)-3-(4-fourth is amino)-6-(indoles-3-ethyl)-piperazine-2,5-diketone is on the impact of SD rat carotid artery thrombus growing amount a
A) n=10; B) with physiological saline than P > 0.05; C) with physiological saline than P < 0.01.
Experimental example 6 evaluates the impact of (3R, 6S)-3-(4-fourth is amino)-6-(indoles-3-ethyl)-piperazine-2,5-diketone p-Xylol inducing mouse ear swelling
1) experiment material
Test-compound: (3R, 6S)-3-(4-fourth is amino)-6-(indoles-3-ethyl)-piperazine-2,5-diketone;
Positive control is acetylsalicylic acid (Aspirin); Negative control is physiological saline (NS);
Laboratory animal: ICR male mice (cleaning grade), body weight 18-22g, tieing up experiment thing Technology Co., Ltd. of tonneau China by Beijing provides.Every 10 mouse one group, blank and each one group of positive control.
2) Pharmaceutical formulations
Take (3R, 6S)-3-(4-fourth is amino)-6-(indoles-3-ethyl)-piperazine-2,5-diketone according to quantity, add physiological saline successively to desired concn; Acetylsalicylic acid is normal saline solution.
3) dosage and administering mode
Dosage: acetylsalicylic acid is 1.11mmol/kg; (3R, 6S)-3-(4-fourth is amino)-6-(indoles-3-ethyl)-piperazine-2,5-diketone is 0.05 μm of ol/kg; According to Mouse Weight, every 10g is to 0.1mL liquid or physiological saline; Gastric infusion.
4) foundation of animal model
ICR male mice 70, body weight 18-22g, is divided into (3R, 6S)-3-(4-fourth is amino)-6-(indoles-3-ethyl)-piperazine-2,5-diketone group, acetylsalicylic acid group and blank group at random, often organizes 10.Each group of according to dosage gastric infusion.Administration is after 30 minutes, uniform application 30 μ L dimethylbenzene inside the left ear auricle of mouse, after 2 hours, cervical dislocation puts to death mouse, respectively outer for left and right two ears auricle is cut and overlapped and be stacked together, to beat at same position with the punch tool of diameter 7mm and get circular auricle, weigh, record and calculate two ear weight differences; Mouse ear swelling degree=left auricle weight-auris dextra sheet weight.
5) statistical method
This experimental data statistics all adopt t inspection and variance analysis, mouse ear swelling degree with ( mg) represent.
6) the results are shown in Table 5, (3S under 0.05 μm of ol/kg dosage, 6S)-3-(4-fourth amino)-6-(indoles-3-ethyl)-piperazine-2, the 5-diketone mice ear that effectively suppresses dimethylbenzene to cause, i.e. inflammation-inhibiting effectively.
Table 5. (3R, 6S)-3-(4-fourth is amino)-6-(indoles-3-ethyl)-piperazine-2,5-diketone is on the impact of ICR mice ear degree a
A) n=10; B) with physiological saline than P < 0.05; C) with physiological saline than P < 0.01.

Claims (5)

1. u-PA inhibitor (3R, 6S)-3-(4-fourth is amino)-6-(indoles-3-ethyl)-piperazine-2, a 5-diketone.Structural formula is as follows:
U-PA inhibitor shown in structural formula, the small molecules u-PA inhibitor that structural formula 4 represents.
2. prepare the method for (3R, 6S)-3-(4-fourth is amino)-6-(indoles-3-ethyl)-piperazine-2, the 5-diketone of claim 1, the method is made up of following steps:
(1) under DCC and HOBt exists, D-Trp-OBzl is L-Boc-Lys (Z)-D-Trp-OBzl with L-Boc-Lys (Z) condensation in anhydrous tetrahydro furan;
(2) in hydrogenchloride-ethyl acetate solution, L-Boc-Lys (Z)-D-Trp-OBzl sloughs Boc and generates L-Lys (Z)-L-Trp-OBzl;
(3) at ethyl acetate and 5%NaHCO 3there is lower L-Lys (Z)-D-Trp-OBzl cyclization and generate (3S, 6S)-3-(4-fourth aminobenzyl)-6-(indoles-3-ethyl)-piperazine-2,5-diketone;
(4) at Pd/C and H 2under existence, (3R in methyl alcohol, 6S)-3-(4-fourth aminobenzyl)-6-(indoles-3-ethyl)-piperazine-2,5-diketone is sloughed benzyl and is generated (3R, 6S)-3-(4-fourth is amino)-6-(indoles-3-ethyl)-piperazine-2,5-diketone.
3. (3R, 6S)-3-(4-fourth is amino)-6-(indoles-3-ethyl)-piperazine-2, the 5-diketone of claim 1 is in preparation metastases and the application of invading in profit suppression medicine.
4. (3R, 6S)-3-(4-fourth is amino)-6-(indoles-3-ethyl)-piperazine-2, the 5-diketone of claim 1 prepares the application of hemostatic agent medicine.
5. (3R, 6S)-3-(4-fourth is amino)-6-(indoles-3-ethyl)-piperazine-2, the 5-diketone of claim 1 prepares the application of anti-inflammatory agent medicine.
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