CN105294824A - 1-(ethyl amino acid benzyl ester)-beta-carboline-3-carboxyilc acid benzyl ester, nanostructure, preparation, activity and application - Google Patents
1-(ethyl amino acid benzyl ester)-beta-carboline-3-carboxyilc acid benzyl ester, nanostructure, preparation, activity and application Download PDFInfo
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- CN105294824A CN105294824A CN201410259504.5A CN201410259504A CN105294824A CN 105294824 A CN105294824 A CN 105294824A CN 201410259504 A CN201410259504 A CN 201410259504A CN 105294824 A CN105294824 A CN 105294824A
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Abstract
The present invention discloses 1-(ethyl-Val-Glu (OBzl)-OBzl)-beta-carboline-3-carboxyilc acid benzyl ester, a preparation method therefor, a nanostructure thereof, and activity thereof in inhibiting tumor cell proliferation, and further discloses activity thereof in inhibiting tumor growth of S180 mice, and an effect thereof in inversing tumor cell drug resistant, and elucidates an application thereof in preparing anti-tumor drugs.
Description
Technical field
The present invention relates to 1-(ethyl-Val-Glu (OBzl)-OBzl)-β-carboline-3-benzyl carboxylate and preparation method thereof, relate to the activity of its inhibition tumor cell propagation, relate to its restraining effect to mice bearing S180 tumor growth, relate to the effect of its reversing tumor cells resistance further.Thus the present invention relates to it and prepare the application in antitumor drug.The invention belongs to biomedicine field.
Technical background
In recent years, in view of global cancer morbidity and mortality ratio sharply rise, cancer has become a world problem.Cancer patients's number of China is in prostatitis, the world, and cancer patients's number constantly increases, and also constantly increases the demand of antitumour drug.There is many limitation in the antitumor drug of current clinical application, along with progress and the reach of science of science and technology, finding anti-cancer agent is safely and effectively one of focus of drug research.
Cancer is one group of common name that can affect the various diseases at any position of health.Other term used is malignant tumour and vegetation.According to World Health Organization's statistics, cancer is one of No.1 cause of the death in the world, especially in developing country.And whole world number of cancer deaths estimates continuation to rise, will more than 1,310 ten thousand to the year two thousand thirty.Therefore, develop new efficient, low toxicity, the antitumor drug that toxic side effect is little is one of important topic of new drug research always.
Along with the understanding to tumor characteristic and morbidity essence, recent years, antitumor drug was constantly from traditional cell toxicity medicament to the transition of development non-cytotoxic drugs.β-carboline is the cytotoxic anti-tumor compound of natural origin.Contriver recognizes, β-carboline antitumoral cytotoxic essence is the intercalation between DNA of tumor cell.The cuttage of this form can cause cytotoxicity.Contriver once found, β-carboline can insert between the duplex base between DNA of tumor cell.In further studying, contriver recognizes, the anti-tumor activity of β-carboline is from intercalation.Contriver also recognizes, introduces dipeptides generate the effect that β-carboline-3-benzyl carboxylate and derivative can strengthen β-carboline and tumour cell, enhancing anti-tumor activity at 1 of β-carboline.According to these understanding, contriver proposes 1-(ethyl-Val-Glu (OBzl)-OBzl)-β-carboline-3-benzyl carboxylate.Compared with invention 1-(ethyl-AA-OBzl)-β-carboline-3-benzyl carboxylate in contriver's early stage, outstanding creativeness of the present invention is, remains the intercalation between β-carboline and DNA of tumor cell, under low dosage, show high anti-tumor activity.So 1-(ethyl-Val-Glu (OBzl)-OBzl)-β-carboline-3-benzyl carboxylate shows good inhibition tumor cell proliferation function and anti-tumor activity.
the content of invention
First content of the present invention is to provide 1-(ethyl-Val-Glu (the OBzl)-OBzl)-β-carboline-3-benzyl carboxylate of following formula.
Second content of the present invention is to provide the preparation method of 1-(ethyl-Val-Glu (OBzl)-OBzl)-β-carboline-3-benzyl carboxylate, and the method comprises:
(1) L-Trp benzyl ester is carried out Pictet-Spengler condensation with 1,1,3,3-tetramethoxy propane under trifluoroacetic catalysis, obtain 1-(2,2-dimethoxy ethyl)-1,2,3,4-tetrahydro-beta-carboline-3-benzyl carboxylate;
(2) by 1-(2,2-dimethoxy ethyl)-1,2,3,4-tetrahydro-beta-carboline-3-benzyl carboxylate in tetrahydrofuran (THF), with potassium permanganate solution oxidation obtain 1-(2,2-dimethoxy ethyl)-β-carboline 3-benzyl carboxylate;
(3) in Glacial acetic acid, concentrated hydrochloric acid, mixed solution, 1-(2,2-dimethoxy ethyl)-β-carboline 3-benzyl carboxylate is hydrolyzed to 1-aldehyde-base-β-carboline 3-benzyl carboxylate;
(4) 1-aldehyde-base-β-carboline 3-benzyl carboxylate and HClVal-Glu (OBzl)-OBzl coupling are obtained 1-(ethyl-Val-Glu (OBzl)-OBzl)-β-carboline-3-benzyl carboxylate.
3rd content of the present invention evaluates the effect of 1-(ethyl-Val-Glu (OBzl)-OBzl)-β-carboline-3-benzyl carboxylate inhibition tumor cell propagation.
4th content of the present invention evaluates the effect of 1-(ethyl-Val-Glu (OBzl)-OBzl)-β-carboline-3-benzyl carboxylate suppression S180 mice with tumor tumor growth.
5th content of the present invention is the effect measuring 1-(ethyl-Val-Glu (OBzl)-OBzl)-β-carboline-3-benzyl carboxylate reversing tumor cells resistance.
6th content of the present invention sets forth the nanostructure of 1-(ethyl-Val-Glu (OBzl)-OBzl)-β-carboline-3-benzyl carboxylate.
Accompanying drawing explanation
The synthetic route .i of Figure 11-(ethyl-Val-Glu (OBzl)-OBzl)-β-carboline-3-benzyl carboxylate) polyphosphoric acid, phenylcarbinol; Ii) trifluoracetic acid, 1,1,3,3-tetramethoxy propane; Iii) potassium permanganate, tetrahydrofuran (THF), water; Iv) molten concentrated hydrochloric acid, Glacial acetic acid, water; V) N-methylmorpholine, anhydrous magnesium sulfate, sodium cyanoborohydride, Val-Glu (OBzl)-OBzl.
Figure 21-(ethyl-Val-Glu (OBzl)-OBzl)-β-carboline-3-benzyl carboxylate is in pH7.4 environment, and concentration is 6 × 10
-7transmission electron microscope photo under M concentration.
Embodiment
In order to set forth the present invention further, providing some row embodiments 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 1-(2,2-dimethoxy ethyl)-1,2,3,4-tetrahydro-beta-carboline-3-benzyl carboxylate
First by the saturated NaHCO of 5gL-tryptophan benzyl ester
3the aqueous solution is washed, use 70mL extraction into ethyl acetate, coextraction 3 times, ester saturated nacl aqueous solution is washed till neutrality, anhydrous sodium sulfate drying, be filtered in the round-bottomed flask of 250mL, filtrate reduced in volume is to doing to obtain 4g colorless solid. in the round-bottomed flask of 100mL, first by 4mL1, 1, 3, 3-tetramethoxy propane is dissolved in 40mL dichloromethane solvent, add 4mL trifluoracetic acid again, activation 45min, under ice bath, the 4g colorless solid just obtained is joined in reaction flask. react 52 hours, TLC (sherwood oil/acetone=4/1) shows reaction to be completed, use saturated NaHCO
3acid in aqueous solution neutralization reaction liquid, then 70mL dichloromethane extraction is used, coextraction 3 times. dichloromethane layer saturated sodium-chloride water solution is washed till neutrality, methylene dichloride uses anhydrous sodium sulfate drying mutually, filter, filtrate reduced in volume, residue silica gel wet method column chromatography purification, obtaining 3.5g (51%) title compound, is yellow oil .ESI-MS (m/e) 395 [M+H]
+.
Embodiment 2 prepares 1-(2,2-dimethoxy ethyl)-β-carboline 3-benzyl carboxylate
By 5g (12.7mmol) 1-(2, 2-dimethoxy ethyl)-1, 2, 3, 4-tetrahydro-beta-carboline-3-benzyl carboxylate, join in the eggplant bottle of 250mL with 150mL tetrahydrofuran (THF), ice bath stirs, add the aqueous solution of 5g (31.6mmol) potassium permanganate in batches, room temperature reaction 5 hours, TLC (sherwood oil/acetone=4/1) shows reaction to be completed, filter, and add tetrahydrofuran (THF) flush cake, filtrate reduced in volume, again by remaining aqueous phase 70mL dichloromethane extraction, extract 3 times altogether, the methylene dichloride phase merged, with saturated common salt water washing 3 times, anhydrous sodium sulfate drying, filter, filtrate reduced in volume, residue silica gel wet method column chromatography purification, 3g (60%) title compound is obtained again with sherwood oil-acetone recrystallization, for colorless solid .ESI/MS (m/e) 391 [M+H]
+.
Embodiment 3 prepares 1-aldehyde-base-β-carboline 3-benzyl carboxylate
First add 72mL Glacial acetic acid and make 344mg (1mmol) 1-(2,2-dimethoxy ethyl)-β-carboline 3-benzyl carboxylate dissolves completely, add 9mL concentrated hydrochloric acid and 9mL water more successively. stir 4h, TLC shows raw material spot and disappears, compound of reaction adds a large amount of mixture of ice and water, stirs and a large amount of solid is separated out, filter and use 90mL frozen water flush cake. collect filter cake, abundant drying, gets single step reaction ready and uses.
Embodiment 4 prepares 1-(ethyl-Val-Glu (OBzl)-OBzl)-β-carboline-3-benzyl carboxylate (5)
Under ice bath, N-methylmorpholine regulator solution pH value to 8 is dripped in the solution of 550mg (1.2mmol) HClVal-Glu (OBzl)-OBzl and 20ml anhydrous tetrahydro furan, the suspension of 344mg (1mmol) 1-aldehyde-base-β-carboline-3-benzyl carboxylate and 20mL methylene dichloride is added in solution, stir and add 200mg anhydrous magnesium sulfate after 10 minutes and stir 15 minutes. in reaction mixture, add 63mg (1mmol) sodium cyanoborohydride, stirring at room temperature 11h.TLC (CHCl
3/ MeOH=27/1) show reaction and complete. reaction mixture filters, and filtrate reduced in volume, residuum adds saturated NaHCO
3aqueous dissolution, the solution 50ml acetic acid ethyl fluid extraction obtained, coextraction 3 times. ethyl acetate layer saturated nacl aqueous solution is washed till neutrality, the ethyl acetate of collecting uses anhydrous sodium sulfate drying mutually, filter, filtrate reduced in volume, through silica gel column chromatography (methylene chloride/methanol=50/1) and Preparative TLC chromatography (methylene chloride/methanol=22/1) purifying after the syrup obtained is first, obtaining 94mg (12.5%) title compound, is pale yellow oil .ESI-MS (m/e) 755.9 [M ± H]
+,
iR (KBr): 3346.50,3078.39,3039.81,2960.73,2872.01,1865.17,1826.59,1718.58,1701.22,1680.00,1653.00,1624.06,1560.41,1458.18,1425.40,1375.25,1340.53,1282.66,1253.73,1213.23,1155.36,1136.07,1001.06,985.62,831.32,785.03,746.45,742.59,731.02,719.45,698.23cm
-1,
1hNMR (300MHz, CDCl
3) δ/ppm:10.43 (s, 1H), 8.77 (s, 1H), 8.16 (d, J=9.0Hz, 1H), 7.92 (d, J=9.0Hz, 1H), 7.59 ~ 7.48 (m, 4H), 7.56 ~ 7.25 (m, 13H), 5.52 (s, 2H), 5.30 (d, J=12.0Hz, 1H), 5.21 (d, J=12.0Hz, 1H), 5.10 (m, 2H), 4.83 (m, 1H), 3.52 (m, 1H), 3.36 (m, 1H), 3.13 (d, J=9.0Hz, 1H), 3.10 (d, J=6.0Hz, 1H), 2.98 (m, 1H), 2.46 (m, 2H), 2.26 (m, 2H), 2.08 (m, 3H), 1.01 (d, J=9.0Hz, 3H), 0.97 (d, J=6.0Hz, 3H).
Experimental example 1 measures the restraining effect of compound 5 pairs of tumor cell proliferations
1) substratum of compound 5 of the present invention containing 0.1%DMSO is mixed with desired concn.
2) tumour cell of experiment is HL-60 (human promyelocytic leukemia), A549 (lung carcinoma cell), Bel7402 (liver cancer cell), SH-sy5y (human neuroblastoma), S180 (mouse ascites oncocyte), MCF-7 (human breast cancer cell).
3) experimental technique HL-60, MCF-7, Bel-7402, A549 and S180 cell selects RPMI-1640 substratum; SH-sy5y 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 MCF-7, the cultivation of Bel-7402, A549, SH-sy5y and half attached cell S180: respectively that growth conditions is good, is in the cell of logarithmic phase with 4 × 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 6 hours, then add 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. 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 centrifugal 10min of .3000rpm, careful sucking-off supernatant liquor, every hole adds 100 μ LDMSO, about 10min dissolve purple of vibrating residue (first a ceremonial jade-ladle, used in libation), in microplate reader, detect O.D. (absorbancy) value immediately, 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 5 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 and table 2.Result shows, compound 5 pairs of HL-60, MCF-7, Bel-7402, A549, S180 and SH-sy5y tumor cell proliferations are without obvious cytotoxicity.
The IC of table 1 compound 5 inhibition tumor cell propagation
50(mean value ± SD μM)
Experimental example 2 assessing compound 5 suppresses the activity of S180 mice tumors grew
1) compound 5 0.5% Xylo-Mucine of the present invention is mixed with suspension. and 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. and feminine gender is 0.5% sodium carboxymethyl cellulose solution.
2) compound 5 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 1.5 × 10
7the cell suspension of individual/mL, in the subcutaneous vaccination of mouse armpit, 0.2mL/ only, manufacture S180 tumor-bearing mice. after tumor inoculation 24h, each group of mouse is treated according to dosage above and administration condition every day. and experiment proceeds to the 8th day, claim Mouse Weight, etherization, de-cervical vertebra puts to death mouse, then the right armpit tumor location of mouse is fixed with tweezers, cut off skin, expose tumour, blunt separation, weigh, be calculated as follows tumour inhibiting rate: heavy × 100%. experimental datas of the average knurl of tumour inhibiting rate %=(the average knurl of negative control group heavy-the average knurl weight of compound 5 groups)/negative control group adopt t inspection and variance analyses, 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 5 treatment group mouse is heavily significantly less than the knurl weight of 0.5% sodium carboxymethyl cellulose solution treatment group mouse, illustrates that it has outstanding anti-tumor activity.The effective dose (8.9 μm of ol/kg) of 1-(ethyl-AA-OBzl)-β-carboline-3-benzyl carboxylate that its this effective dose (1 μm of ol/kg) is delivered than contriver is low 8.9 times.
Table 3 compound 5 is on the impact (mean value ± SDg) of mice bearing S180 tumor weight
N=12; A) with 0.5% sodium carboxymethyl cellulose solution than P < 0.05, compare P > 0.05 with cytosine arabinoside and Zorubicin group.
The effect of experimental example 3 compound 5 reversing tumor cells resistance
Survey the IC of compound 5 pairs of MCF-7/ADR cells
50value: the substratum of MCF-7/ADR cell will add the Zorubicin that concentration is 1mg/L. must reagent removal process be carried out in kind of plate last generation: namely inhale and abandon supernatant, use 1mL trysinization, 37 DEG C and 5%CO
2hatch 3 minutes in incubator, add 5mL, do not add in the substratum of Zorubicin and serum, 3000r/min, centrifugal 3min, supernatant discarded, add not containing the substratum Secondary Culture of Zorubicin after .3 days by MCF-7/ADR cell good for growth conditions by 1 × 10
5the density of individual/mL is inoculated in 96 orifice plates, and every hole 100 μ L. is placed in 37 DEG C, 5%CO
2cultivating in incubator treats adherent in 6 hours. then add by the concentration gradient preset the solution that the compound 5 through sterilising treatment is mixed with the substratum containing 0.1%DMSO, every 25 μ L, control group adds the solvent of isopyknic sample dissolution. and positive controls is verapamil (10 μMs), every hole 25 μ L, parallel 5 holes. at 37 DEG C, 5%CO
2cultivate 48 hours in incubator, every hole adds the MTT solution that 25 μ L concentration are 5mg/mL, continues to be placed in 37 DEG C, 5%CO
2cultivate 4 hours in incubator. 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 O.D. value (absorbancy), wavelength 570nm in 570nm microplate reader.
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 5 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.
Test parallel repetition 3 times, the IC of compound 5
50be greater than 100 μMs.
Survey Zorubicin to the IC of MCF-7/ADR cell
50value: method is the same, and Zorubicin is to the IC of MCF-7/ADR
50value: 28.94 ± 9.08 μMs.
The IC50 value of Zorubicin to MCF-7 sensitive strain can be obtained: 0.50 ± 0.33 μM from experimental example 1.
Reversing drug resistance multiple=IC
50(MCF-7/ADR)/IC
50(MCF-7).
So the resistance multiple of Zorubicin to MCF-7/ADR is 57.88.
Survey compound 5 and reverse the drug-resistant effect of Zorubicin to MCF-7/ADR cell: by aforesaid operations method, MCF-7/ADR cell is inoculated in 96 orifice plates, every hole 100 μ L. is placed in 37 DEG C, 5%CO
2cultivating in incubator treats adherent in 6 hours. every for compound 5 of the present invention hole is added 12.5 μ L, its final concentration is made to be 10 μMs, the Zorubicin of 5 gradient concentrations be mixed with containing the substratum of 0.1%DMSO through sterilising treatment is added by the concentration gradient preset, every hole 12.5 μ L after 2 hours; Blank group adds isopyknic RPMI-1640, every hole 25 μ L; Positive controls is verapamil group (10 μMs), every hole 25 μ L, all parallel 5 holes of all given the test agent. at 37 DEG C, 5%CO
2cultivate 48 hours in incubator, every hole adds the MTT solution that 25 μ L concentration are 5mg/mL, continues to be placed in 37 DEG C, 5%CO
2to cultivate 4 hours in incubator. careful sucking-off supernatant liquor, every hole adds 100 μ LDMSO dissolve purple residues (first a ceremonial jade-ladle, used in libation), and Oscillating Flat makes precipitation all dissolve in 10 minutes, measures O.D. value (absorbancy), wavelength 570nm in microplate reader.
Calculate as stated above compound 5 exist under Zorubicin to the IC of MCF-7/ADR cell
50, i.e. IC
50(compound+ADR), be used alone the IC of Zorubicin to MCF-7/ADR cell
50, i.e. IC
50(ADR); Calculate its reversing drug resistance multiple, reversing drug resistance multiple=IC
50(ADR)/IC
50(compound+ADR).
The IC of compound 5 couples of MCF-7/ADR
50all be greater than 100 μMs, but Zorubicin can be made under the concentration of 10 μMs to the IC of MCF-7/ADR cell
50value is 5.19 ± 3.50 μMs, reduces 5.58 times, shows the trend of certain reversing drug resistance.
Experimental example 6 measures the transmission electron microscope photo of compound 5
By compound 5 according to 6 × 10
-7the pH7.4PBS solution of the concentration configuration compound of M, be layered on uniformly on copper mesh, at transmission electron microscope (TEM, JEM-1230, JEOL) self-assembly property of compound is observed under. obtain the photo as Fig. 2. result shows, compound 5 can form nano particle in pH7.4PBS solution, and nanometer particle size diameter is between 71-214nm.
Claims (4)
1. 1-(ethyl-Val-Glu (the OBzl)-OBzl)-β-carboline-3-benzyl carboxylate of following formula.
2. the preparation method of 1-(ethyl-Val-Glu (the OBzl)-OBzl)-β-carboline-3-benzyl carboxylate of claim 1, the method comprises:
(1) L-Trp benzyl ester is carried out Pictet-Spengler condensation with 1,1,3,3-tetramethoxy propane under trifluoroacetic catalysis, obtain 1-(2,2-dimethoxy ethyl)-1,2,3,4-tetrahydro-beta-carboline-3-benzyl carboxylate;
(2) by 1-(2,2-dimethoxy ethyl)-1,2,3,4-tetrahydro-beta-carboline-3-benzyl carboxylate in tetrahydrofuran (THF), with potassium permanganate solution oxidation obtain 1-(2,2-dimethoxy ethyl)-β-carboline 3-benzyl carboxylate;
(3) in Glacial acetic acid, concentrated hydrochloric acid, mixed solution, 1-(2,2-dimethoxy ethyl)-β-carboline 3-benzyl carboxylate is hydrolyzed to 1-aldehyde-base-β-carboline 3-benzyl carboxylate;
(4) 1-aldehyde-base-β-carboline-3-benzyl carboxylate and HClVal-Glu (OBzl)-OBzl coupling are obtained 1-(ethyl-Val-Glu (OBzl)-OBzl)-β-carboline-3-benzyl carboxylate.
3. the nanostructure of 1-(ethyl-Val-Glu (the OBzl)-OBzl)-β-carboline-3-benzyl carboxylate of claim 1.
4. 1-(ethyl-Val-Glu (the OBzl)-OBzl)-β-carboline-3-benzyl carboxylate of claim 1 is preparing the application in antitumor drug.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101906102A (en) * | 2009-06-02 | 2010-12-08 | 首都医科大学 | Beta-carboline alkaloid derivative, preparation method and application thereof |
| CN102241675A (en) * | 2010-05-14 | 2011-11-16 | 首都医科大学 | (1R,3S)-1-(4-hydroxyl-3-methoxycarboxyl)-1,2,3,4-tetrahydro-beta-carboline-3-formyl amino acid derivatives as well as preparation method and application thereof |
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2014
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101906102A (en) * | 2009-06-02 | 2010-12-08 | 首都医科大学 | Beta-carboline alkaloid derivative, preparation method and application thereof |
| CN102241675A (en) * | 2010-05-14 | 2011-11-16 | 首都医科大学 | (1R,3S)-1-(4-hydroxyl-3-methoxycarboxyl)-1,2,3,4-tetrahydro-beta-carboline-3-formyl amino acid derivatives as well as preparation method and application thereof |
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