CN105218624A - 1-(ethylamino acid benzyl ester)-β-carboline-3-benzyl carboxylate, preparation, nanostructure, active and application - Google Patents
1-(ethylamino acid benzyl ester)-β-carboline-3-benzyl carboxylate, preparation, nanostructure, active and application Download PDFInfo
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- CN105218624A CN105218624A CN201410271581.2A CN201410271581A CN105218624A CN 105218624 A CN105218624 A CN 105218624A CN 201410271581 A CN201410271581 A CN 201410271581A CN 105218624 A CN105218624 A CN 105218624A
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Abstract
The invention discloses 1-(ethyl-Leu-Phe-OBzl)-β-carboline-3-benzyl carboxylate of following formula.Disclose its preparation method, disclose its nanostructure, disclose its inhibit activities to tumor cell proliferation, disclose the activity that it suppresses S180 mice tumors grew, further disclose its interaction as a class intercalation agent and DNA, thus the present invention illustrates it in preparation is application in the antitumor drug of target spot with DNA.
Description
Invention field
The present invention relates to 1-(N-ethyl-Leu-Phe-OBzl)-β-carboline-3-benzyl carboxylate, relate to its preparation method, relate to their nanostructure, relate to their inhibit activities to tumor cell proliferation, relate to the activity that it suppresses S180 mice tumors grew, relate to it as intercalation agent and the interactional result of DNA.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.
the content of invention
First content of the present invention is to provide 1-(N-ethyl-Leu-Phe-OBzl)-β-carboline-3-benzyl carboxylate.
Second content of the present invention is to provide the preparation method of formula 1-(N-ethyl-Leu-Phe-OBzl)-β-carboline-3-benzyl carboxylate, and 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-Phe-OBzl coupling is obtained Boc-Leu-Phe-OBzl;
5) in hydrogenchloride-ethyl acetate solution, Boc-Leu-Phe-OBzl is converted into Leu-Phe-OBzl;
6) 1-(2-oxoethyl)-3-carboline carboxylate benzyl ester and Leu-Phe-OBzl coupling are obtained 1-(ethyl-Leu-Phe-OBzl)-β-carboline-3-benzyl carboxylate.
3rd content of the present invention is the nanostructure measuring 1-(ethyl-Leu-Phe-OBzl)-β-carboline-3-benzyl carboxylate.
4th content of the present invention evaluates 1-(ethyl-Leu-Phe-OBzl)-β-carboline-3-benzyl carboxylate to Bel7402, HepG with mtt assay
2, HeLa, SH-Sy5y, MCF-7, S180 and HL60 seven restraining effect of strain cell proliferation.
5th content of the present invention evaluates 1-(ethyl-Leu-Phe-OBzl)-β-carboline-3-benzyl carboxylate to the restraining effect of the tumor growth of mice bearing S180.
6th content of the present invention evaluates the interaction of 1-(ethyl-Leu-Phe-OBzl)-β-carboline-3-benzyl carboxylate and CT-DNA.
Accompanying drawing explanation
The synthetic route .i of Figure 11-(ethyl-Leu-Phe-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
3cNandH-L-Phe-OBzl.
The UV spectrum of Figure 21-(ethyl-Leu-Phe-OBzl)-β-carboline-3-benzyl carboxylate and CT-DNA effect changes.
The fluorescence spectrum of Figure 31-(ethyl-Leu-Phe-OBzl)-β-carboline-3-benzyl carboxylate and CT-DNA effect changes.
The CD spectrogram of Figure 41-(ethyl-Leu-Phe-OBzl)-β-carboline-3-benzyl carboxylate and CT-DNA effect changes.
The viscosity profile of Figure 51-(ethyl-Leu-Phe-OBzl)-β-carboline-3-benzyl carboxylate and CT-DNA effect.
Figure 61-(ethyl-Leu-Phe-OBzl)-β-carboline-3-benzyl carboxylate is in pure water environment 5 × 10
-6transmission electron microscope photo under M concentration.
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-Phe-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.The 3mmolPhe-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-Phe-OBzl
Be dissolved in by 2mmolBoc-Leu-Phe-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.Be evaporated to dry, 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-(N-ethyl-Leu-Phe-OBzl)-β-carboline-3-benzyl carboxylate (4)
By 956mg (2.61mmol) HClLeu-Phe-OBzl, 28.8mgNaOH solid is dissolved in 30ml methyl alcohol, activate after 10 minutes and add 600mg (1.74mol) 1-(2-oxoethyl)-β-carboline-3-benzyl carboxylate, after 30min, add 54mgNaBH
3cN and appropriate anhydrous MgSO
4, react after 12 hours, TLC thin plate monitoring reaction has newly puts generation, and reaction solution is evaporated to dry, acetic acid ethyl dissolution, saturated NaHCO
3(50ml × 3) extraction is washed, and saturated NaCl (50ml × 3) extraction is washed, anhydrous Na SO
4drying, filter, organic phase is evaporated to dry, and through purification by silica gel column chromatography, (methylene dichloride: methyl alcohol=80: 1), obtain the titled and thing of 200mg (16%), be faint yellow oily to product.ESI
+-MS(m/e)：697[M+H]
+；Mp：178-179℃；
；
1H-NMR(300MHz，CDCl
3)：δ/ppm＝11.45(s，1H)，8.74(s，1H)，8.46(d，J＝7.8Hz，1H)，8.33(s，1H)，8.01(d，J＝7.8Hz，1H)，7.39-7.56(m，7H)，7.10-7.30(m，10H)，5.45(s，2H)，5.08(m，3H)，3.73(m，1H)，3.56(m，1H)，3.40(m，1H)，3.23(m，3H)，3.03(m，1H)，2.10(s，1H)，1.75(m，2H)，1.47(m，1H)，0.91(d，J＝6.6Hz，2H)，0.85(d，J＝6.6Hz，2H).
13C-NMR(75MHz，CDCl
3)：δ/ppm＝171.47，165.54，142.41，141.01，136.21，136.06，135.48，134.78，128.88，128.66，128.62，128.58，128.55，128.50，128.46，128.43，128.12，127.88，121.38，120.60，116.41，112.52，67.26，67.05，61.27，53.21，45.32，40.89，37.36，24.71，22.89，21.75。
Experimental example 1 experimental example 1 measures the restraining effect of compound 4 pairs of tumor cell proliferations
1) substratum of compound 4a of the present invention 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 by the concentration gradient preset the solution that the compound 4 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.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 4 groups 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.Inhibiting rate is calculated according to inhibiting rate=1-[(RPMI-1640 group mean OD value-4 group mean OD value)/RPMI-1640 group mean OD value] × 100%.Each compound repeats 3 times, maps, obtain IC with inhibiting rate to 4 concentration
50value.
Result shows, compound 4 only has selective active to HL60, IC
50it is 4.43 μMs.
The IC of table 1 compound 4 inhibition tumor cell propagation
50(mean value ± SD μM)
The anti-tumor in vivo of experimental example 2 assessing compound 4 is active
1) compound 4 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 4 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, the knurl of compound 4 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 4 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 2 compound 4 is on the impact (mean value ± SDg) of S180 tumor weight
N=12; A) with 0.5% carboxymethyl cellulose group than p < 0.01, with Zorubicin group and cytosine arabinoside group than p > 0.05.
The interaction of experimental example 3 assessing compound 4 and DNA
Getting 1ml concentration is 5.0 × 10
-7the compound 4 of M is placed in cuvette, measures UV spectrum.In cuvette, successively add 10 μ L concentration is 3.0 × 10
-4the CT-DNA solution of M (add 10 μ L at every turn, therefore think and keep test system constancy of volume, namely system concentration keeps constant), after 5min, (final concentration of CT-DNA is 0 to measure the UV spectrum of mixed solution, 0.2,0.4,0.6,0.8,1.0,1.2,1.4,1.6 μMs).Fig. 2 is shown in compound 4 is combined front and back UV spectrum change with CT-DNA.As seen from Figure 2, DNA and 4 acts on later absorption peak and increases generation hypochromic effect, and peak shape peak position keeps substantially.Exist between the change explanation 4 of UV spectrum and DNA and interact.
Getting 2mL concentration is 5.0 × 10
-7the compound 4 of M is placed in quartz cuvette, measures fluorescence spectrum.In cuvette, successively add concentration is 3.0 × 10
-4mCT-DNA solution (add 10 μ L at every turn, therefore think and keep test system constancy of volume, namely system concentration keeps constant), after 5min, (final concentration of CT-DNA is 0 to measure fluorescence quenching spectrum, 0.3,0.6,0.9,1.2,1.5,1.8,2.1,2.4 μMs).Fluorescent emission and excite slit to be respectively 5nm, 5nm, fixing excitation wavelength 275nm, sweep velocity is 1500nm/min, emmission spectrum scope 300 ~ 500nm, 37 DEG C of mensuration.As seen from Figure 3, along with adding of CT-DNA, 4 produce quenching of fluorescence, and peak shape and peak position there occurs change.The change of fluorescence spectrum alternatively exists between bright 4 and DNA and interacts.
Test fluid 1 is the solution of CT-DNA, and concentration is 8 × 10
-4m.Test fluid 2 be testing compound 4 and CT-DNA etc. mole mixed solution, its concentration is 8 × 10
-4m.Compound 4 and CT-DNA mixed solution empirically require to prepare in advance, and mixing, hatches 24 hours in 37 DEG C, measure and record the CT-DNA within the scope of 190nm-750nm, the circular dichroism of compound 4 and CT-DNA mixed solution under room temperature.As seen from Figure 4, after 4 Interaction with DNAs, the CD spectrum posivtive spike of DNA and the molar ellipticity θ value of negative peak reduce, and amplitude weakens; And posivtive spike red shift; Negative peak blue shift.Visible, exist between compound 4 and DNA and interact.
Ubbeholde viscometer is placed in 37 DEG C of water-baths.With PBS (volume is for 12mL) for blank, measure flowing time, in triplicate.Pipette 12mL10
-4the CT-DNA solution of M is placed in viscometer, after 5min, measures flowing time, in triplicate.In viscometer, successively add concentration is 10
-3compound 4 solution of M (add 130 μ L at every turn, therefore think and keep test system constancy of volume, namely system concentration keeps constant), after 5min, (final concentration of compound 4 is 10 to measure the flowing time of mixed solution, 20,30,40,50,60,70,80 μMs, in triplicate.By formula η=(t-t
0)/t
0calculate relative viscosity, t in formula
0for damping fluid PBS flows through the time needed for kapillary, t is for CT-DNA solution (title complex containing concentration does not wait) is through the time needed for kapillary.With (η/η
0)
1/3to combining ratio C
5k/ C
cT-DNAmapping.η
0for not adding the relative viscosity of the DNA solution of title complex.As seen from Figure 5, CT-DNA viscosity after acting on compound 4 constantly increases, and shows that compound 4 intercalation can enter the base pair of DNA.
Experimental example 4 measures the transmission electron microscope photo of compound 4
By compound 4 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 as Fig. 6 photo.Structure shows, 4 all can form nano particle in water, and diameter is between 91-173nm.
Claims (4)
1. 1-(ethyl-Leu-Phe-OBzl)-β-carboline-3-benzyl carboxylate of structure below.
2. the preparation method of 1-(ethyl-Leu-Phe-OBzl)-β-carboline-3-benzyl carboxylate 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-Phe-OBzl coupling is obtained Boc-Leu-Phe-OBzl;
5) in hydrogenchloride-ethyl acetate solution, Boc-Leu-Phe-OBzl is converted into Leu-Phe-OBzl;
6) 1-(2-oxoethyl)-3-carboline carboxylate benzyl ester and Leu-Phe-OBzl coupling are obtained 1-(ethyl-Leu-Phe-OBzl)-β-carboline-3-benzyl carboxylate.
3. the nanostructure of 1-(ethyl-Leu-Phe-OBzl)-β-carboline-3-benzyl carboxylate of claim 1.
4. 1-(ethyl-Leu-Phe-OBzl)-β-carboline-3-benzyl carboxylate of claim 1 is preparing the application in antitumor drug.
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| CN103159828A (en) * | 2011-12-14 | 2013-06-19 | 首都医科大学 | 1-(4-hydroxy-3-methoxycarbonyl)-beta-carboline-3-formyl tryptophyl amino acid benzyl ester, and synthesis and application thereof |
| CN103539838A (en) * | 2012-07-15 | 2014-01-29 | 彭莉 | 1-methyl-tetrahydro-beta-carbolinyl-3-formyl RGD peptides, and synthesis, nano structure, antithrombotic action and application thereof |
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