CN105273044A - 1-(ethylamino acid benzyl ester)-beta-carboline-3-benzyl carboxylate, preparation, nano-structure, activity and application - Google Patents
1-(ethylamino acid benzyl ester)-beta-carboline-3-benzyl carboxylate, preparation, nano-structure, activity and application Download PDFInfo
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Abstract
The invention discloses 1-(ethyl-Leu-AA-OBzl)-beta-carboline-3-benzyl carboxylate in the formula, wherein AA is L-Glu and L-Pro residue. The invention also discloses a preparation method of 1-(ethyl-Leu-AA-OBzl)-beta-carboline-3-benzyl carboxylate and its nano-structure, discloses an inhibitory activity to tumor cell proliferation, discloses a reverse effect on adriamycin resistant cells and further discloses an activity of inhibiting growth of S180 mouse tumor. Thereby, the invention expounds an application of 1-(ethyl-Leu-AA-OBzl)-beta-carboline-3-benzyl carboxylate in the preparation of antitumor drugs and in the preparation of drugs of reversing drug resistance of tumor.
Description
Technical field
The present invention relates to 1-(ethyl-Leu-AA-OBzl)-β-carboline-3-benzyl carboxylate, AA is L-Glu and L-Pro residue.Relate to their preparation method, relate to their nanostructure, relate to their inhibit activities to tumor cell proliferation, relate to their and reverse effect to the cell of Adriamycin resistant, relate to the activity that their suppress S180 mice tumors grew.Result shows that 2 kinds of 1-of the present invention (N-ethyl-Leu-AA-OBzl)-β-carboline-3-benzyl carboxylate has outstanding anti-tumor activity and reversing tumor resistance is active.The invention belongs to biomedicine field.
Technical background
The health of the malignant tumour serious threat mankind.In clinical cancer therapy, chemotherapy still occupies most important status., tumor multi-medicine drug-resistant and crossing drug resistant make the antitumor drug paying huge work invention lose curative effect very soon.So it is the forward position that antitumor drug is studied with medicine that is reversing tumor resistance that invention has antitumor always.
In antitumor drug research, applicant, once with the β-carboline-3-carboxylic acid that amino-acid benzyl ester modifies tetrahydro-beta-carboline-3-carboxylic acid, β-carboline-3-carboxylic acid and 1-position replace, comprises tetrahydro-beta-carboline-3-carboxylic acid that 1-position replaces or the β-carboline-3-carboxylic acid that 1-position replaces prepares efficient antineoplastic compound.Wherein 1-(ethyl-AA-OBzl)-β-carboline-3-benzyl carboxylate of structure shows clear and definite antitumor action under 8.9 μm of ol/kg dosage below.According to structural requirement interactional with DNA of tumor cell, contriver believes that between the ethyl-AA-OBzl of 1-(ethyl-AA-OBzl)-β-carboline-3-benzyl carboxylate, insert L-Leu residue can produce favourable influence to antitumor action.Under the guiding of this thinking, inventors herein propose the present invention.
Summary of the invention
First content of the present invention is to provide 1-(ethyl-Leu-AA-OBzl)-β-carboline-3-benzyl carboxylate, and AA is L-Glu and L-Pro residue.
Second summary of the invention of the present invention is to provide preparation method's (AA is L-Glu and L-Pro residue) of preparation 2 kinds of novel 1-(ethyl-Leu-AA-OBzl)-β-carboline-3-benzyl carboxylate, and the method comprises:
1) L-Trp carries out Pictet-Spengler condensation with 1,1,3,3-tetramethoxy propane under trifluoroacetic catalysis, obtains (s)-1-(2,2-dimethoxy ethyl)-2,3,4,9-tetrahydro-beta-carboline-3-benzyl carboxylate;
2) (s)-1-(2,2-dimethoxy ethyl)-2,3,4,9-tetrahydro-beta-carboline-3-benzyl carboxylate is generated 1-(2,2-dimethoxy ethyl)-β-carboline-3-benzyl carboxylate by potassium permanganate oxidation;
3) 1-(2,2-dimethoxy ethyl)-β-carboline-3-benzyl carboxylate is generated 1-(2-oxoethyl)-β-carboline-3-benzyl carboxylate under hydrochloric acid, Glacial acetic acid and water catalysis;
4) Boc-Leu and 2 kind of AA-OBzl coupling is obtained 2 kinds of Boc-Leu-AA-OBzl;
5) 2 kinds of Boc-Leu-AA-OBzl are obtained 2 kinds of L-Leu-AA-OBzl respectively under the catalysis of hydrochloric acid/ethyl acetate;
6) 1-(2-oxoethyl)-β-carboline-3-benzyl carboxylate is obtained 2 kinds of 1-(ethyl-Leu-AA-OBzl)-β-Ka quinoline-3-benzyl carboxylate respectively with the coupling of L-Leu-AA-OBzl hydrochloride.
3rd content of the present invention is the nanostructure measuring 1-(ethyl-Leu-AA-OBzl)-β-carboline-3-benzyl carboxylate.
4th content of the present invention evaluates 1-(ethyl-Leu-AA-OBzl)-β-carboline-3-benzyl carboxylate to the restraining effect of tumor cell proliferation with mtt assay.
5th content of the present invention evaluates 1-(ethyl-the Leu-AA-OBzl)-activity of β-carboline-3-benzyl carboxylate reverse to the MCF-7/ADR cells resistance of Adriamycin resistant with mtt assay.
6th content of the present invention is that evaluation 2 kinds of 1-(ethyl-Leu-AA-OBzl)-β-carboline-3-benzyl carboxylate is to the restraining effect of the tumor growth of mice bearing S180.
Accompanying drawing explanation
The synthetic route .i of Fig. 1 .1-(ethyl-Leu-AA-OBzl)-β-carboline-3-benzyl carboxylate) TFA,
1,1,3,3-tetramethoxypropane, CH
2cl
2; Ii) KMnO
4, THF; Iii) HCl, HOAc, H
2o; Iv) HOBt, DCC, NMM, THF; V) HCl/EtOAc; Vi) NaBH
3in CNandH-L-AA-OBzl.4a, AA is L-Glu residue, and 4b is L-Pro residue.
The transmission electron microscope photo of Fig. 2 .1-(ethyl-Leu-AA-OBzl)-β-Ka quinoline-3-benzyl carboxylate.
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 (3S)-1-(2,2-dimethoxy ethyl)-2,3,4,9-tetrahydro-beta-carboline-3-benzyl carboxylate
In 200ml methylene dichloride, add 20ml1,1,3,3-tetramethoxy propane, 20ml trifluoracetic acid, activate 45 minutes under stirring at room temperature, add 18g (0.37mol) L-Trp benzyl ester, room temperature reaction 48 hours.Compound of reaction uses saturated NaHCO successively
3the aqueous solution (50ml × 3) and the saturated NaCl aqueous solution (50ml × 3) extraction are washed, separation obtains organic layer through anhydrous sodium sulfate drying, filter, filtrate reduced in volume is to dry, residue over silica gel column chromatography purification (sherwood oil: acetone=3: 1), obtain 10.8g (60%) title compound, R
f=0.25 (sherwood oil: acetone=3: 1) is yellow oil.ESI-MS(m/z)：395[M+H]
+。
Embodiment 2 prepares 1-(2,2-dimethoxy ethyl)-3-carboline carboxylate benzyl ester
10.8g (0.02mol) (3S)-1-(2,2-dimethoxy ethyl)-2,3,4,9-tetrahydro-beta-carboline-3-benzyl carboxylate is dissolved in 100ml tetrahydrofuran (THF), under ice bath, adds 7.8g (0.04mol) KMnO in batches
4with the solution of 50ml water, room temperature reaction 4 hours, TLC monitors raw material spot and disappears, in reaction flask, add 20ml ethanol, stir after 20 minutes, filter, filter cake, with after hot ethyl acetate extraction, discards waste residue, merges organic phase, be evaporated to dry, with acetic acid ethyl dissolution, water (30ml × 3) and the saturated NaCl aqueous solution (50ml × 3) extraction is then used to wash successively, anhydrous sodium sulfate drying, filter, filtrate reduced in volume is to dry.Residue over silica gel column chromatography purification (sherwood oil: acetone=3: 1) obtain 3g (28%) title compound, R
f=0.2 (sherwood oil: acetone=3: 1) is yellow powder.ESI-MS(m/e)：391[M+H]
+。
Embodiment 31-(2-oxoethyl)-3-carboline carboxylate benzyl ester
By 1g (0.002mol) 1-(2,2-dimethoxy ethyl)-3-carboline carboxylate benzyl ester is dissolved in 7.2ml Glacial acetic acid, add 0.9ml water and 0.9ml hydrochloric acid, stirring at room temperature 4 hours, TLC monitors raw material point and disappears, and adds 50ml mixture of ice and water, filter after stirring 10min under ice bath, filter cake frozen water washs, and dries, the not purified reaction be directly used in below.
Embodiment 4 prepares Boc-Leu-Glu-OBzl and Boc-Leu-Pro-OBzl
750mg (3mmol) Boc-Leu is dissolved in 30ml anhydrous tetrahydro furan, adds 425mgHOBt, after ice bath stirs 10 minutes, add the solution of 630mgDCC and anhydrous tetrahydro furan, stir 30 minutes, obtain reaction solution.3mmolGlu-OBzl or the Pro-OBzl NMM dissolved by anhydrous tetrahydro furan regulates pH to 7, add in reaction solution obtained above, pH is adjusted to be 9 with NMM again, react under room temperature after 8 hours, reaction solution is evaporated to dry, add 30mL acetic acid ethyl dissolution, the DCU (dicyclohexylurea (DCU)) that filtering is separated out, filtrate uses saturated NaHCO successively
3the aqueous solution (20mL × 3), the saturated NaCl aqueous solution (20mL × 3), 5%KHSO
4the aqueous solution, the saturated NaCl aqueous solution (20mL × 3), 5%NaHCO
3the aqueous solution (20mL × 3), the saturated NaCl aqueous solution (20mL × 3) respectively wash three times.Ethyl acetate layer, after anhydrous sodium sulfate drying, filters, and filtrate reduced in volume, to dry, obtains product through purification by silica gel column chromatography (methylene dichloride: methyl alcohol=80: 1).
Embodiment 5 prepares Leu-Glu-OBzl and Leu-Pro-OBzl
Be dissolved in by 2mmolBoc-Leu-Glu-OBzl and Boc-Leu-Pro-OBzl in 5ml ethyl acetate, add the ethyl acetate solution of 20ml4N hydrogenchloride under ice bath, room temperature reaction 4 hours, TLC monitors raw material point and disappears.Concentrating under reduced pressure as, residue adds 30ml acetic acid ethyl dissolution, then is evaporated to dry.This operation three times repeatedly.Residue adds 30ml anhydrous diethyl ether and dissolves, then is evaporated to dry.This operation also repeatedly three times.The product obtained is for the next step.
Embodiment 6 prepares 1-(ethyl-Leu-Glu-OBzl)-β-carboline-3-benzyl carboxylate (4a)
By 1148mg (2.61mmol) Leu-Glu-OBzl, 28.8mgNaOH solid is dissolved in 30ml methyl alcohol, activate after 10 minutes and add 600mg (1.74mol) 1-(2-oxoethyl)-3-carboline carboxylate benzyl ester, after 30min, add 54mgNaBH
3cN and appropriate anhydrous MgSO
4, react after 12 hours, the new dot generation of TLC thin plate monitoring reaction, reaction solution is evaporated to dry, and residue with Ethyl acetate dissolves, and the solution obtained uses saturated NaHCO successively
3the aqueous solution (50ml × 3) and the saturated NaCl aqueous solution (50ml × 3) extraction are washed, ethyl acetate layer anhydrous Na SO
4drying, filter, concentrating under reduced pressure, through purification by silica gel column chromatography, (methylene dichloride: methyl alcohol=60: 1), obtains 186mg (13%) title compound to residue, is pale yellow oil.ESI
+-MS(m/e)：769[M+H]
+；Mp∶150-151℃；
1H-NMR(300MHz，CDCl
3)：δ/ppm＝10.37(s，1H)，8.74(s，1H)，8.14(d，J＝8.1Hz，1H)，8.03(d，J＝8.4Hz，1H)，7.50-7.56(m，4H)，7.25-7.44(m，14H)，5.51(s，2H)，5.25(m，2H)，5.10(s，2H)，4.81(m，1H)，3.52(m，1H)，3.47(m，1H)，3.13-3.22(m，3H)，2.45(m，2H)，2.35(m，1H)，2.09(m，1H)，1.68(m，2H)，1.48(m，1H)，0.93(d，J＝6.3Hz，2H)，0.87(d，J＝6.3Hz，2H).
13C-NMR(75MHz，CDCl
3)：δ/ppm＝172.85，172.40，165.98，143.63，140.77，136.35，136.29，135.61，134.81，128.71，128.61，128.55，128.39，128.35，128.31，128.19，128.04，122.02，121.80，120.65，116.72，112.08，67.59，66.96，66.61，61.79，51.28，47.18，44.16，30.36，27.17，25.10，23.07，21.79。
Embodiment 7 prepares 1-(ethyl-Leu-Pro-OBzl)-β-carboline-3-benzyl carboxylate 4 (b)
According to the method for embodiment 6, obtaining the titled and thing of 120mg (10%) from 600mg (1.74mol) 1-(2-oxoethyl)-3-carboline carboxylate benzyl ester (4) and 783mg (2.61mmol) Leu-Pro-OBzl, is pale yellow powder.ESI
+-MS(m/e)：663[M+H]
+；Mp∶93-94.5℃；
1H-NMR(300MHz，CDCl
3)：δ/ppm＝8.69(s，1H)，8.13(d，J＝8.1Hz，1H)，7.49-7.56(m，4H)，7.17-7.44(m，7H)，7.1(m，1H)，5.50(s，2H)，5.18(m，2H)，4.68(m，1H)，3.59(m，4H)，3.25(m，1H)，3.08(m，1H)，2.23(m，1H)，2.02(m，4H)，1.62(m，2H)，1.27(m，1H)，1.05(d，J＝18Hz，3H)，0.90(d，J＝15Hz，3H).
13C-NMR(75MHz，CDCl
3)：δ/ppm＝171.43，169.96，165.59，142.84，141.02，136.41，136.04，135.84，134.73，131.81，128.61，128.36，128.15，127.94，127.53，121.45，121.24，120.35，116.51，112.64，67.94，67.02，59.26，58.78，57.64，47.14，45.68，40.62，28.91，24.84，24.61，23.55，23.05。
Experimental example 1 measures compound 4a, and b is to the restraining effect of tumor cell proliferation
1) compound 4a, the b of the present invention substratum containing 0.1%DMSO is mixed with desired concn.
2) tumour cell of experiment is HepG
2(human liver cell cancer cells), HL60 (human promyelocytic leukemia), Bel-7402 (human liver cancer cell), HT-29 (human colon cancer cell), HeLa (human cervical carcinoma cell), A549 (human lung carcinoma cell), S180 (mouse ascites oncocyte) and HCCLM3 (people's height transfer liver cancer cell).
3) experimental technique HL-60, HT-29, Bel-7402, A549 and S180 cell selects RPMI-1640 substratum; HepG
2, HeLa and HCCLM3 cell selects DMEM substratum.In substratum all containing 10% through the foetal calf serum and 1 × 10 of deactivation
5u/L penicillin and 100mg/L Streptomycin sulphate.
Attached cell HepG2, the cultivation of HT-29, Bel-7402, A549, HeLa, HCCLM3 and half attached cell S180: respectively that growth conditions is good, is in the cell of logarithmic phase with 3 × 10
4the density of individual/mL is inoculated in 96 orifice plates, and every hole 100 μ L, is placed in 37 DEG C and 5%CO
2cell incubation case in cultivate 4 hours, then add compound 5a-c through sterilising treatment and the solution be mixed with containing the substratum of 0.1%DMSO by the concentration gradient preset, every hole 25 μ L, control group adds the solvent of isopyknic sample dissolution.Continue cultivation after 48 hours, every hole adds the MTT solution that 25 μ L concentration are 5mg/mL, is placed in 37 DEG C and 5%CO
2cell incubation case in cultivate 4 hours.After careful removing supernatant liquor, every hole adds the DMSO of 100 μ L, and about 10min dissolve purple of vibrating residue (first a ceremonial jade-ladle, used in libation), detects O.D. (absorbancy) value immediately in microplate reader, and wavelength is 570nm.
The cultivation of suspension cell HL60: respectively that growth conditions is good, is in the cell of logarithmic phase with 5 × 10
4the density of individual/mL is inoculated in 96 orifice plates, every hole 100 μ L, then adds by the concentration gradient preset the solution that the compound 5 through sterilising treatment is mixed with the substratum containing 0.1%DMSO, every hole 25 μ L, control group adds the solvent of isopyknic sample dissolution, is placed in 37 DEG C and 5%CO
2cell incubation case in cultivate 48 hours.Every hole adds the MTT solution that 25 μ L concentration are 5mg/mL, and continuing the condition that is placed in is 37 DEG C and 5%CO
2cell incubation case in cultivate 4 hours.The centrifugal 10min of 2500rpm, careful sucking-off supernatant liquor, every hole adds 100 μ LDMSO, and about 10min dissolve purple of vibrating residue (first a ceremonial jade-ladle, used in libation), detects O.D. (absorbancy) value immediately in microplate reader, and wavelength is 570nm.
The activity of compound 5 inhibition tumor cell propagation under each concentration is obtained by following formula:
Cell proliferation (%)=(the average O.D. value of compound 4a, b group average O.D. value/control group) × 100%, experiment repetition 3 times, maps to drug level with cell proliferation, obtains IC by graphing method
50(half effective inhibition concentration) value.
4) the results are shown in Table 1.Result shows, in vitro in cytotoxicity test, compound 4a only has clear and definite restraining effect to HL60 and S180 tumor cell proliferation, and compound 4b is then to Bel-7402, HepG
2, HL60, HT-29, HeLa, S180, A549 and HCCLM3 etc. 8 strain tumor cell proliferation all show clear and definite restraining effect.
Table 1 compound 4a, the IC of b inhibition tumor cell propagation
50(mean value ± SD μM)
Experimental example 2 assessing compound 4a, b reverse the activity of MCF-7/ADR resistance
Compound 4a, b are all mixed with desired concn with the PBS containing 1%DMSO.MCF-7/ADR cell, adopts the RPMI-1640 substratum containing 10% foetal calf serum, at 37 DEG C, CO
2volume fraction is cultivate in the incubator of the saturated humidity of 5%, for maintaining its resistance, adds the ADR of 1mg/L in Secondary Culture process in substratum, tests withdrawal in first 3 days.
By growth conditions, the good and reagent removal MCF-7 cell being in logarithmic phase is with 5 × 10
4the density of individual/mL is inoculated in 96 orifice plates, every hole 100 μ L.37 DEG C, hatch 4 hours in 5%CO2 incubator, add test-compound through ultraviolet sterilization and ADR by the concentration gradient preset, control group adds equal-volume solvent.After continuing to hatch 48 hours, every hole adds the MTT solution that 25 μ L concentration are 5mg/mL, after continuing to hatch 4 hours, careful sucking-off supernatant liquor, every hole adds 100 μ LDMSO dissolve purple residues (first a ceremonial jade-ladle, used in libation), Oscillating Flat makes precipitation all dissolve in 10 minutes, measures OD value (absorbancy), wavelength 570nm in 570nm microplate reader.Inhibiting rate is calculated according to inhibiting rate=1-[(RPMI-1640 group mean OD value-4a, b group mean OD value)/RPMI-1640 group mean OD value] × 100%.Each compound repeats 3 times, with inhibiting rate to the mapping of compound 4a, b concentration, obtains IC
50value.
Zorubicin is to the reversal index of MCF-7/ADR cell as table 2 under 1 μM of concentration for compound 4a, b, and the reversal index of compound 4a and 4b to MCF-7/ADR mdr cell is respectively 3.72 and 5.09, effectively can reverse the resistance of MCF-7/ADR to Zorubicin.
Table 2 compound under 1 μM of concentration Zorubicin to the restraining effect of the cell proliferation of MCF-7/ADR
The anti-tumor in vivo of experimental example 3 assessing compound 4a, b is active
1) compound 4a, b 0.5% Xylo-Mucine of the present invention is mixed with suspension.Positive control Zorubicin is mixed with 2 μm of ol/kg normal saline solutions, and positive control cytosine arabinoside is mixed with 8.2 μm of ol/kg normal saline solutions.
2) compound 4a, b gastric infusion, dosage is 1 μm of ol/kg, successive administration 7 days, altogether administration 7 times; Zorubicin abdominal injection, dosage is 2 μm of ol/kg, successive administration 7 days, altogether administration 7 times; Cytosine arabinoside abdominal injection, dosage is 8.2 μm of ol/kg, administration 7 days in continuous 7 days, altogether administration 7 times; 0.5% sodium carboxymethyl cellulose solution gastric infusion, dosage is 0.2mL/20g, continuous 7 days.
3) laboratory animal is ICR male mice (cleaning grade), body weight 20 ± 2g, often organizes 12 mouse.
4) knurl source is mouse S 180 sarcoma, purchased from Department Of Medicine, Peking University's animal experimental center, and maintenance of going down to posterity voluntarily.
5) extract and inoculate eugonic S180 ascitic tumor knurl liquid under animal model and treatment aseptic condition, the liquid of (1: 2) is become fully to mix with normal saline dilution, by freshly prepared 0.2% Trypan Blue of tumor cell suspension, by white blood cell count(WBC) method counting after mixing, contaminate blue person for dead cell, tinter is not viable cell, and is calculated as follows cell concn and cell survival rate.
Viable count/4 × 10 in the block plaid of cell concn=4
4× extension rate=cell count/mL
Cell survival rate=viable count/(viable count+dead cell number) × 100%
Knurl liquid homogenate method survival rate being greater than 90% is prepared into 2.0 × 10
7the cell suspension of individual/mL, in the subcutaneous vaccination of mouse armpit, 0.2mL/ only, manufactures S180 tumor-bearing mice.After tumor inoculation 24h, each group mouse is treated according to dosage above and administration condition every day.Experiment proceeds to the 8th day, claim Mouse Weight, etherization, de-cervical vertebra puts to death mouse, then fixes the right armpit tumor location of mouse with tweezers, cuts off skin, expose tumour, blunt separation, weighs, and is calculated as follows tumour inhibiting rate: the average knurl of tumour inhibiting rate %=(negative control group average knurl weight-administration group average knurl weight)/negative control group heavy × 100%.Experimental data adopts t inspection and variance analysis, and knurl is heavy to be represented with mean value ± SDg.The results are shown in Table 3.As can be seen from Table 3, under the oral dosage of 1 μm of ol/kg, compound 4a, the knurl of b treatment group mouse is heavily significantly less than the knurl weight of 0.5% sodium carboxymethyl cellulose solution treatment group mouse, illustrates that the effective dose of 1-(ethyl-AA-OBzl)-β-carboline-3-benzyl carboxylate 8.9 μm of ol/kg that their effective dose is delivered than contriver is low 8.9 times.Under the oral dosage of 1 μm of ol/kg, the knurl heavy phase that the cytosine arabinoside that the knurl of compound 4a treatment group mouse is heavy is 8.2 μm of ol/kg with dosage treats mouse is worked as, and illustrates that its effective dose is lower than the effective dose of cytosine arabinoside 8.2 times.Under the oral dosage of 1 μm of ol/kg, the heavy knurl heavy phase being the doxorubicin mouse of 2 μm of ol/kg with dosage of knurl of compound 4b treatment group mouse is worked as, and illustrates that its effective dose is lower than the effective dose of Zorubicin 2 times.
Table 3 compound 4a, b are on the impact (mean value ± SDg) of S180 tumor weight
N=12; A) with 0.5% carboxymethyl cellulose group than p < 0.01, with cytosine arabinoside group than p > 0.05; B) with 0.5% carboxymethyl cellulose group and cytosine arabinoside group than p < 0.01, with Zorubicin group than p > 0.05.
Experimental example 4 measures compound 4a, the transmission electron microscope photo of b
By compound 4a, b is according to 5 × 10
-6the pure water solution of the concentration configuration compound of M, is layered on uniformly on copper mesh, observes the self-assembly property of compound under transmission electron microscope (TEM, JEM-1230, JEOL).Obtain the photo as Fig. 2.Result shows, compound 4a, b all can form nano particle in water, and nanometer particle size diameter is between 35-124nm.
Claims (5)
1. 1-(ethyl-Leu-AA-OBzl)-β-carboline-3-benzyl carboxylate of structure below, AA is L-Glu and L-Pro residue.
2. the preparation method of 1-(ethyl-Leu-AA-OBzl)-β-carboline-3-benzyl carboxylate (AA is L-Glu and L-Pro residue) of claim 1, the method comprises:
1) L-Trp benzyl ester under trifluoroacetic catalysis with the condensation of 1,1,3,3-tetramethoxy propane, obtain (3S)-1-(2,2-dimethoxy ethyl)-2,3,4,9-tetrahydro-beta-carboline-3-benzyl carboxylate;
2) by (3S)-1-(2,2-dimethoxy ethyl)-2,3,4,9-tetrahydro-beta-carboline-3-benzyl carboxylate potassium permanganate oxidation, 1-(2,2-dimethoxy ethyl)-3-carboline carboxylate benzyl ester is generated;
3) at hydrochloric acid, in Glacial acetic acid and aqueous systems, 1-(2,2-dimethoxy ethyl)-3-β-carboline-3-benzyl carboxylate is converted into 1-(2-oxoethyl)-3-carboline carboxylate benzyl ester;
4) Boc-Leu and L-Glu-OBzl and L-Pro-OBzl coupling are obtained Boc-Leu-Glu-OBzl and Boc-Leu-Pro-OBzl;
5) in hydrogenchloride-ethyl acetate solution, Boc-Leu-Glu-OBzl and Boc-Leu-Pro-OBzl is converted into Leu-Glu-OBzl and Leu-Pro-OBzl;
6) 1-(2-oxoethyl)-3-carboline carboxylate benzyl ester is obtained 1-(ethyl-Leu-AA-OBzl)-β-carboline-3-benzyl carboxylate (AA is L-Glu and L-Pro residue) respectively with Leu-Glu-OBzl and Leu-Pro-OBzl coupling.
3. the nanostructure of 1-(ethyl-Leu-AA-OBzl)-β-carboline-3-benzyl carboxylate of claim 1.
4. 1-(ethyl-Leu-AA-OBzl)-β-carboline-3-benzyl carboxylate of claim 1 is preparing the application in antitumor drug.
5. 1-(ethyl-Leu-AA-OBzl)-β-carboline-3-benzyl carboxylate of claim 1 is preparing the application in reversing tumor medicine.
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