CN105218623A - 1-(ethylamino acid benzyl ester)-β-carboline-3-benzyl carboxylate, nanostructure, preparation, active and application - Google Patents
1-(ethylamino acid benzyl ester)-β-carboline-3-benzyl carboxylate, nanostructure, preparation, active and application Download PDFInfo
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Abstract
The invention discloses 1-(ethyl-Val-Tyr-OBzl)-β-carboline-3-benzyl carboxylate, disclose its preparation method, disclose its nanostructure, disclose the activity of its inhibition tumor cell propagation, further disclose the activity that it suppresses S180 mice tumors grew, disclose the effect of it and DNA, illustrate it and preparing the application in antitumor drug.
Description
Technical field
The present invention relates to 1-(ethyl-Val-Tyr-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 further, relate to its DNA intercalation ability, thus the present invention relates to it preparing 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. and cancer patients's number of China is in prostatitis, the world, cancer patients's number constantly increases, the demand of antitumour drug is also constantly increased. there is many limitation in the antitumor drug of clinical application at present, 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 of use is malignant tumour and vegetation. and adds up according to the World Health Organization, 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. and β-carboline is the cytotoxic anti-tumor compound of natural origin. and contriver recognizes, β-carboline antitumoral cytotoxic essence is the intercalation between DNA of tumor cell. and the cuttage of this form can cause cytotoxicity. and 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. and contriver also recognizes, introduce dipeptides at 1 of β-carboline and generate the effect that β-carboline-3-benzyl carboxylate and derivative can strengthen β-carboline and tumour cell, strengthen anti-tumor activity. according to these understanding, contriver proposes 1-(ethyl-Val-Tyr-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, remain the intercalation between β-carboline and DNA of tumor cell, high anti-tumor activity is shown under low dosage, show 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-Tyr-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-Tyr-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 l-(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 HCl.Val-Tyr-OBzl coupling are obtained 1-(ethyl-Val-Tyr-OBzl)-β-carboline-3-benzyl carboxylate.
3rd content of the present invention evaluates the effect of 1-(ethyl-Val-Tyr-OBzl)-β-carboline-3-benzyl carboxylate inhibition tumor cell propagation.
4th content of the present invention evaluates the effect of 1-(ethyl-Val-Tyr-OBzl)-β-carboline-3-benzyl carboxylate suppression S180 mice with tumor tumor growth.
5th content of the present invention is the intercalation measuring 1-(ethyl-Val-Tyr-OBzl)-β-carboline-3-benzyl carboxylate and CT-DNA.
6th content of the present invention is the nanostructure measuring 1-(ethyl-Val-Tyr-OBzl)-β-carboline-3-benzyl carboxylate.
Accompanying drawing explanation
The synthetic route chart .i of Fig. 1 compound 1-(ethyl-Val-Tyr-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-Tyr-OBzl.
The viscosity B coefficent .DNA (100 μMs) of Fig. 2 compound 5 and CT-DNA effect, the final concentration of 5 is followed successively by 10, and 20,30,40,50,60,70,80,90,100 μMs.
The UV spectrum .DNA (200 μMs) of intercalation between Fig. 3 compound 5 and CT-DNA, 5 final concentrations are followed successively by 2, and 10,20,30,40,50 μMs.
The fluorescence spectrum of intercalation between Fig. 4 compound 5 and CT-DNA, the Raw fluorescence spectrum of 5 (20 μMs), adds the DNA that 20 μ L concentration are 605 μMs at every turn.
It is 200 μMs that the circular double dispersion of intercalation between Fig. 5 compound 5 and CT-DNA composes .DNA concentration, and the final concentration of compound 5 is followed successively by 0,50,100, and 200 μMs.
Fig. 6 compound 5 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, is filtered in the round-bottomed flask of 250mL, is spin-dried for obtain 4g white 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, joins above-mentioned 4g white solid in reaction flask. reacts 52 hours, TLC (PE/Actone=4/1) shows reaction to be completed, and uses saturated NaHCO
3acid in aqueous solution neutralization reaction system, then 70mL dichloromethane extraction is used, coextraction 3 times, then be washed till neutrality with saturated nacl aqueous solution, methylene dichloride uses anhydrous sodium sulfate drying mutually, filter, removal of solvent under reduced pressure, adds silica gel mixed sample after filtrate reduced in volume, is evaporated to dry rear 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 the THF of about 150mL, ice bath stirs, add the aqueous solution of potassium permanganate 5g (31.6mmol) in batches, room temperature reaction 5 hours, TLC (PE/Actone=4/1) shows reaction to be completed, filter, and add tetrahydrofuran (THF) flush cake, filtrate reduced in volume removing THF, again by remaining aqueous phase 70mL dichloromethane extraction, extract 3 times altogether, merge ester phase, with saturated common salt water washing 3 times, anhydrous sodium sulfate drying, filter, decompression and solvent recovery, silica gel mixed sample is added after filtrate reduced in volume, be evaporated to after doing and obtain product with silica gel wet method column chromatography purification, the developping agent 5: 1 of sherwood oil-acetone system is adopted to collect product. adopt the method for sherwood oil-acetone or acetone-diethyl ether recrystallization to obtain sterling 3g (60%) fluffy white solid .ESI/MS (m/e) 391 [M+H] again
+.
Embodiment 3 prepares 1-aldehyde-base-β-carboline 3-benzyl carboxylate
First adding Glacial acetic acid 72mL makes 344mg (1mmol) raw material dissolve completely, add 9mL concentrated hydrochloric acid and 9mL water .TLC monitoring raw material spot disappearance aftertreatment reaction more successively, add a large amount of mixture of ice and water to stir, a large amount of solid filters after separating out, and by 90mL frozen water flush cake. collect filter cake, abundant drying, uses in order to next step reaction.
Embodiment 4 prepares 1-(ethyl-Val-Tyr-OBzl)-β-carboline-3-benzyl carboxylate (5)
Under ice bath, N-methylmorpholine regulator solution pH value to 8 is dripped in the solution of 488mg (1.2mmol) HClVal-Tyr-OBzl and 20ml anhydrous tetrahydro furan, the suspension of 344mg (1mmol) 1-aldehyde-base-β-carboline 3-benzyl carboxylate 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 14h, TLC (CHCl
3/ MeOH=24/1) 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 121mg (17%) title compound, is pale yellow oil .ESI-MS (m/e) 699.9 [M+H]
+,
iR (KBr): 3329.14,3066.82,3028.24,2960.73,2933.73,2881.65,1830.45,1797.66,1743.65,1724.36,1654.92,1680.00,1597.06,1498.69,1348.24,1301.95,1247.94,1213.23,1174.65,1155.36,1134.14,1105.21,1078.21,1028.06,1012.63,966.34,950.91,896.90,788.89,746.45,738.74,698.23,680.87cm
-1,
1hNMR (300MHz, CDCl
3) δ/ppm:10.96 (brs, 1H), 8.76 (s, 1H), 8.15 (d, J=9.0Hz, 1H), 7.54 ~ 7.42 (m, 4H), 7.42 ~ 7.30 (m, 11H), 6.95 (m, 1H), 6.88 (d, J=9.0Hz, 2H), 6.67 (d, J=9.0Hz, 2H), 5.36 (s, 2H), 5.27 (d, J=12.0Hz, 1H), 5.17 (d, J=12.0Hz, 1H), 4.99 (m, 1H), 3.18 (m, 1H), 3.09 (m, 1H), 3.00 (m, 1H), 2.82 (m, 1H), 2.68 (d, J=6.0Hz, 1H), 2.55 (m, 1H), 2.43 (m, 1H), 1.94 (m, 1H), 0.96 (d, J=12.0Hz, 3H), 0.87 (d, J=12.0Hz, 3H).
Experimental example 1 measures the restraining effect of compound 5 pairs of tumor cell proliferations
1) substratum of compound 5 containing 0.1%DMSO is mixed with desired concn.
2) tumour cell of experiment is HL-60 (human promyelocytic leukemia), A549 (lung carcinoma cell), Be17402 (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 show, in vitro in cytotoxicity test, compound 5 couples of HL-60, MCF-7, Bel-7402, A549 and S180 and SH-sy5y tumor cell proliferation all show clear and definite restraining effect.
The IC of table 1 compound 5 inhibition tumor cell propagation
50(mean value ± SD μM)
The IC of table 2 compound 5 inhibition tumor cell propagation
50(mean value ± SD μM)
The anti-tumor in vivo of experimental example 2 assessing compound 5 is active
1) compound 5 0.5% Xylo-Mucine of the present invention is mixed with suspension, dosage is that 1 μm of ol/kg. positive control Zorubicin is mixed with normal saline solution, dosage is that 2 μm of ol/kg. positive control cytosine arabinosides are mixed with normal saline solution, and dosage is 8.2 μm of ol/kg. feminine genders is 0.5% sodium carboxymethyl cellulose solution.
2) compound 5 gastric infusion, dosage is 1 μm of ol/kg, successive administration 7 days, administration 7 times altogether. 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 .0.5% sodium carboxymethyl cellulose solution gastric infusions, dosage is 0.2mL/20g, continuous 7 days, administration 7 times altogether.
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 effective antitumour activity. and the effective dose (8.9 μm of ol/kg) of 1-(ethyl-AA-OBzl)-β-carboline-3-benzyl carboxylate that its 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 group than P < 0.01.
Experimental example 3 viscosimetry measures the intercalation of compound 5 and CT-DNA
Ubbeholde viscometer is placed in 37 DEG C of water-baths, the viscosity (parallel three times) of test PBS, as T
0, then measuring the viscosity of CT-DNA (100 μMs) solution, sample size is that 10mL. gets 10 μ L compounds 5 (concentration is 10mM), namely in sample, the final concentration of compound 5 is 10 μMs. piping and druming mixing mensuration gets average three times, and cumulative l0 μ L is in sample liquid successively later, and namely in sample, the final concentration of compound 5 is followed successively by 20 μMs, 30 μMs, 40 μMs, 50 μMs, 60 μMs, 70 μMs, 80 μMs, 90 μMs, 100 μMs. η=(t-t
0)/t
0, wherein t
0for PBS is through the time needed for kapillary, t is for the CT-DNA solution containing medicine is through the time needed for kapillary. with (η/η
0)
1/3to combining ratio C
5/ C
cT-DNAthe viscosity B coefficent of mapping .CT-DNA is shown in Fig. 2. result shows that the viscosity of CT-DNA solution increases thereupon along with compound 5 concentration increases, and the trend increased reduces gradually, illustrates that cuttage occurs for compound 5 and CT-DNA.
The intercalation of experimental example 4 spectrographic determination compound 5 and CT-DNA
In order to confirm the intercalation between 5 and DNA of tumor cell, selection CT-DNA is model, with the intercalation of UV spectrum, fluorescence spectrum and circular double dispersion profiling 5 with CT-DNA.
1) with the intercalation of UV profiling 5 with CT-DNA
Adopt fixed dna concentration, in DNA solution, the method for cumulative compound 5 detects its UV spectrum variation tendency .DNA concentration 200 μMs, survey its UV spectrum, wavelength is 240nm ~ 330nm, compound 5 is added in DNA solution successively, its final concentration is made to be followed successively by 2, 10, 20, 30, 40, 50 μMs. show that 7 wavelength are the ultraviolet spectrogram of 240nm ~ 330nm altogether. the DNA solution maximum absorption peak intensity after compound 5 acts on obviously declines, and maximum absorption band generation slight red shift, see Fig. 3, this meets Long, what EC etc. proposed utilizes spectroscopic method confirmation small molecules and DNA that the phenomenon of intercalation occurs, and this spectrogram presents certain concentration-dependent relation. hypochromic effect is the result of DNA conformational change, illustrate to there is intercalation between compound 5 and DNA.
2) intercalation of 5 and CT-DNA is described with fluorescence spectrum
Pipetting 2mL concentration is that the compound 5 of 20 μMs is placed in quartz cuvette, fixed drug concentration determination fluorescence spectrum. in cuvette, successively add 20 μ L concentration is that the CT-DNA solution of 605 μMs (adds 20 μ L at every turn, therefore think and keep test system constancy of volume, namely system concentration keeps constant), (final concentration of CT-DNA is respectively 0 to measure fluorescence quenching spectrum, 6, 12, 18, 24, 30 μMs). fluorescent emission and excite slit to be respectively 5nm, 2.5nm, fixing excitation wavelength 270nm, sweep velocity is 1500nm/min, emmission spectrum scope 320 ~ 500nm, measuring under 37 DEG C of conditions. the fluorescence spectrum figure obtained is shown in Fig. 4.Result shows, compound 5 is fluorescent substance, and along with constantly adding CT-DNA, fluorescence intensity reduces gradually, visible, and DNA has fluorescence quenching to compound 5, illustrates that compound 5 and CT-DNA there occurs cuttage.
3) with the intercalation of circular double dispersion profiling 5 with CT-DNA
DNA concentration is 200 μMs, the final concentration of compound 5 is followed successively by 0,50,100,200 μMs, be mixed with 1mL, hatch 3h for 37 DEG C, measure its circular double dispersion (CD) spectrum, adopt the sample pool of 0.1cm to add 600 μ L samples in experiment, the results are shown in Figure 5. parameters as follows: sweep velocity 500nmmin
-1s, resolving power 0.2nm, sweep limit 200 ~ 350nm, sensitivity 50mdeg, time of response 0.5s, frequency span 15nm, stacking degree 5.
The stacking effect of base and the Conformation of the DNA after compound 5 acts on change to some extent, illustrate to there is intercalation between compound 5 and DNA.
Experimental example 5 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, is layered on uniformly on copper mesh, observes the self-assembly property of compound, obtain the photo as Fig. 6 under transmission electron microscope (TEM, JEM-1230, JEOL).Result shows, compound 5 can form nano particle in pH7.4PBS solution, and nanometer particle size is between 36-143nm.
Claims (4)
1. 1-(ethyl-Val-Tyr-OBzl)-β-carboline-3-benzyl carboxylate of following formula.
2. the preparation method of 1-(ethyl-Val-Tyr-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-Tyr-OBzl coupling are obtained 1-(ethyl-Val-Tyr-OBzl)-β-carboline-3-benzyl carboxylate.
3. the nanostructure of 1-(ethyl-Val-Tyr-OBzl)-β-carboline-3-benzyl carboxylate of claim 1.
4. 1-(ethyl-Val-Tyr-OBzl)-β-carboline-3-benzyl carboxylate of claim 1 is preparing the application in antitumor drug.
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Application publication date: 20160106 |