CN105237616A - Amino acid benzyl ester-modified beta-carbolines, activities, nanostructures, synthesis, and applications thereof - Google Patents

Amino acid benzyl ester-modified beta-carbolines, activities, nanostructures, synthesis, and applications thereof Download PDF

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CN105237616A
CN105237616A CN201410260129.6A CN201410260129A CN105237616A CN 105237616 A CN105237616 A CN 105237616A CN 201410260129 A CN201410260129 A CN 201410260129A CN 105237616 A CN105237616 A CN 105237616A
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obzl
asp
residue
carboline
benzyl carboxylate
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彭师奇
赵明
吴建辉
王玉记
姜璐
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Capital Medical University
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Capital Medical University
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Abstract

The invention relates to 15 1-[ethyl-Asp(AA-OBzl)AA-OBzl]-beta-carboline-3-benzyl carboxylates represented by a general formula, wherein AA is used for representing L-Leu residue, L-Phe residue, L-Val residue, L-Ala residue, L-Gly residue, L-Asp (OBzl) residue, L-Glu (OBzl) residue, L-Trp residue, L-Tyr residue, L-Ser residue, L-Thr residue, L-Pro residue, L-Met residue, L-Arg (NO2) residue, L-Asn residue, L-Gln residue, and L-Lys (Fmoc) residue; preparation methods and nanostructures thereof; activities thereof in inhibiting tumor cell proliferation; and tumor cell proliferation inhibition activities thereof in inhibiting S180 solid tumor in mice. It is shown by experiment results that the 1-[ethyl-Asp(AA-OBzl)AA-OBzl]-beta-carboline-3-benzyl carboxylates possess excellent antitumor activity and a promising clinical application prospect.

Description

The β-carboline that amino-acid benzyl ester is modified, active, nanostructure, synthesis and application
Technical field
The present invention relates to that 15 kinds of 1-[ethyl-Asp (AA-OBzl) AA-OBzl]-(in formula, AA is L-Leu residue to β-carboline-3-benzyl carboxylate, L-Phe residue, L-Val residue, L-Ala residue, L-Gly residue, L-Asp (OBzl) residue, L-Glu (OBzl) residue, L-Trp residue, L-Tyr residue, L-Ser residue, L-Thr residue, L-Pro residue, L-Met residue, L-Arg (NO 2) residue, L-Asn residue, L-Gln residue and L-Lys (Fmoc) residue), relate to their preparation method, relate to their nanostructure, relate to the activity of their inhibition tumor cell propagation, relate to the tumour increment inhibit activities of their suppression S180 solid tumors in Mice Body further.Experimental result shows, compound of the present invention has excellent anti-tumor activity.There is good potential applicability in clinical practice.The invention belongs to biomedicine field.
Background technology
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-Asp (AA-OBzl) AA-OBzl]-β-carboline-3-benzyl carboxylate of following formula.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-Asp (AA-OBzl) AA-OBzl]-β-carboline-3-benzyl carboxylate shows good inhibition tumor cell proliferation function and anti-tumor activity.
Summary of the invention
First content of the present invention is to provide 15 kinds of 1-[ethyl-Asp (AA-OBzl) AA-OBzl]-β-carboline-3-benzyl carboxylate of following formula, and in general formula, AA is L-Leu residue, L-Phe residue, L-Val residue, L-Ala residue, L-Gly residue, L-Asp (OBzl) residue, L-Glu (OBzl) residue, L-Trp residue, L-Tyr residue, L-Ser residue, L-Thr residue, L-Pro residue, L-Met residue, L-Arg (NO 2) residue, L-Asn residue, L-Gln residue, L-Lys (Fmoc) residue.
Second content of the present invention is to provide the method for preparation 15 kinds of 1-[ethyl-Asp (AA-OBzl) AA-OBzl]-β-carboline-3-benzyl carboxylate, and the method is made up of following steps:
1) there is Pictet-Spengler condensation in Trp-OBzl and 1,1,3,3-tetramethoxy propane under trifluoracetic acid (TFA) exists, generate 3S-1-(2,2-dimethoxy-ethyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] Indole-3-Carboxylic Acid benzyl ester;
2) in the mixing solutions of tetrahydrofuran (THF) (THF) with water, 3S-1-(2,2-dimethoxy-ethyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] Indole-3-Carboxylic Acid benzyl ester is 1-(2 by potassium permanganate oxidation, 2-dimethoxy-ethyl)-1H-pyrido [3,4-b] Indole-3-Carboxylic Acid benzyl ester;
3), at acetic acid, in the mixing solutions of water and hydrochloric acid, 1-(2,2-dimethoxy-ethyl)-1H-pyrido [3,4-b] Indole-3-Carboxylic Acid benzyl Ester hydrolysis obtains 1-aldehyde-base-β-carboline-3-benzyl carboxylate;
4) under dicyclohexylcarbodiimide (DCC) and N-hydroxy benzo triazole (HOBt) exist, Boc-Asp is that (AA is L-Leu residue to Boc-Asp (AA-OBzl) AA-OBzl with AA-OBzl condensation in anhydrous tetrahydro furan (THF), L-Phe residue, L-Val residue, L-Ala residue, L-Gly residue, L-Asp (OBzl) residue, L-Glu (OBzl) residue, L-Trp residue, L-Tyr residue, L-Ser residue, L-Thr residue, L-Pro residue, L-Met residue, L-Arg (NO 2) residue, L-Asn residue, L-Gln residue and L-Lys (Fmoc) residue);
5) in the ethyl acetate solution of hydrogenchloride, Boc-Asp (AA-OBzl)-AA-OBzl is removed Boc and obtain Asp (AA-OBzl)-AA-OBzl;
6) in THF solution, 1-aldehyde-base-β-carboline-3-benzyl carboxylate and Asp (Gly-OBzl)-Gly-OBzl are 1-[ethyl-Asp (Gly-OBzl) Gly-OBzl]-β-carboline-3-benzyl carboxylate by sodium cyanoborohydride reduction amination;
7) in THF solution, 1-aldehyde-base-β-carboline-3-benzyl carboxylate and Asp (Phe-OBzl)-Phe-OBzl are 1-[ethyl-Asp (Phe-OBzl) Phe-OBzl]-β-carboline-3-benzyl carboxylate by sodium cyanoborohydride reduction amination;
8) in THF solution, 1-aldehyde-base-β-carboline-3-benzyl carboxylate and Asp (Val-OBzl) Val-OBzl are 1-[ethyl-Asp (Val-OBzl) Val-OBzl]-β-carboline-3-benzyl carboxylate by sodium cyanoborohydride reduction amination;
9) in THF solution, 1-aldehyde-base-β-carboline-3-benzyl carboxylate and Asp (Leu-OBzl)-Leu-OBzl are 1-[ethyl-Asp (Leu-OBzl) Leu-OBzl]-β-carboline-3-benzyl carboxylate by sodium cyanoborohydride reduction amination;
10) in THF solution, 1-aldehyde-base-β-carboline-3-benzyl carboxylate and Asp (Ile-OBzl)-Ile-OBzl are 1-[ethyl-Asp (Ile-OBzl) Ile-OBzl]-β-carboline-3-benzyl carboxylate by sodium cyanoborohydride reduction amination;
11) in THF solution, 1-aldehyde-base-β-carboline-3-benzyl carboxylate and Asp (Trp-OBzl) Trp-OBzl are 1-[ethyl-Asp (Trp-OBzl) Trp-OBzl]-β-carboline-3-benzyl carboxylate by sodium cyanoborohydride reduction amination;
12) in THF solution, 1-aldehyde-base-β-carboline-3-benzyl carboxylate and Asp (Thr-OBzl) Thr-OBzl are 1-[ethyl-Asp (Thr-OBzl) Thr-OBzl]-β-carboline-3-benzyl carboxylate by sodium cyanoborohydride reduction amination;
13) in THF solution, 1-aldehyde-base-β-carboline-3-benzyl carboxylate and Asp (Ser-OBzl) Ser-OBzl are 1-[ethyl-Asp (Ser-OBzl) Ser-OBzl]-β-carboline-3-benzyl carboxylate by sodium cyanoborohydride reduction amination;
14) in THF solution, 1-aldehyde-base-β-carboline-3-benzyl carboxylate and Asp (Tyr-OBzl) Tyr-OBzl are 1-[ethyl-Asp (Tyr-OBzl) Tyr-OBzl]-β-carboline-3-benzyl carboxylate by sodium cyanoborohydride reduction amination;
15) in THF solution, 1-aldehyde-base-β-carboline-3-benzyl carboxylate and Asp [Lys (Fmoc)-OBzl]-Lys (Fmoc)-OBzl are 1-[ethyl-Asp [Lys (Fmoc)-OBzl]-Lys (Fmoc)-OBzl]-β-carboline-3-benzyl carboxylate by sodium cyanoborohydride reduction amination;
16) in THF solution, 1-aldehyde-base-β-carboline-3-benzyl carboxylate and Asp [Asp (OBzl) OBzl]-Asp (OBzl)-OBzl are 1-[ethyl-Asp [Asp (OBzl) OBzl] Asp (OBzl)-OBzl]-β-carboline-3-benzyl carboxylate by sodium cyanoborohydride reduction amination;
17) in THF solution, 1-aldehyde-base-β-carboline-3-benzyl carboxylate and Asp [Glu (OBzl) OBzl]-Glu (OBzl)-OBzl are 1-[ethyl-Asp [Glu (OBzl) OBzl] Glu (OBzl)-OBzl]-β-carboline-3-benzyl carboxylate by sodium cyanoborohydride reduction amination;
18) in THF solution, 1-aldehyde-base-β-carboline-3-benzyl carboxylate and Asp (Pro-OBzl) Pro-OBzl are 1-[ethyl-Asp (Pro-OBzl) Pro-OBzl]-β-carboline-3-benzyl carboxylate by sodium cyanoborohydride reduction amination;
19) in THF solution, 1-aldehyde-base-β-carboline-3-benzyl carboxylate and Asp [Arg (NO 2)-OBzl]-Arg (NO 2)-OBzl is reduced to 1-[ethyl-Asp [Arg (NO by sodium cyanoborohydride ammonification 2)-OBzl]-Arg (NO 2)-OBzl]-β-carboline-3-benzyl carboxylate;
20) in THF solution, 1-aldehyde-base-β-carboline-3-benzyl carboxylate and Asp (Met-OBzl)-Met-OBzl are 1-[ethyl-Asp (Met-OBzl) Met-OBzl]-β-carboline-3-benzyl carboxylate by sodium cyanoborohydride reduction amination.
3rd content of the present invention is the nanostructure of mensuration 15 kinds of 1-[ethyl-Asp (AA-OBzl) AA-OBzl]-β-carboline-3-benzyl carboxylate.
4th content of the present invention is the effect of evaluation 15 kinds of 1-[ethyl-Asp (AA-OBzl) AA-OBzl]-β-carboline-3-benzyl carboxylate inhibition tumor cell propagation.
5th content of the present invention is the effect that evaluation 15 kinds of 1-[ethyl-Asp (AA-OBzl) AA-OBzl]-β-carboline-3-benzyl carboxylate suppresses mice bearing S180 tumor growth.
Accompanying drawing explanation
The synthetic route .i of Fig. 1 compound 4a-o) thionyl chloride, phenylcarbinol; Ii) trifluoroacetic acid, 1,1,3,3-tetramethoxy propane, methylene dichloride; Iii) potassium permanganate, tetrahydrofuran (THF) ice bath; Iv) concentrated hydrochloric acid, Glacial acetic acid, water; V) sodium cyanoborohydride, N-methylmorpholine, Asp (AA-OBzl) AA-OBzl.Wherein AA=Arg (NO in 4a 2) AA=Glu (OBzl) residue in residue 4b; AA=Asp (OBzl) residue in 4c; AA=Val residue in 4d; AA=Ile residue in 4e; AA=Leu residue in 4f; AA=Gly residue in 4g; AA=Phe residue in 4h; AA=Met residue in 4i; AA=Trp residue in 4j; AA=Ser residue in 4k; AA=Thr residue in 41; AA=Lys (Fmoc) residue in 4m; AA=Tyr residue in 4n; AA=Pro residue in 4o.
Fig. 2 compound 4a-o is in pure water 1 × 10 -5transmission 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-tetrahydrochysene-1H-pyrido [3,4-b] Indole-3-Carboxylic Acid benzyl ester (1)
5g (15.2mmol) tryptophan benzyl ester is poured in 250mL round-bottomed flask, be dissolved in 50mL methylene dichloride, 5mL1 is added in round-bottomed flask, 1, 3, 3-tetramethoxy propane and 5mL trifluoroacetic acid, room temperature reaction, reaction TLC (sherwood oil/acetone, 4: 1) monitor, after 48h raw material point disappears, pH=7 is regulated with strong aqua, decompression is spin-dried for, residue with ethyl acetate dissolves, ethyl acetate solution saturated sodium bicarbonate solution, saturated nacl aqueous solution, potassium hydrogen sulfate saturated solution is washed, rear ethyl acetate layer is with anhydrous sodium sulfate drying, filter, filtrate is spin-dried for, resistates is through column chromatography (sherwood oil/acetone, 4: 1) purifying obtains 2.8g (47%) title compound is pale yellow oil matter.ESI-MS(m/e)：395[M+H] +。
Embodiment 2 prepares 3S-1-(2,2-dimethoxy-ethyl)-pyrido [3,4-b] Indole-3-Carboxylic Acid benzyl ester (2)
By 3.5g (8.9mmol) 1-(2, 2-dimethoxy-ethyl)-2, 3, 4, 9-tetrahydrochysene-1H-pyrido [3, 4-b] Indole-3-Carboxylic Acid's benzyl ester pours in 250ml round-bottomed flask, be dissolved in 100mL tetrahydrofuran (THF), 2.8g (17.77mmol) potassium permanganate is added under ice bath, reaction 4h, TLC (sherwood oil/acetone, 4: 1) show reaction to complete, reacting liquid filtering, and add THF flush cake, filtrate reduced in volume removing THF, again by remaining aqueous phase 70mL dichloromethane extraction, extract 3 times altogether, the methylene dichloride saturated common salt merged washes 3 times, anhydrous sodium sulfate drying, filter, decompression and solvent recovery, residue over silica gel column chromatography (sherwood oil: acetone, 3: 1) purifying, obtain 1.8mg (51.9%) title compound, for faint yellow solid.ESI-MS(m/e)：391[M+H] +。
Embodiment 3 prepares 1-aldehyde-base-β-carboline-3-benzyl carboxylate (3)
1g (2.56mmol) 3S-1-(2 is added in the round-bottomed flask of 100ml, 2-dimethoxy-ethyl)-pyrido [3,4-b] Indole-3-Carboxylic Acid's benzyl ester, 10ml acetic acid is by it dissolving, add 1.25ml water and 1.25ml hydrochloric acid again, stirring at room temperature 4h, TLC (sherwood oil: acetone, 3: 1) show reaction to complete, in round-bottomed flask, add 100ml mixture of ice and water, filter after stirring 10min under ice bath, filter cake water and 5% sodium bicarbonate aqueous solution, washing, dries, and is applied directly to next step reaction.
Embodiment 4 prepares 1-[ethyl-Asp [Arg (NO 2)-OBzl] Arg (NO 2)-OBzl]-β-carboline-3-benzyl carboxylate (4a)
By 1690mg (2.25mmol) HClAsp [Arg (NO 2)-OBzl] Arg (NO 2)-OBzl tripeptides, 20mL tetrahydrofuran (THF) adds in round-bottomed flask, stir under ice bath, drip the desalination of 2mLN-methylmorpholine, regulate PH to 8, the tetrahydrofuran solution of 500mg (1.45mmol) 1-aldehyde-base-β-carboline-3-benzyl carboxylate has been dissolved in rear dropping, add appropriate anhydrous magnesium sulfate, stirring at room temperature 30min, add 45mg (0.714mmol) sodium cyanoborohydride, stirring at room temperature 24h, TLC plate (methylene chloride/methanol, 30: 1) monitor raw material spot to disappear, stopped reaction.Aftertreatment: reacting liquid filtering, obtain filtrate, filtrate is spin-dried for, dissolve with 150mL methylene dichloride, three times are washed respectively with saturated sodium bicarbonate solution, saturated nacl aqueous solution, potassium hydrogen sulfate saturated solution, washings anhydrous sodium sulfate drying, filter, the thick product of syrupy shape is obtained after filtrate reduced in volume, silica gel column chromatography (methylene chloride/methanol, 50: 1) purifying, recrystallization (methanol/ether), obtaining 20mg (1.32%) title compound is yellow syrup material.Mp121-123℃； (c＝0.21，CH 3OH)；ESI-MS(m/e)：1044[M+H] +。IR(KBr)：3325.3，2931.8，2854.7，1735.9，1716.7，1600.9，1543.1，1500.6，1458.2，1384.9，1346.3，1253.7，1215.2，1176.6，1141.9，732.9，698.2. 1HNMR(DMSO-d 6)δ：12.07(s，1H)，8.81(s，1H)，8.37(m，4H)，7.92(m，4H)，7.68(d，1H，J＝9Hz)，7.58(m，1H)，7.58(m，2H)，7.43-7.22(m，15H)，5.41(s，2H)，5.06(m，4H)，4.30(m，2H)，3.08(m，7H)，2.43(m，2H)，1.72(m，3H)，1.49(m，7H)。
Embodiment 5 prepares 1-[ethyl-Asp (Glu-OBzl) Glu-OBzl]-β-carboline-3-benzyl carboxylate (4b)
According to the method for embodiment 4, obtaining 80mg (5.11%) title compound by 1637mg (2.25mmol) Asp [Glu (OBzl)-OBzl]-Glu (OBzl)-OBzl and 500mg (1.45mmol) 1-aldehyde-base-β-carboline-3-benzyl carboxylate is colorless solid.Mp142-143℃； (c＝0.14，CH 3OH)；ESI-MS(m/e)：1080[M+H] +；IR(KBr)：3298.3，3209.6，3089.9，3066.8，3032.1，2947.2，1732.1，1651.1，1600.9，1543.1，1500.6，1454.3，1381.0，1346.3，1303.9，1249.9，1203.6，1165.0，1138.0，740.7，694.4； 1HNMR(300MHz，CDCl 3)δ/ppm：11.73(s，1H)，8.54(s，1H)，8.00(s，1H)，7.84(d，1H，J＝7.5Hz)，7.32(m，29H)，5.35(dd，2H，J 1＝11.7HzJ 2＝29.1Hz)，5.03(m，8H)，4.59(d，3H)，3.94(s，1H)，3.71(s，2H)，3.56(s，1H)，3.39(d，1H，J＝14.0Hz)，3.01(s，1H)，2.45(s，4H)，2.26(s，2H)，2.09(s，2H)。
Embodiment 6 prepares 1-[ethyl-Asp (Asp-OBzl) Asp-OBzl]-β-carboline-3-benzyl carboxylate (4c)
According to the method for embodiment 4, obtaining 630mg (41.3%) title compound by 1580mg (2.25mmol) .Asp (Asp (OBzl)-OBzl)-Asp (OBzl)-OBzl and 500mg (1.45mmol) 1-aldehyde-base-β-carboline-3-benzyl carboxylate, is colorless solid.Mp134-135℃； (c＝0.22，CH 3OH)；ESI-MS(m/e)：1052[M+H] +；IR(KBr)：3282.8，3297.9，3182.6，3066.8，3035.9，2951.1，1735.9，1662.6，1558.5，1500.6，1454.3，1381.0，1249.9，1215.1，736.8，698.2 1HNMR(300MHz，CDCl 3)δ/ppm：11.80(s，1H)，8.47(d，1H，J＝7.8Hz)，7.93(s，1H)，7.84(d，1H，J＝7.8Hz)，7.46(m，6H)，7.28(m，21H)，7.15(m，3H)，5.37(dd，2H，J 1＝12.3HzJ 2＝34.5Hz)，5.11(s，2H)，5.02(m，4H)，4.98(d，2H，J＝2.7Hz)，4.93(m，2H)，4.45(d，2H，J＝6Hz)，3.98(t，1H)，3.69(m，2H)，3.40(q，2H)，3.01(m，5H)。
Embodiment 7 prepares 1-[ethyl-Asp (Val-OBzl) Val-OBzl]-β-carboline-3-benzyl carboxylate (4d)
According to the method for embodiment 4, obtaining 275mg (22.7%) title compound by 1149mg (2.25mmol) Asp (Val-OBzl)-Val-OBzl and 500mg (1.45mmol) 1-aldehyde-base-β-carboline-3-benzyl carboxylate, is colorless solid.Mp123-125℃； (c＝0.22，CH 3OH)；ESI-MS(m/e)：840[M+H] +；IR(KBr)：3290.6，3201.8，3163.3，2962.7，2873.9，1735.9，1654.9，1543.1，1500.6，1458.2，1377.2，1346.3，1249.9，1207.4，1141.9，748.4，698.3. 1HNMR(300MHz，CDCl 3)δ/ppm：11.80(s，1H)，8.38(d，1H，J＝6.9Hz)，8.01(s，1H)，7.86(d，1H，J＝7.8Hz)，7.46(m，6H)，7.30(t，11H)，7.15(t，2H，J＝7.5Hz)，7.09(s，1H)，5.38(dd，2H，J 1＝12.3Hz，J 2＝42.6Hz)，5.11(m，4H)，4.62(m，2H)，4.50(m，1H)，4.02(s，1H)，3.90(d，1H，J＝16.5Hz)，3.75(s，1H)，3.60(t，2H)，2.94(q，2H)，2.20(t，2H)，0.94(m，12H)。
Embodiment 8 prepares 1-[ethyl-Asp (Ile-OBzl) Ile-OBzl]-β-carboline-3-benzyl carboxylate (4e)
According to the method for embodiment 4, obtaining 150mg (11.9%) title compound by 1212mg (2.25mmol) Asp (Ile-OBzl)-Ile-OBzl and 500mg (1.45mmol) 1-aldehyde-base-β-carboline-3-benzyl carboxylate is yellow solid.Mp92-95℃； (c＝0.18，CH 3OH)；IR(KBr)：3275.1，2962.7，2931.8，2877.8，1732.1，1647.2，1627.9，1500.6，1458.2，1377.2，1346.3，1249.9，1211.3，1141.9，748.4，698.2.ESI-MS(m/e)：868[M+H] +； 1HNMR(300MHz，CDCl 3)δ/ppm：10.55(s，1H)，8.76(s，1H)，8.14(d，1H，J＝7.8Hz)，7.90(d，1H，J＝9.0Hz)，7.55(m，3H)，7.30(t，14H)，7.03(d，1H，J＝8.4Hz)，5.51(s，2H)，5.19(m，4H)，4.63(m，2H)，3.62(q，1H)，3.24(m，3H)，2.67(dd，1H，J 1＝4.2HzJ 2＝15.0Hz)，2.50(m，3H)，1.91(m，2H)，1.33(m，2H)，1.12(m，2H)，0.87(m，12H)。
Embodiment 9 prepares 1-[ethyl-Asp (Leu-OBzl) Leu-OBzl]-β-carboline-3-benzyl carboxylate (4f)
According to the method for embodiment 4, obtaining 160mg (12.8%) title compound by 1212mg (2.25mmol) Asp (Leu-OBzl)-Leu-OBzl and 500mg (1.45mmol) 1-aldehyde-base-β-carboline-3-benzyl carboxylate is colorless solid.Mp132-134℃； (c＝0.27，CH 3OH)；ESI-MS(m/e)：868[M+H] +；IR(KBr)：3325.3，3167.1，2954.9，2954.9，1739.8，1651.1，1597.1，1539.2，1504.5，1454.3，1373.3，1346.3，1195.9，1153.4，740.7，698.2 1HNMR(300MHz，CDCl 3)δ/ppm：10.84(s，1H)，8.76(s，1H)，8.14(d，1H，J＝8.1Hz)，7.79(d，1H，J＝8.4Hz)，7.55(m，4H)，7.30(t，14H)，7.12(d，1H，J＝7.8Hz)，5.51(s，2H)，5.17(m，4H)，4.63(m，2H)，3.63(t，1H)，3.46(m，2H)，3.17(m，2H)，2.67(m，3H)，2.50(m，3H)，1.62(m，6H)，0.89(q，12H)。
Embodiment 10 prepares 1-[ethyl-Asp (Gly-OBzl) Gly-OBzl]-β-carboline-3-benzyl carboxylate (4g)
According to the method for embodiment 4, obtaining 180mg (16.5%) title compound by 960mg (2.25mmol) Asp (Gly-OBzl)-Gly-OBzl and 500mg (1.45mmol) 1-aldehyde-base-β-carboline-3-benzyl carboxylate is colorless solid.Mp178-181℃； (c＝0.14，CH 3OH)；ESI-MS(m/e)：756[M+H] +；IR(KBr)：3282.8，3178.7，3089.9，3062.9，3032.1，2954.9，2704.2，1743.7，1708.9，1647.2，1600.9，1558.5，1543.1，1500.6，1454.3，1435.0，1346.3，1253.7，1203.6，1130.3，1103.3. 1HNMR(300MHz，DMSO-d 6)δ/ppm：12.53(s，1H)，9.75(s，2H)，9.20(t，1H，J＝6.0Hz)，8.88(s，1H)，9.20(t，1H，J＝5.7Hz)，8.40(d，1H，J＝8.1Hz)，7.70(d，1H，J＝8.1Hz)，7.62(t，1H)，7.52(d，2H)，7.52(t，13H)，5.42(s，2H)，5.09(m，4H)，4.45(s，1H)，3.99(m，2H)，3.92(d，2H，J＝5.7Hz)，3.69(m，2H)，3.56(m，3H)，2.96(m，1H)。
Embodiment 11 prepares 1-[ethyl-Asp (Phe-OBzl) Phe-OBzl]-β-carboline-3-benzyl carboxylate (4h)
According to the method for embodiment 4, obtaining 100mg (7.38%) title compound by 1365mg (2.25mmol) Asp (Phe-OBzl)-Phe-OBz and 500mg (1.45mmol) 1-aldehyde-base-β-carboline-3-benzyl carboxylate is colorless solid.Mp89-90℃； (c＝0.14，CH 3OH)；ESI-MS(m/e)：936[M+H] +；IR(KBr)：3275.1，3089.9，3062.9，3032.1，2927.9，1735.9，1654.9，1600.9，1496.8，1454.3，1377.2，1346.3，1211.3，1138.0，744.5，698.2 1HNMR(300MHz，CDCl 3)δ/ppm：10.50(s，1H)，8.67(s，1H)，8.12(d，1H，J＝7.8Hz)，7.80(d，1H，J＝7.5Hz)，7.54(m，4H)，7.32(t，14H)，7.15(m，6H)，7.01(m，6H)，5.48(s，2H)，5.15(m，4H)，4.90(m，2H)，3.60(s，1H)，3.27(s，2H)，3.20(m，1H)，3.04(m，4H)，2.95(m，2H)，2.56(m，1H)。
Embodiment 12 prepares 1-[ethyl-Asp (Met-OBzl) Met-OBzl]-β-carboline-3-benzyl carboxylate (4i)
According to the method for embodiment 4, obtaining 80mg (6.11%) title by 1293mg (2.25mmol) Asp (Phe-OBzl)-Phe-OBz and 500mg (1.45mmol) 1-aldehyde-base-β-carboline-3-benzyl carboxylate, to obtain compound be colorless solid.Mp87-89℃； (c＝0.11，CH 3OH)；ESI-MS(m/e)：904[M+H] +. 1HNMR(CDCl 3)δ：10.60(s，1H)，8.74(s，1H)，8.28(d，1H，J＝7.8Hz)，8.44(d，1H，J＝8.1Hz)，7.59-7.22(m，20H)，5.49(s，2H)，5.14(m，4H)，4.74(m，2H)，3.64(m，1H)，3.40(m，2H)，3.17(t，2H，J＝6.6Hz)，2.79(dd，1H，J 1＝3.2Hz，J 2＝15.0Hz)，2.61(m，2H)，2.45(m，5H)，2.12(m，2H)，1.98(m，6H)。
Embodiment 13 prepares 1-[ethyl-Asp (Trp-OBzl) Trp-OBzl]-β-carboline-3-benzyl carboxylate (4j)
According to the method for embodiment 4, obtaining 40mg (2.72%) title compound by 1541mg (2.25mmol) Asp (Trp-OBzl)-Trp-OBzl and 500mg (1.45mmol) 1-aldehyde-base-β-carboline-3-benzyl carboxylate is colorless solid.Mp152-154℃； (c＝0.12，CH 3OH)；ESI-MS(m/e)：1014[M+H] +。IR(KBr)：3443.0，3417.9，2958.8，2931.8，2835.4，1635.6，1504.5，1446.6，1338.6，1246.0，1064.7，1045.4，783.1，740.7. 1HNMR(CDCl 3)δ：10.01(s，1H)，9.56(s，1H)，9.27(s，1H)，8.83(s，1H)，8.16(m，2H)，7.57-7.51(m，5H)，7.46-7.28(m，16H)，7.14(d，2H，J＝9Hz)，6.96(q，4H，J＝9Hz)，6.86(m，2H)，6.74(s，1H)，5.54(s，2H)，5.19(m，4H)，5.02(q，1H，J＝6Hz)，4.88(q，1H，J＝6Hz)，3.21(m，3H)，2.65(m，3H)，2.42(m，1H)，2.32(s，1H)，2.10(m，3H)。
Embodiment 14 prepares 1-[ethyl-Asp (Ser-OBzl) Ser-OBzl]-β-carboline-3-benzyl carboxylate (4k)
According to the method for embodiment 4, obtaining 80mg (6.78%) title compound by 1095mg (2.25mmol) Asp (Phe-OBzl)-Phe-OBz and 500mg (1.45mmol) 1-aldehyde-base-β-carboline-3-benzyl carboxylate is colorless solid.Mp137-139℃； (c＝0.12，CH 3OH)；ESI-MS(m/e)：816[M+H] +.IR(KBr)：3286.7，3062，9，2920.2，2889.4，2854.7，1732.1，1620.2，1504.5，1454.3，1384.9，1346.3，1249.9，1215.2，1141.9，1141.9，748.4，698.2. 1HNMR(DMSO-d 6)δ：12.69(s，1H)，9.72(s，1H)，9.16(m，1H)，8.88(m，2H)，8.38(m，2H)，7.71-7.34(m，16H)，5.43(s，2H)，5.12(m，6H)，4.42(m，3H)，3.73(m，6H)，3.52(s，1H)，3.37(m，1H)，2.98(s，2H)，2.79(m，1H)。
Embodiment 15 prepares 1-[ethyl-Asp (Thr-OBzl) Thr-OBzl]-β-carboline-3-benzyl carboxylate (4l)
According to the method for embodiment 4, obtaining 40mg (3.31%) title compound by 1145mg (2.25mmol) Asp (Thr-OBzl)-Thr-OBzl and 500mg (1.45mmol) 1-aldehyde-base-β-carboline-3-benzyl carboxylate is colorless solid.Mp142-143℃； (c＝0.14，CH 3OH)；IR(KBr)：3387.0，2924.1，1732.1，1616.4，1539.2，1504.5，1454.3，1377.2，1346.3，1249.9，1215.2，1145.7，1022.3，752.2，698.2.ESI-MS(m/e)：844[M+H] +。 1HNMR(CDCl 3)δ：10.90(s，1H)，8.61(s，1H)，8.05(m，1H)，7.63-6.93(m，20H)，5.42(s，2H)，5.11(m，4H)，4.57(s，2H)，4.27(m，3H)，3.54(m，2H)，3.32(m，1H)，2.94(m，2H)，0.87(m，6H)。
Embodiment 16 prepares 1-[ethyl-Asp (Lys (Fmoc)-OBzl) Lys (Fmoc)-OBzl-ethyl-1-base]-β-carboline-3-benzyl carboxylate (4m)
According to the method for embodiment 4, obtaining 120mg (6.15%) title compound by 2286mg (2.25mmol) Asp (Lys (Fmoc)-OBzl)-Lys (Fmoc)-OBzl and 500mg (1.45mmol) 1-aldehyde-base-β-carboline-3-benzyl carboxylate is yellow powder.Mp121-123℃；ESI-MS(m/e)：1342[M+H] +.IR(KBr)：3309.9，3066.8，3035.9，2927.92858.51732.1，1647.2，1600.9，1543.1，1500.6，1450.5，1377.2，1346.3，1249.9，1180.4，740.7，698.2. 1HNMR(DMSO-d 6)δ：12.10(s，1H)，9.20(m，1H)，8.80(m，1H)，8.34(m，2H)，7.86(m，4H)，7.71-7.19(m，31H)，5.40(s，2H)，5.06(m，4H)，4.26(m，5H)，4.16(m，2H)，3.57(s，2H)，3.27(s，2H)，2.89(m，5H)，2.42(s，1H)，1.63(m，4H)，1.22(m，9H)。
Embodiment 17 prepares 1-[ethyl-Asp (Tyr-OBzl) Tyr-OBzl]-β-carboline-3-benzyl carboxylate (4n)
According to the method for embodiment 4, obtaining 30mg (2.14%) title compound by 1470mg (2.25mmol) Asp (Tyr-OBzl)-Tyr-OBzl and 500mg (1.45mmol) 1-aldehyde-base-β-carboline-3-benzyl carboxylate is white powder.Mp126-128℃； (c＝0.14，CH 3OH)；ESI-MS(m/e)：968[M+H] +；IR(KBr)：3317.6，3035，9，1716.7，1651.1，1516.1，1446.6，，1346.3，1246，1215，825.5，740.7，698.2. 1HNMR(DMSO-d 6)δ：12.02(s，1H)，9.16(d，2H，J＝9Hz)，8.80(s，1H)，8.45(d，1H，J＝6Hz)，8.35(d，1H，J＝9Hz)，8.24(d，1H，J＝6Hz)，7.68(d，1H，J＝9Hz)，7.54(m，3H)，7.41-7.18(m，14H)，6.88(t，4H，J＝6Hz)，6.58(m，4H)，5.39(s，2H)，5.00(m，4H)，4.41(m，2H)，3.47(d，1H，J＝9Hz)，3.21(s，2H)，2.86(m，3H)，2.77(m，2H)，2.66(m，2H)，2.37(m，1H)，2.24(m，1H)。
Embodiment 18 prepares 1-[ethyl-Asp (Pro-OBzl) Pro-OBzl]-β-carboline-3-benzyl carboxylate (4o)
According to the method for embodiment 4, obtaining 78mg (6.43%) title compound by 1184mg (2.25mmol) Asp (Pro-OBzl)-Pro-OBzl and 500mg (1.45mmol) 1-aldehyde-base-β-carboline-3-benzyl carboxylate is yellow syrup material.Mp162-163℃； (c＝0.16，CH 3OH)；ESI-MS(m/e)：836[M+H] +。IR(KBr)：3425.6，3197.9，1716.7，1627.9，1381.0，1354.03，1315.5，1246.0，1138.0，767.7. 1HNMR(CDCl 3)δ：11.55(s，1H)，8.76(m，1H)，8.13(m，1H)，7.85-7.48(m，3H)，7.40-7.29(m，3H)，7.28-7.12(m，3H)，5.51(s，2H)，5.14(m，4H)，4.64(m，1H)，4.57(m，1H)，4.28(m，1H)，3.40(m，2H)，3.17(t，2H，J＝6.6Hz)，2.79(dd，1H，J 1＝3.2HzJ 2＝15.0Hz)，2.61(m，2H)，2.45(m，5H)，2.12(m，2H)，1.98(m，6H)。
The effect of experimental example 1 assessing compound 4a-o inhibition tumor cell propagation
1640 substratum of compound 4a-o containing 0.4%DMSO are mixed with desired concn.Respectively by A549 that is good for growth conditions, that be in logarithmic phase, MCF-7, HL60, S180, SF-295 cell is according to 4 × 10 4the density of individual/mL is inoculated in 96 orifice plates, every hole 100 μ L.At 37 DEG C, 5%CO 2cultivate 4 hours in incubator, by the concentration gradient 100 μMs preset, 50 μMs, 25 μMs and the 12.5 μMs solution adding the compound 4a-o through sterilising treatment, control group adds 1640 substratum containing 0.4%DMSO of equal-volume 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 hatches 4 hours, and after careful removing supernatant liquor, every hole adds 100 μ lDMSO, and vibrate about 15min dissolution precipitation.OD (absorbancy) value is measured under 570nm wavelength immediately in microplate reader.By inhibiting rate=[(the OD mean value containing the OD mean value-compound 4a-o group of the 1640 substratum groups of 0.4%DMSO)/containing the OD value of the 1640 substratum groups of 0.4%DMSO] × 100% " calculate inhibiting rate.Test parallel repetition 3 times, with inhibiting rate, the concentration of compound 4a-o is mapped, calculate the IC of the compounds of this invention 50(half effective inhibition concentration) value.
The DMEM substratum of compound 4a-o containing 0.4%DMSO is mixed with desired concn.Respectively by U2OS that is good for growth conditions, that be in logarithmic phase, HaCaT cell is according to 4 × 10 4the density of individual/mL is inoculated in 96 orifice plates, every hole 100 μ L.At 37 DEG C, 5%CO 2cultivate 4 hours in incubator, by the concentration gradient 100 μMs preset, 50 μMs, 25 μMs and the 12.5 μMs solution adding the compound 4a-o through sterilising treatment, control group adds the DMEM substratum containing 0.4%DMSO of equal-volume 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 hatches 4 hours, and after careful removing supernatant liquor, every hole adds 100 μ lDMSO, and vibrate about 15min dissolution precipitation.OD (absorbancy) value is measured under 570nm wavelength immediately in microplate reader.Inhibiting rate is calculated by inhibiting rate=[(the OD mean value containing the OD mean value-compound 4a-o group of the DMEM substratum group of 0.4%DMSO)/containing the OD mean value of the DMEM substratum group of 0.4%DMSO] × 100%.Test parallel repetition 3 times, with inhibiting rate, the concentration of compound 4a-o is mapped, calculate the IC of the compounds of this invention 50(half effective inhibition concentration) value.
Result lists table 1 in, table 2.
Result shows, target compound all generally has restraining effect to tumour cell, and less to normal skin cells HaCaT injury, IC 50all be greater than 100.1-disclosed in contriver (ethyl-AA-OBzl)-β-carboline-3-benzyl carboxylate is compared, and the cytotoxicity of 4g, 4n, 4o is significantly improved.
Cytotoxicity (the IC of table 14a-o 50, )
n＝18
Cytotoxicity (the IC of table 24a-o 50, )
n＝18
The activity of experimental example 2 assessing compound 4a-o Tumor suppression growth
Before measuring, compound 4a-o is added DMSO (dimethyl sulfoxide (DMSO)) hydrotropy, the CMC-Na with 0.5% suspends, and Zorubicin is dissolved in physiological saline.Get under aseptic condition and be inoculated in the ICR mouse S180 sarcoma of 7-10 days, add appropriate normal saline tumor cells suspension, cell count is 1.4 × 10 7individual/mL, is inoculated in healthy male ICR mouse forelimb armpit subcutaneous, every injected in mice 0.2mL.After tumor inoculation 24h, the aqueous solution for the treatment of group mouse oral 0.2mL compound every day 4a-o, successive administration 7 days, dosage is 1 μm of ol/kg.The every oral 0.2mL0.5% Xylo-Mucine of naive mice.Positive control is made with Zorubicin (dosage is 2 μm of ol/kg).Experiment proceeds to the 8th day, and claim Mouse Weight, put to death after etherization, and take the tumour of each group of mouse, the heart finally adds up the tumour inhibiting rate of each treated animal.The curative effect of solid tumor represents with the heavy inhibition percentage of knurl, is calculated as follows: tumor-like hyperplasia %=[1-(administration group knurl heavy/blank group knurl weight)] × 100%.
The knurl of each group of mouse is rearranged into table 3.Table 3 result shows, outside removing 4e, f, m, the knurl representation work of other compounds for treating mouse is less than the knurl weight of naive mice, illustrates that they have good anti-tumor activity.The effective dose (1 μm of ol/kg) of compound 4a-o is lower 8.9 times than the effective dose (8.9 μm of ol/kg) of 1-(ethyl-AA-OBzl)-β-carboline-3-benzyl carboxylate disclosed in contriver.
Table 34a-o on the impact of S180 tumor-bearing mice tumor growth ( )
Note: n=15; A) compared with 0.5% Xylo-Mucine, p < 0.01;
The transmission electron microscope of experimental example 3 compound 4a-o
Sample tri-distilled water is made into 1 × 10 respectively -5m, 1 × 10 -7m, 1 × 10 -9the solution of M, draws trace (about 10 μ L) and drips in copper mesh surface, serve as a contrast filter paper, naturally dry, observe its form and particle diameter under transmission electron microscope (JEOL, JEM-1230), and use photo record below copper mesh.
4a-o target compound can be self-assembled into diameter 40-260nm nanometer ball in aqueous, the difform nano net that these nanometer balls series winding is formed, and nanometer necklace etc. are existing with bulk concentration 1 × 10 -5m (theoretical Plasma Concentration) is example, enumerates the Electronic Speculum figure (Fig. 2) of each compound.

Claims (6)

1. 15 kinds of 1-[ethyl-Asp (AA-OBzl) AA-OBzl]-β-carboline-3-benzyl carboxylate of following formula,
In formula, AA is L-Leu residue, L-Phe residue, L-Val residue, L-Ala residue, L-Gly residue, L-Asp (OBzl) residue, L-Glu (OBzl) residue, L-Trp residue, L-Tyr residue, L-Ser residue, L-Thr residue, L-Pro residue, L-Met residue, L-Arg (NO 2) residue, L-Asn residue, L-Gln residue, L-Lys (Fmoc) residue.
2. prepare the method for 15 kinds of 1-[ethyl-Asp (AA-OBzl) AA-OBzl]-β-carboline-3-benzyl carboxylate of the general formula of claim 1, the method is made up of following steps:
1) there is Pictet-Spengler condensation in Trp-OBzl and 1,1,3,3-tetramethoxy propane under trifluoracetic acid (TFA) exists, generate 3S-1-(2,2-dimethoxy-ethyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] Indole-3-Carboxylic Acid benzyl ester;
2) in the mixing solutions of tetrahydrofuran (THF) (THF) with water, 3S-1-(2,2-dimethoxy-ethyl)-2,3,4,9-tetrahydrochysene-1H-pyrido [3,4-b] Indole-3-Carboxylic Acid benzyl ester is 1-(2 by potassium permanganate oxidation, 2-dimethoxy-ethyl)-1H-pyrido [3,4-b] Indole-3-Carboxylic Acid benzyl ester;
3) in the mixing solutions of acetic acid, water and hydrochloric acid, 1-(2,2-dimethoxy-ethyl)-1H-pyrido [3,4-b] Indole-3-Carboxylic Acid benzyl ester is hydrolyzed and obtains 1-aldehyde-base-β-carboline-3-benzyl carboxylate;
4) under dicyclohexylcarbodiimide (DCC) and N-hydroxy benzo triazole (HOBt) exist, Boc-Asp is that (AA is L-Leu residue to Boc-Asp (AA-OBzl) AA-OBzl with AA-OBzl condensation in anhydrous tetrahydro furan (THF), L-Phe residue, L-Val residue, L-Ala residue, L-Gly residue, L-Asp (OBzl) residue, L-Glu (OBzl) residue, L-Trp residue, L-Tyr residue, L-Ser residue, L-Thr residue, L-Pro residue, L-Met residue, L-Arg (NO 2) residue, L-Ash residue, L-Gln residue, L-Lys (Fmoc) residue);
5) in the ethyl acetate solution of hydrogenchloride, Boc-Asp (AA-OBzl)-AA-OBzl is removed Boc and obtain Asp (AA-OBzl)-AA-OBzl;
6) in THF solution, 1-aldehyde-base-β-carboline-3-benzyl carboxylate and Asp (Gly-OBzl)-Gly-OBzl are reduced to 1-[ethyl-Asp (Gly-OBzl) Gly-OBzl]-β-carboline-3-benzyl carboxylate by sodium cyanoborohydride ammonification;
7) in THF solution, 1-aldehyde-base-β-carboline-3-benzyl carboxylate and Asp (Phe-OBzl)-Phe-OBzl are reduced to 1-[ethyl-Asp (Phe-OBzl) Phe-OBzl]-β-carboline-3-benzyl carboxylate by sodium cyanoborohydride ammonification;
8) in THF solution, 1-aldehyde-base-β-carboline-3-benzyl carboxylate and Asp (Val-OBzl) Val-OBzl are reduced to 1-[ethyl-Asp (Val-OBzl) Val-OBzl]-β-carboline-3-benzyl carboxylate by sodium cyanoborohydride ammonification;
9) in THF solution, 1-aldehyde-base-β-carboline-3-benzyl carboxylate and Asp (Leu-OBzl)-Leu-OBzl are reduced to 1-[ethyl-Asp (Leu-OBzl) Leu-OBzl]-β-carboline-3-benzyl carboxylate by sodium cyanoborohydride ammonification;
10) in THF solution, 1-aldehyde-base-β-carboline-3-benzyl carboxylate and Asp (Ile-OBzl)-Ile-OBzl are reduced to 1-[ethyl-Asp (Ile-OBzl) Ile-OBzl]-β-carboline-3-benzyl carboxylate by sodium cyanoborohydride ammonification;
11) in THF solution, 1-aldehyde-base-β-carboline-3-benzyl carboxylate and Asp (Trp-OBzl) Trp-OBzl are reduced to 1-[ethyl-Asp (Trp-OBzl) Trp-OBzl]-β-carboline-3-benzyl carboxylate by sodium cyanoborohydride ammonification;
12) in THF solution, 1-aldehyde-base-β-carboline-3-benzyl carboxylate and Asp (Thr-OBzl) Thr-OBzl are reduced to 1-[ethyl-Asp (Thr-OBzl) Thr-OBzl]-β-carboline-3-benzyl carboxylate by sodium cyanoborohydride ammonification;
13) in THF solution, 1-aldehyde-base-β-carboline-3-benzyl carboxylate and Asp (Ser-OBzl) Ser-OBzl are reduced to 1-[ethyl-Asp (Ser-OBzl) Ser-OBzl]-β-carboline-3-benzyl carboxylate by sodium cyanoborohydride ammonification;
14) in THF solution, 1-aldehyde-base-β-carboline-3-benzyl carboxylate and Asp (Tyr-OBzl) Tyr-OBzl are reduced to 1-[ethyl-Asp (Tyr-OBzl) Tyr-OBzl]-β-carboline-3-benzyl carboxylate by sodium cyanoborohydride ammonification;
15) in THF solution, 1-aldehyde-base-β-carboline-3-benzyl carboxylate and Asp [Lys (Fmoc)-OBzl]-Lys (Fmoc)-OBzl are reduced to 1-[ethyl-Asp [Lys (Fmoc)-OBzl]-Lys (Fmoc)-OBzl]-β-carboline-3-benzyl carboxylate by sodium cyanoborohydride ammonification;
16) in THF solution, 1-aldehyde-base-β-carboline-3-benzyl carboxylate and Asp [Asp (OBzl) OBzl]-Asp (OBzl)-OBzl are reduced to 1-[ethyl-Asp [Asp (OBzl) OBzl] Asp (OBzl)-OBzl]-β-carboline-3-benzyl carboxylate by sodium cyanoborohydride ammonification;
17) in THF solution, 1-aldehyde-base-β-carboline-3-benzyl carboxylate and Asp [Glu (OBzl) OBzl]-Glu (OBzl)-OBzl are reduced to 1-[ethyl-Asp [Glu (OBzl) OBzl] Glu (OBzl)-OBzl]-β-carboline-3-benzyl carboxylate by sodium cyanoborohydride ammonification;
18) in THF solution, 1-aldehyde-base-β-carboline-3-benzyl carboxylate and Asp (Pro-OBzl) Pro-OBzl are reduced to 1-[ethyl-Asp (Pro-OBzl) Pro-OBzl]-β-carboline-3-benzyl carboxylate by sodium cyanoborohydride ammonification;
19) in THF solution, 1-aldehyde-base-β-carboline-3-benzyl carboxylate and Asp [Arg (NO 2)-OBzl]-Arg (NO 2)-OBzl is reduced to 1-[ethyl-Asp [Arg (NO by sodium cyanoborohydride ammonification 2)-OBzl]-Arg (NO 2)-OBzl]-β-carboline-3-benzyl carboxylate;
20) in THF solution, 1-aldehyde-base-β-carboline-3-benzyl carboxylate and Asp (Met-OBzl)-Met-OBzl are reduced to 1-[ethyl-Asp (Met-OBzl) Met-OBzl]-β-carboline-3-benzyl carboxylate by sodium cyanoborohydride ammonification.
3. 15 kinds of 1-[ethyl-Asp (AA-OBzl) AA-OBzl]-β-carboline-3-benzyl carboxylate nanostructure of the general formula of claim 1.
4. the effect of the tumor cell in vitro Proliferation Ability of 1-[ethyl-Asp (AA-OBzl) AA-OBzl]-β-carboline-3-benzyl carboxylate of the general formula representative of claim 1.
5. the restraining effect to mice bearing S180 tumor growth of 1-[ethyl-Asp (AA-OBzl) AA-OBzl]-β-carboline-3-benzyl carboxylate of the general formula representative of claim 1.
6. 1-[ethyl-Asp (AA-OBzl) AA-OBzl]-β-carboline-3-benzyl carboxylate of the general formula representative of claim 1 is preparing the purposes in antitumor drug.
CN201410260129.6A 2014-06-10 2014-06-10 Amino acid benzyl ester-modified beta-carbolines, activities, nanostructures, synthesis, and applications thereof Pending CN105237616A (en)

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