CN105294825B - Nanostructure, preparation, activity and the application of 1- (ethylamino acid benzyl ester)-B-carboline -3- benzyl carboxylates - Google Patents
Nanostructure, preparation, activity and the application of 1- (ethylamino acid benzyl ester)-B-carboline -3- benzyl carboxylates Download PDFInfo
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Abstract
The invention discloses 1 (ethyl Val AA OBzl) β carbolines, 3 benzyl carboxylate and L Lys residues and preparation methods, disclose their nanostructure, disclose the activity that they inhibit tumor cell proliferation, the activity that they inhibit S180 mice tumors grews is further disclosed, their application in preparations of anti-tumor drugs are illustrated.
Description
Technical field
The present invention relates to 1- (ethyl-Val-AA-OBzl)-B-carboline -3- benzyl carboxylates and L-Lys residues, are related to them
Preparation method, be related to their nanostructure, be related to their tumor cell in vitro proliferation inhibition activity, further to it
To the inhibiting effect of mice bearing S180 tumour growth, thus the present invention relates to their application in preparation of anti-tumor drugs
The invention belongs to biomedicine fields.
Technical background
In recent years, it is steeply risen in view of global cancer morbidity and the death rate, cancer has become a world problem.
Cancer patient's number in China is in world forefront, and cancer patient's number is continuously increased, and the demand to antineoplastic also constantly increases
Add.There are many limitations for the antitumor drug of clinical application at present, and with advances in technology and the reach of science, searching are pacified
Full effective antitumour new drug is one of hot spot of drug research.
Cancer is the common name of one group of a variety of disease that can influence any position of body.The other terms used are malignant tumour
And neoplasm.According to the statistics of 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 is estimated will to continue to rise, and will be more than 13,100,000 to the year two thousand thirty.Therefore, new efficient, low toxicity is developed,
The small antitumor drug of toxic side effect is always that new drug grinds high one of important topic.
With the understanding to tumor characteristic and morbidity essence, recent years, antitumor drug was constantly from traditional Cytotoxic drugs
Object to development non-cytotoxic drugs transition.B-carboline is natural cytotoxic anti-tumor compound.It was recognized by the inventor that
B-carboline antitumoral cytotoxic essence is the intercalation between DNA of tumor cell.The cuttage of this form can cause cell
Toxicity.Inventor it is found that, B-carboline can be inserted between the double helix base between DNA of tumor cell.Further
In research, it was recognized by the inventor that the antitumor activity of B-carboline comes from intercalation.Inventor is also to be recognized that 1 in B-carboline is drawn
Enter the effect that dipeptides generates B-carboline -3- benzyl carboxylates and derivative can enhance B-carboline and tumour cell, enhances antitumor work
Property.According to these understanding, inventor proposes 1- (ethyl-Val-AA-OBzl)-B-carboline -3- benzyl carboxylates.With inventor early period
Invention 1- (ethyl-AA-OBzl)-B-carboline -3- benzyl carboxylates compare, protrusion creativeness of the invention is, remains β -
Intercalation between carboline and DNA of tumor cell shows high anti-tumor activity under low dosage.Then, 1- (ethyl-Val-
AA-OBzl)-B-carboline -3- benzyl carboxylates show good inhibition tumor cell proliferation effect and antitumor activity.
The content of invention
First content of the present invention is to provide 1- (ethyl-Val-AA-OBzl)-B-carboline -3- benzyl carboxylates of following formula
AA represents Gly, L-Ala, L-Phe, L-Val, L-Asp (OBzl), L-Trp, L-Ile, L-Leu, L-Thr, L-Ser, L- in formula
Met, L-Pro, L-Asn, L-Gln, L-Cys (pMeOBzl), L-Arg (NG-NO2) and L-Lys residues.
Second content of the present invention is to provide the preparation of 1- (ethyl-Val-AA-OBzl)-B-carboline -3- benzyl carboxylates
Method, this method include：
(1) by L-Trp benzyl ester under trifluoroacetic catalysis with 1,1,3,3- tetramethoxy propane carries out Pictet-
Spengler is condensed, and obtains -1,2,3,4- tetrahydro-beta-carboline -3- benzyl carboxylates of 1- (2,2- dimethoxy ethyl)；
(2) it by -1,2,3,4- tetrahydro-beta-carboline -3- benzyl carboxylates of 1- (2,2- dimethoxy ethyl) in tetrahydrofuran, uses
Potassium permanganate solution aoxidizes to obtain 1- (2,2- dimethoxy ethyl)-B-carboline 3- benzyl carboxylates；
(3) 1- (2,2- dimethoxy ethyl)-B-carboline 3- benzyl carboxylates are hydrolyzed in glacial acetic acid, concentrated hydrochloric acid, mixed liquor
1- aldehyde-bases-B-carboline 3- benzyl carboxylates；
(4) it is coupled 1- aldehyde-bases-B-carboline -3- benzyl carboxylates and HClVal-Ala-OBzl to obtain 1- (ethyls -
Val-Ala-OBzl)-B-carboline -3- benzyl carboxylates；
(5) it is coupled 1- aldehyde-bases-B-carboline -3- benzyl carboxylates and HClVal-Phe-OBzl to obtain 1- (ethyls -
Val-Phe-OBzl)-B-carboline -3- benzyl carboxylates；
(6) it is coupled 1- aldehyde-bases-B-carboline -3- benzyl carboxylates and HClVal-Trp-OBzl to obtain 1- (ethyls -
Val-Trp-OBzl)-B-carboline -3- benzyl carboxylates；
(7) it is coupled 1- aldehyde-bases-B-carboline -3- benzyl carboxylates and HClVal-Val-OBzl to obtain 1- (ethyls -
Val-Val-OBzl)-B-carboline -3- benzyl carboxylates；
(8) it is coupled 1- aldehyde-bases-B-carboline -3- benzyl carboxylates and HClVal-Asp (OBzl)-OBzl to obtain 1- (second
Base-Val-Asp (OBzl)-OBzl)-B-carboline -3- benzyl carboxylates；
(9) it is coupled 1- aldehyde-bases-B-carboline -3- benzyl carboxylates and HClVal-Ile-OBzl to obtain 1- (ethyls -
Val-Ile-OBzl)-B-carboline -3- benzyl carboxylates；
(10) it is coupled 1- aldehyde-bases-B-carboline -3- benzyl carboxylates and HClVal-Leu-OBzl to obtain 1- (ethyls -
Val-Leu-OBzl)-B-carboline -3- benzyl carboxylates；
(11) it is coupled 1- aldehyde-bases-B-carboline -3- benzyl carboxylates and HClVal-Gly-OBzl to obtain 1- (ethyls -
Val-Gly-OBzl)-B-carboline -3- benzyl carboxylates；
(12) it is coupled 1- aldehyde-bases-B-carboline -3- benzyl carboxylates and HClVal-Thr-OBzl to obtain 1- (ethyls -
Val-Thr-OBzl)-B-carboline -3- benzyl carboxylates；
(13) it is coupled 1- aldehyde-bases-B-carboline -3- benzyl carboxylates and HClVal-Ser-OBzl to obtain 1- (ethyls -
Val-Ser-OBzl)-B-carboline -3- benzyl carboxylates；
(14) it is coupled 1- aldehyde-bases-B-carboline -3- benzyl carboxylates and HClVal-Met-OBzl to obtain 1- (ethyls -
Val-Met-OBzl)-B-carboline -3- benzyl carboxylates；
(15) it is coupled 1- aldehyde-bases-B-carboline -3- benzyl carboxylates and HClVal-Pro-OBzl to obtain 1- (ethyls -
Val-Pro-OBzl)-B-carboline -3- benzyl carboxylates；
(16) by 1- aldehyde-bases-B-carboline -3- benzyl carboxylates and HClVal-Lys (Nω- Fmoc)-OBzl is coupled to obtain
1- (ethyl-Va1-Lys (Nω- Fmoc)-OBzl)-B-carboline -3- benzyl carboxylates；By 1- (ethyl-Val-Lys (Nω-Fmoc)-
OBzl)-B-carboline -3- benzyl carboxylates are added dropwise hexahydropyridine in anhydrous methylene chloride, under ice bath and obtain 1- (ethyl-Val-
Lys-OBzl)-B-carboline -3- benzyl carboxylates；
(17) by 1- aldehyde-bases-B-carboline -3- benzyl carboxylates and HClVal-Arg (NG-NO2)-OBzl is coupled to obtain 1-
(ethyl-Val-Arg (NG-NO2)-OBzl)-B-carboline -3- benzyl carboxylates；
(18) it is coupled 1- aldehyde-bases-B-carboline -3- benzyl carboxylates and HClVal-Asn-OBzl to obtain 1- (ethyls -
Val-Asn-OBzl)-B-carboline -3- benzyl carboxylates；
(19) it is coupled 1- aldehyde-bases-B-carboline -3- benzyl carboxylates and HClVal-Gln-OBzl to obtain 1- (ethyls -
Val-Gln-OBzl)-B-carboline -3- benzyl carboxylates；
(20) 1- aldehyde-bases-B-carboline -3- benzyl carboxylates and HClVal-Cys (pMeOBzl)-OBzl are coupled to obtain
1- (ethyl-Val-Cys (pMeOBzl)-OBzl)-B-carboline -3- benzyl carboxylates.
The third content of the present invention is that evaluation 1- (ethyl-Val-AA-OBzl)-B-carboline -3- benzyl carboxylates inhibit swollen
The effect of tumor cell proliferation.
The 4th content of the present invention is that evaluation 1- (ethyl-Val-AA-OBzl)-B-carboline -3- benzyl carboxylates inhibit lotus
The effect of S180 mice tumors grews.
The 5th content of the present invention is to measure the nanometer of 1- (ethyl-Val-AA-OBzl)-B-carboline -3- benzyl carboxylates
Structure.
Description of the drawings
The synthetic route chart .i of Fig. 1 compounds 5a-q) compound 1- (ethyl-Val-AA-OBzl)-B-carboline -3- carboxylic acids
The synthetic route chart .i of benzyl ester) polyphosphoric acids, benzyl alcohol；Ii) trifluoracetic acid, 1,1,3,3- tetramethoxy propane；Iii) Gao Meng
Sour potassium, tetrahydrofuran, water；Iv) molten concentrated hydrochloric acid, glacial acetic acid, water；V) N-methylmorpholine, anhydrous magnesium sulfate, sodium cyanoborohydride,
AA=Ala residues in Val-AA-OBzl.5a, AA=Phe residues in 5b, AA=Trp residues in 5c, AA=Val residues in 5d,
AA=Asp (OBzl) residue in 5e, AA=Ile residues in 5f, AA=Leu residues in 5g, AA=Gly residues in 5h, AA in 5i
=Thr residues, AA=Ser residues in 5j, AA=Met residues in 5k, AA=Lys residues in AA=Pro in 51,5m, AA in 5n
=Arg (NG-NO2) residue, AA=Asn residues in 5o, AA=Gln residues in 5p, AA=Cys (pMeOBzl) residue in 5q.
Fig. 2 compounds 5a-q is in pH7.4 environment, and a concentration of 6 × 10-7Transmission electron microscope photo under M concentration.
Specific implementation mode
In order to which the present invention is further explained, be given below some row embodiments these embodiments be entirely it is illustrative, it
Only be used for the present invention is specifically described, be not construed as limitation of the present invention.
Embodiment 1 prepares 1- (2,2- dimethoxy ethyl) -1,2,3,4- tetrahydro-beta-carboline -3- benzyl carboxylates
First by 5gL- tryptophan benzyl esters saturation NaHCO3Aqueous solution is washed, and is extracted with 70mL ethyl acetate, coextraction 3 times,
Ester is mutually washed till neutrality with saturated nacl aqueous solution, and anhydrous sodium sulfate drying is filtered into the round-bottomed flask of 250mL, filtrate decompression
It is concentrated to dryness to obtain 4g colorless solids.In the round-bottomed flask of 100mL, first by 4mL1,1,3,3- tetramethoxy propane is dissolved in 40mL
In dichloromethane solvent, 4mL trifluoracetic acids are added, activation 45min adds the 4g colorless solids just obtained under ice bath
Enter into reaction bulb to react 52 hours, TLC (petroleum ether/acetone=4/1) display reactions are completed, with saturation NaHCO3Aqueous solution
Then acid in neutralization reaction liquid uses 70mL dichloromethane to extract, coextraction 3 times.Dichloromethane layer saturated sodium-chloride is water-soluble
Liquid is washed till neutrality, and dichloromethane is mutually dried with anhydrous sodium sulfate, filtering, filtrate decompression concentration, residue silica gel wet method column layer
Analysis purifying, obtains 3.5g (51%) title compound, is yellow oil.ESl-MS(m/e)395[M+H]+。
Embodiment 2 prepares 1- (2,2- dimethoxy ethyl)-B-carboline 3- benzyl carboxylates
By -1,2,3,4- tetrahydro-beta-carboline -3- benzyl carboxylates of 5g (12.7mmol) 1- (2,2- dimethoxy ethyl), with
150mL tetrahydrofurans are added in the eggplant bottle of 250mL, and the water-soluble of 5g (31.6mmol) potassium permanganate is added portionwise in ice bath stirring
Liquid reacts at room temperature 5 hours, and TLC (petroleum ether/acetone=4/1) display reactions are completed, filtering, and tetrahydrofuran is added and rinses filter
Cake, filtrate decompression concentration, then remaining water phase 70mL dichloromethane is extracted, it extracts 3 times, combined dichloromethane phase, uses altogether
Saturated common salt water washing 3 times, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, residue are pure with silica gel wet method column chromatography
Change, then 3g (60%) title compound is obtained with petroleum ether-acetone recrystallization, is colorless solid.ESI/MS(m/e)391[M+H
]+。
Embodiment 3 prepares 1- aldehyde-bases-B-carboline 3- benzyl carboxylates
72mL glacial acetic acid, which is first added, keeps 344mg (1mmol) 1- (2,2- dimethoxy ethyl)-B-carboline 3- benzyl carboxylates complete
Dissolving, sequentially adds 9mL concentrated hydrochloric acids and 9mL water.4h is stirred, TLC shows that raw material spot disappears, and compound of reaction is added a large amount of
Mixture of ice and water, stirring make a large amount of solids be precipitated, and filter and rinse filter cake with 90mL ice water.Filter cake is collected, it is fully dry, under standby
Single step reaction uses.
Embodiment 4 prepares 1- (ethyl-Val-Ala-OBzl)-B-carboline -3- benzyl carboxylates (5a)
Under ice bath, dripped into the solution of 377mg (1.2mmol) HClVal-Ala-OBzl and 20ml anhydrous tetrahydro furans
Add N-methylmorpholine to adjust solution ph to 8,344mg (1mmol) 1- aldehyde-bases-B-carboline -3- benzyl carboxylates are added into solution
The suspension of 20mL dichloromethane, stirring are added 200mg anhydrous magnesium sulfates and stir 15 minutes into reaction mixture after ten minutes
Add 63mg (1mmol) sodium cyanoborohydride, 14h, TLC (CHCl is stirred at room temperature3/ MeOH=28/1) display reaction completion reactions
Mixture filters, and saturation NaHCO is added in filtrate decompression concentration, residue3Aqueous dissolution, obtained solution 50ml acetic acid second
Ester liquid extracts, and 3 ethyl acetate layers of coextraction are washed till neutrality with saturated nacl aqueous solution, and the ethyl acetate phase of collection is with anhydrous
Sodium sulphate is dried, filtering, filtrate decompression concentration, obtained syrup successively through silica gel column chromatography (methylene chloride/methanol=
65/1) and thin-layer chromatography (methylene chloride/methanol=26/1) purifying is prepared, obtains 117mg (19%) title compound, is yellowish
Color grease .ESI-MS (m/e) 608.4 [M+H]+； IR(KBr)：
3412.08,2960.73,2889.37,1647.21,1496.76,1456.26,1448.54,1373.32,1373.32,
1348.24,1340.53,1251.80,1209.37,1151.50,1138.00,1097.50,1047.35,997.20,
962.48,875.68,854.47,833.25,790.81,696.30,669.30cm-1；1H NMR (300MHz, CDCl3)δ/
ppm：10.58 (s, 1H), 8.73 (s, 1H), 8.14 (d, J=7.8Hz, 1H), 7.83 (d, J=8.1Hz, 1H), 7.61~7.26
(m, 14H), 5.51 (s, 2H), 5.29 (d, J=12.3Hz, 1H), 5.18 (d, J=12.3Hz, 1H), 4.81 (m, 1H), 3.51
(m, 1H), 3.41 (m, 1H), 3.17 (d, J=6.9Hz, 1H), 3.15 (d, J=6.9Hz, 1H), 3.05 (d, J=4.8Hz,
1H), 2.14 (m, 1H), 1.46 (d, J=7.2Hz, 3H), 1.03 (d, J=6.9Hz, 3H), 0.97 (d, J=6.9Hz, 3H).
Embodiment 5 prepares 1- (ethyl-Val-Phe-OBzl)-B-carboline -3- benzyl carboxylates (5b)
According to the method for embodiment 4, by 425mg (1.2mmol) HClVal-Phe-OBzl and 344mg (1mmol) 1- second
Aldehyde radical-B-carboline -3- benzyl carboxylates obtain 177mg (26%) title compound, are pale yellow oil .ESI-MS (m/e) 715.3
[M+MeOH]+=IR(KBr)：3743.83 3089.96,3030.17,
2960.73,2852.72,1734.01,1716.65,1647.21,1624.06,1597.06,1496.76,1456.26,
1448.54,1436.97,1379.10,1348.24,1301.95,1253.73,1215.15,1176.58,1155.36,
1134.14,1107.14,1085.92,1026.13,987.55,956.69,875.68,738.74,698.26,684.73cm-1
；1H NMR (300MHz, CDCl3)δ/ppm：9.67 (s, 1H), 8.78 (s, 1H), 8.17 (d, J=7.8Hz, 1H), 7.57~
7.53 (m, 5H), 7.44~7.22 (m, 15H), 5.99 (s, 1H), 5.82 (s, 1H), 5.50 (s, 2H), 4.25 (m, 3H), 3.90
(s, 1H), 3.50 (d, J=3.00Hz, 1H), 3.44 (d, J=3.00Hz, 1H), 3.43 (d, J=3.00Hz, 1H), 2.91 (m,
1H), 2.36 (m, 1H), 1.03 (d, J=7.2Hz, 3H), 0.86 (d, J=6.9Hz, 3H).
Embodiment 6 prepares 1- (ethyl-Val-Trp-OBzl)-B-carboline -3- benzyl carboxylates (5c)
According to the method for embodiment 4, by 515mg (1.2mmol) HClVal-Trp-OBzl and 344mg (1mmol) 1- second
Aldehyde radical-B-carboline -3- benzyl carboxylates obtain 63mg (9%) title compound, are 723.4 [M of pale yellow oil .ESI-MS (m/e)
+H]+；IR(KBr)：3323.35,3062.96,3035.96,2958.80,
2924.09,2854.65,1718.58,1649.14,1597.06,1554.63,1521.84,1489.05,1456.26,
1379.10,1348.24,1249.87,1213.23,1176.58,1153.43,1136.07,1101.35,1002.98,
966.34,908.47,786.96,742.59,723.31,696.30cm-1；1H NMR (300MHz, CDCl3)δ/ppm：10.39
(br s, 1H), 8.80 (s, 1H), 8.77 (s, 1H), 8.13 (d, J=7.8Hz, 1H), 7.71 (d, J=9.0Hz, 1H), 7.53
~7.49 (m, 4H), 7.45~7.22 (m, 11H), 7.07 (m, 2H), 6.94 (m, 1H), 5.51 (s, 2H), 5.13 (m, 2H),
5.08 (m, 1H), 3.32 (m, 2H), 3.01 (m, 2H), 2.84 (m, 3H), 1.93 (m, 1H), 1.85 (s, 1H), 0.86 (d, J=
6.0Hz, 3H)；0.84 (d, J=6.0Hz, 3H).
Embodiment 7 prepares 1- (ethyl-Val-Val-OBzl)-B-carboline -3- benzyl carboxylates (5d)
According to the method for embodiment 4, by 411mg (1.2mmol) HClVal-Val-OBzl and 344mg (1mmol) 1- second
Aldehyde radical-B-carboline -3- benzyl carboxylates obtain 134mg (21%) title compound, are pale yellow oil .ESI-MS (m/e) 636.0
[M+H]+；IR(KBr)：3736.12 3574.10,3527.80,
3406.29,3379.39,3360.00,3346.50,3334.92,3267.41,3207.62,2362.80,2345.44,
1724.36,1680.00,1653.00,1602.85,1558.44,1516.05,1506.41,1448.54,1375.25,
1348.24,1253.73,1215.15,1136.07,1122.57,983.70,808.17,754.17,644.22cm-1；1H NMR
(300MHz, CDCl3)δ/ppm：10.37 (br s, 1H), 8.78 (s, 1H), 8.18 (d, J=15.0Hz, 1H), 7.87 (d, J=
9.3Hz, 1H), 7.56~7.54 (m, 4H), 7.45~7.22 (m, 10H), 5.53 (s, 2H), 5.37 (d, J=12.3Hz, 1H),
5.24 (d, J=12.3Hz, 1H), 4.76 (q, J=9.6Hz, 1H), 3.49 (m, 2H), 3.19 (d, J=11.7Hz, 1H), 3.16
(d, J=6.6Hz, 1H), 3.02 (d, J=3.3Hz, 1H), 2.31 (m, 1H), 2.11 (m, 1H), 1.04 (d, J=7.5Hz,
3H), 1.02 (d, J=4.2Hz, 3H), 0.99 (d, J=3.3Hz, 3H), 0.92 (d, J=6.9Hz, 3H).
Embodiment 8 prepares 1- (ethyl-Val-Asp (OBzl)-OBzl)-B-carboline -3- benzyl carboxylates (5e)
According to the method for embodiment 4, by 538mg (1.2mmol) HClVal-Asp (OBzl)-OBzl and 344mg
(1mmol) 1- aldehyde-bases-B-carboline -3- benzyl carboxylates obtain 74mg (10%) title compounds .ESI-MS (m/e) 742.6 [M+H
]+；IR(KBr)：3225.28,3269.34,3089.96,3064.89,
3034.03,2958.80,2873.94,2640.55,1992.47,1951.96,1942.32,1861.31,1732.08,
1645.28,1625.99,1597.06,1566.20,1558.48,1498.69,1456.26,1411.89,1379.10,
1348.24,1251.80,1213.23,1166.93,1157.29,1136.07,1105.21,1082.07,1047.35,
1028.06,968.27,910.40,825.53,806.25,786.96,738.74,696.30,677.01cm-1；1H NMR
(300MHz, CDCl3)δ/ppm：10.23 (br s, 1H), 8.78 (s, 1H), 8.31 (d, J=9.3Hz, 1H), 8.17 (d, J=
7.8Hz, 1H), 7.57~7.19 (m, 19H), 5.53 (s, 2H), 5.26 (d, J=12.3Hz, 1H), 5.18 (d, J=9.3Hz,
1H), 5.11 (d, J=6.9Hz, 1H), 5.02 (d, J=6.6Hz, 1H), 5.10 (m, 2H), 3.48 (m, 1H), 3.36 (m, 1H),
3.27 (dd, J=4.2Hz, J=4.2Hz, 1H), 3.06 (m, 1H), 2.95 (d, J=8.1Hz, 1H), 2.87 (d, J=4.5Hz,
1H), 2.06 (m, 1H), 1.85 (m, 1H), 0.98 (d, J=6.9Hz, 3H), 0.81 (d, J=6.9Hz, 3H).
Embodiment 9 prepares 1- (ethyl-Val-Ile-OBzl)-B-carboline -3- benzyl carboxylates (5f)
According to the method for embodiment 4, by 450mg (1.2mmol) HClVal-Ile-OBzl and 344mg (1mmol) 1- second
Aldehyde radical-B-carboline -3- benzyl carboxylates obtain 174mg (27%) title compound, are pale yellow oil .ESI-MS (m/e) 650.5
[M+H]+；IR(KBr)：3558.67 3450.65,2964.59,
2927.94,2885.51,1951.96,1909.53,1847.81,1716.65,1647.21,1595.13,1456.26,
1373.32,1348.24,1336.27,1300.02,1251.80,1215.15,1172.72,1155.36,1138.00,
1089.78,1080.14,1026.13,952.84,852.54,792.74,725.23,696.30cm-1；1H NMR (300MHz,
CDCl3)δ/ppm：10.36 (br s, 1H), 8.75 (s, 1H), 8.15 (d, J=7.8Hz, 1H), 7.87 (d, J=8.7Hz,
1H), 7.57~7.50 (m, 4H), 7.46~7.32 (m, 7H), 7.28~7.22 (m, 3H), 5.52 (s, 2H), 5.37 (d, J=
12.0Hz, 1H), 5.22 (d, J=12.6Hz, 1H), 4.78 (q, J=9.0Hz, 1H), 3.50 (m, 2H), 3.10 (m, 2H),
2.15 (m, 2H), 2.03 (m, 1H), 1.39 (m, 1H), 1.19 (m, 1H), 1.05 (d, J=5.1Hz, 3H), 0.95 (d, J=
3.9Hz, 3H), 0.92 (d, J=4.2Hz, 3H), 0.87 (d, J=7.5Hz, 3H).
Embodiment 10 prepares 1- (ethyl-Val-Leu-OBzl)-B-carboline -3- benzyl carboxylates (5g)
According to the method for embodiment 4, by 450mg (1.2mmol) HClVal-Leu-OBzl and 344mg (1mmol) 1- second
Aldehyde radical-B-carboline -3- benzyl carboxylates obtain 199mg (31%) title compound, are pale yellow oil .ESI-MS (m/e) 650.4
[M+H]+；IR(KBr)：3568.31 3315.63,3072.60,
3035.96,2960.73,2870.08,1890.24,1865.17,1830.45,1772.58,1718.58,1701.22,
1597.06,1490.97,1458.18,1446.61,1436.97,1419.61,1436.97,1419.61,1375.25,
1348.24,1301.95,1251.80,1209.37,1151.50,1139.93,1103.28,1083.99,904.61,
844.82,788.89,746.45,721.38,590.22cm-1；1H NMR (300MHz, CDCl3)δ/ppm：10.39 (br s,
1H), 8.78 (s, 1H), 8.16 (d, J=8.1Hz, 1H), 7.63 (d, J=6.3Hz, 1H), 7.56~7.51 (m, 4H), 7.45
~7.28 (m, 11H), 5.53 (s, 2H), 5.32 (d, J=12.3Hz, 1H), 5.23 (d, J=12.3Hz, 1H), 4.82 (m,
1H), 3.52 (m, 1H), 3.39 (m, 1H), 3.16 (d, J=6.9Hz, 1H), 3.14 (d, J=7.2Hz, 1H), 3.01 (d, J=
3.9Hz, 1H), 2.10 (m, 1H), 1.67 (m, 2H), 1.57 (m, 1H), 1.02 (d, J=7.2Hz, 3H), 1.00 (d, J=
9.0Hz, 3H), 0.94 (d, J=5.7Hz, 3H), 0.94 (d, J=5.7Hz, 3H).
Embodiment 11 prepares 1- (ethyl-Val-Gly-OBzl)-B-carboline -3- benzyl carboxylates (5h)
According to the method for embodiment 4, by 360mg (1.2mmol) HClVal-Gly-OBzl and 344mg (1mmol) 1- second
Aldehyde radical-B-carboline -3- benzyl carboxylates obtain 89mg (15%) title compound, are pale yellow oil .ESI-MS (m/e) 594.4
[M+H]+；IR(KBr)：3336.85 3269.34,3217.27,
3091.89,3034.03,2958.80,2933.73,2870.08,1953.89,1909.53,1857.45,1718.58,
1647.21,1624.06,1597.06,1570.06,1498.69,1456.26,1436.97,1375.25,1348.24,
1300.02,1251.80,1213.23,1188.15,1155.36,1138.00,1105.21,1083.99,1029.99,
964.41,950.91,943.19,904.61,893.04,810.10,788.89,725.23,696.30,669.30cm-1；1H
NMR (300MHz, CDCl3)δ/ppm：10.73 (s, 1H), 8.77 (s, 1H), 8.16 (d, J=7.8Hz.1H), 7.83 (m, 1H),
7.56~7.51 (m, 3H), 7.42~7.28 (m, 9H), 5.50 (s, 2H), 5.20 (s, 2H), 4.38 (dd, J=7.5Hz, J=
7.8Hz, 1H), 3.96 (dd, J=4.5Hz, J=4.5Hz, 1H), 3.41 (m, 1H), 3.31 (m, 1H), 3.16 (m, 1H), 3.06
(m, 1H), 3.01 (d, J=5.1Hz.1H), 2.33 (br s, 2H), 2.03 (m, 1H), 1.01 (d, J=10.2Hz, 3H), 0.95
(d, J=6.6Hz, 3H).
Embodiment 12 prepares 1- (ethyl-Val-Thr-OBzl)-B-carboline -3- benzyl carboxylates (5i)
According to the method for embodiment 4, by 411mg (1.2mmol) HClVal-Thr-OBzl and 344mg (1mmol) l- second
Aldehyde radical-B-carboline -3- benzyl carboxylates obtain 72mg (11%) title compound, are pale yellow oil .ESI-MS (m/e) 638.4
[M+H]+；IR(KBr)：3348.42 3078.39,3034.03,
2962.66,2933.73,2873.94,1768.72,1718.58,1647.21,1627.92,1597.06,1500.62,
1456.26,1375.25,1348.24,1321.24,1301.95,1251.80,1213.23,1155.36,1139.93,
1103.28,1082.07,1028.06,1012.63,968.27,914.26,896.90,883.40,825.53,742.59,
698.23,663.51cm-1；1HNMR (300MHz, CDCl3)δ/ppm：10.50 (s, 1H), 8.47 (s, 1H), 8.23 (d, J=
9.0Hz, 1H), 7.95 (d, J=6.0Hz, 1H), 7.51~7.49 (m, 2H), 7.45~7.31 (m, 5H), 7.28~7.21 (m,
7H), 5.46 (s, 2H), 5.19 (d, J=12.0Hz, 1H), 5.08 (d, J=12.0Hz, 1H), 4.63 (m, 2H), 3.72 (m,
1H), 3.40 (m, 1H), 3.31 (m, 1H), 2.99 (m, 3H), 2.09 (m, 1H), 1.31 (d, J=6.0Hz, 3H), 1.00 (d, J
=6.0Hz, 3H), 0.98 (d, J=6.0Hz, 3H).
Embodiment 13 prepares 1- (ethyl-Val-Ser-OBzl)-B-carboline -3- benzyl carboxylates (5j)
According to the method for embodiment 4, by 397mg (1.2mmol) HClVal-Ser-OBzl and 344mg (1mmol) 1- second
Aldehyde radical-B-carboline -3- benzyl carboxylates obtain 122mg (18%) title compound, are pale yellow oil .ESI-MS (m/e) 624.4
[M+H]+；IR(KBr)：3439.08 2974.23,2883.58,
1830.45,1776.44,1743.65,1705.07,1653.00,1647.21,1600.92,1560.41,1508.33,
1458.18,1436.97,1375.25,1348.24,1340.53,1247.94,1209.37,1155.36,1136.07,
883.40 731.02,700.16cm-1；1H NMR (300MHz, CDCl3)δ/ppm：10.89 (s, 1H), 8.43 (s, 1H), 8.39
(d, J=6.0Hz, 1H), 7.96 (d, J=6.3Hz, 1H), 7.55~7.17 (m, 15H), 5.44 (s, 2H), 5.18 (d, J=
12.0Hz, 1H), 5.10 (d, J=12.0Hz, 1H), 4.80 (m, 1H), 4.28 (dd, J=6.0Hz, J=3.0Hz, 1H), 4.03
(dd, J=3.0Hz, J=3.0Hz, 1H), 3.35 (m, 1H), 3.22 (m, 1H), 3.02 (m, 1H), 2.94 (d, J=6.0Hz,
1H), 2.87 (m, 1H), 2.02 (m, 1H), 0.99 (d, J=3.0Hz, 3H), 0.97 (d, J=3.0Hz, 3H).
Embodiment 14 prepares 1- (ethyl-Val-Met-OBzl)-B-carboline -3- benzyl carboxylates (5k)
According to the method for embodiment 4, by 470mg (1.2mmol) HClVal-Met-OBzl and 344mg (1mmol) 1- second
Aldehyde radical B-carboline -3- benzyl carboxylates obtain 122mg (19%) title compound, are pale yellow oil .ESI-MS (m/e) 668.5
[M+H]+；IR(KBr)：3331.08 3091.89,3034.03,
2958.80,2916.37,2873.94,1992.47,1942.32,1869.02,1734.01,1718.58,1705.07,
1647.21,1624.06,1597.06,1521.84,1498.69,1456.26,1436.97,1419.61,1375.25,
1348.24,1300.02,1251.80,1213.23,1203.58,1166.93,1155.36,1134.14,1103.28,
1082.07,1060.85,1026.13,968.27,956.69,902.69,823.60,786.96,736.81,696.30,
619.15cm-1；1H NMR (300MHz, CDCl3)δ/ppm：10.58 (s, 1H), 8.87 (s, 1H), 8.13 (d, J=6.0Hz,
1H), 7.96 (d, J=6.0Hz, 1H), 7.63~7.21 (m, 12H), 5.53 (s, 2H), 5.30 (d, J=12.0Hz, 1H),
5.19 (d, J=12.0Hz, 1H), 4.93 (m, 1H), 3.47 (m, 1H), 3.32 (m, 1H), 3.11 (m, 2H), 3.09 (m, 1H),
2.94 (m, 2H), 2.50 (d, J=9.0Hz, 1H), 2.47 (d, J=9.0Hz, 1H), 2.15 (m, 2H), 2.10~1.90 (m,
5H), 0.98 (d, J=9.0Hz, 3H), 0.94 (d, J=6.0Hz, 3H).
Embodiment 15 prepares 1- (ethyl-Val-Pro-OBzl)-B-carboline -3- benzyl carboxylates (5l)
According to the method for embodiment 4, by 409mg (1.2mmol) HClVal-Pro-OBzl and 344mg (1mmol) 1- second
Aldehyde radical-B-carboline -3- benzyl carboxylates obtain 139mg (22%) title compound, are pale yellow oil .ESI-MS (m/e) 634.4
[M+H]+；CH3OH)；IR(KBr)：3462.22,3228.84,2960.73,2879.72,
1768.72,1739.79,1718.58,1701.22,1676.14,1618.28,1560.41,1541.12,1498.69,
1458.18,1419.61,1379.10,1348.24,1305.81,1253.73,1211.30,1170.79,1138.00,
1105.21,966.34,900.76,742.59,696.30cm-1；1H NMR (300MHz, CDCl3)δ/ppm：12.46 (s, 1H),
8.70 (s, 1H), 8.14 (d, J=6.0Hz, 1H), 7.59~7.07 (m, 15H), 5.52 (s, 2H), 5.24 (d, J=12.0Hz,
1H), 5.18 (d, J=12.0Hz, 1H), 4.70 (q, J=3.0Hz, J=3.0Hz, 1H), 3.62 (m, 3H), 3.44 (m, 2H),
3.25 (m, 1H), 2.97 (m, 1H), 2.23 (m, 2H), 2.02 (m, 2H), 1.23 (d, J=9.0Hz, 3H), 1.20 (d, J=
6.0Hz, 3H).
Embodiment 16 prepares 1- (ethyl-Val-Lys-OBzl)-B-carboline -3- benzyl carboxylates (5m)
According to the method for embodiment 4, by 752mg (1.2mmol) HClVal-Lys (Fmoc)-OBzl and 344mg
(1mmol) 1- aldehyde-bases-B-carboline -3- benzyl carboxylates obtain 179mg (20%) 1- (ethyl-Val-Lys (ω N-
Fmoc)-OBzl)-B-carboline -3- benzyl carboxylates are white solid .ESI-MS (m/e) 887.6 [M+H]+； IR(KBr)：3427.51,3313.71,3064.89,3032.10,
2956.87,2929.87,2866.22,1772.58,1753.29,1739.79,1718.58,1649.14,1618.28,
1541.12,1473.62,1346.31,1332.81,1303.88,1267.23,1246.02,1213.23,1201.65,
1180.44,1139.93,1105.21,1039.63,1020.34,974.05,950.91,900.76,883.40,846.75,
823.60,777.31,756.10,734.88,700.16cm-1；1H NMR (300MHz, CDCl3)δ/ppm：10.36 (s, 1H),
8.77 (s, 1H), 8.16 (d, J=9Hz, 1H), 7.79~7.73 (m, 3H), 7.62~7.49 (m, 6H), 7.43~7.27 (m,
10H), 5.52 (s, 2H), 5.33 (d, J=12.0Hz, 1H), 5.20 (d, J=15.0Hz, 1H), 4.77 (m, 1H), 4.40 (m,
2H), 4.20 (m, 1H), 3.48 (m, 2H), 3.38 (m, 1H), 3.13 (m, 4H), 3.01 (m, 1H), 2.09 (m, 1H), 1.88 (m,
2H), 1.78 (m, 2H), 1.49 (m, 2H), 1.35 (m, 3H), 1.01 (d, J=6.0Hz, 3H), 0.97 (d, J=6.0Hz, 3H).
57mg (0.064mmol) 1- (ethyl-Val-Lys (N-Fmoc)-OBzl)-B-carboline -3- benzyl carboxylates are used
25mL anhydrous methylene chlorides dissolve in the eggplant bottle of 100mL, and hexahydropyridine 5mL, TLC after ice bath reacts 2 hours are added dropwise under ice bath
(CHCl3/ MeOH=8/1) reaction completes petroleum ethers and wears away repeatedly, purify (methylene chloride/methanol with thin-layer chromatography is prepared
=10/1, be unfolded twice), title compound 6mg (14%) is obtained, is pale yellow oil .ESI-MS (m/e) 665.6 [M+H]+；IR(KBr)：3435.22,2960.73,2924.09,2873.94,
1734.01,1718.58,1597.06,1456.26,1448.54,1375.25,1348.24,1305.81,1251.80,
1203.58,1193.94,1155.36,1141.86,1083.99,1002.98,985.62,937.40,908.47,848.68,
823.60 765.74,756.10cm-1；1H NMR (300MHz, CDCl3)δ/ppm：11.69 (br s, 1H), 8.13 (br s,
1H), 7.81 (br s, 1H), 7.55~7.28 (m, 12H), 7.15 (m, 1H), 5.33 (m, 2H), 5.19 (d, J=12.0Hz,
1H), 5.10 (d, J=12.0Hz, 1H), 4.66 (m, 1H), 3.50 (m, 2H), 3.11 (m, 4H), 2.09 (m, 1H), 1.99~
1.85 (m, 5H), 1.64 (m, 4H), 1.28 (s, 2H), 0.95 (d, J=3.0Hz, 3H), 0.94 (d, J=6.0Hz, 3H).
Embodiment 17 prepares 1- (ethyl-Val-Arg (NG-NO2)-OBzl)-B-carboline -3- benzyl carboxylates (5n)
According to the method for embodiment 4, by 533.4mg (1.2mmol) HClVal-Arg (NG-NO2)-OBzl and 344mg
(1mmol) 1- aldehyde-bases-B-carboline -3- benzyl carboxylates obtain 59mg (8%) title compound, are pale yellow oil .ESI-MS
(m/e)737.9[M+H]+；IR(KBr)：3408.22,2958.80,
2931.80,2872.01,1735.93,1718.58,1676.14,1637.56,1577.77,1560.41,1541.12,
1458.18,1375.25,1336.67,1247.94,1213.23,1182.36,1151.50,1136.07,1101.35,
1074.35,1055.06,1028.06,1012.63,974.05,939.33,9000.76,848.68,837.11,785.03,
738.40 696.30,634.58cm-1；1H NMR (300MHz, CDCl3)δ/ppm：10.49 (br s, 1H), 8.72 (s, 1H),
8.11 (d, J=9.0Hz, 2H), 7.86 (br s, 2H), 7.65~7.28 (m, 13H), 5.47 (s, 2H), 5.23 (d, J=
12.0Hz, 1H), 5.10 (d, J=12.0Hz, 1H), 4.66 (m, 1H), 3.42 (m, 1H), 3.28 (m, 1H), 3.22 (m, 2H),
3.05~2.89 (m, 3H), 2.41 (m, 2H), 1.98 (m, 2H), 1.80~1.45 (m, 3H), 0.91 (d, J=6.0Hz, 3H),
0.86 (d, J=6.0Hz, 3H).
Embodiment 18 prepares 1- (ethyl-Val-Asn-OBzl)-B-carboline -3- benzyl carboxylates (5o)
According to the method for embodiment 4, by 429mg (1.2mmol) HClVal-Asn-OBzl and 344mg (1mmol) 1- second
Aldehyde radical-B-carboline -3- benzyl carboxylates obtain 30mg (5%) title compound, are 649.9 [M of pale yellow oil .ESI-MS (m/e)
+H]+；IR(KBr)：3334.92,3226.91,3066.82,3034.03,
2960.73,2870.08,1718.58,1676.14,1662.64,1647.21,1624.06,1600.92,1570.06,
1560.41,1500.62,1456.26,1379.10,1348.24,1307.74,1249.87,1215.15,1157.29,
1139.93,1103.28,1039.63,1028.06,914.26,894.97,742.59,696.30,619.15,605.65,
540.07cm-1；1HNMR (300MHz, CDCl3)δ/ppm：10.49 (s, 1H), 8.66 (d, J=9.0Hz, 1H), 8.50 (s,
1H), 8.03 (d, J=6.0Hz, 1H), 7.57 (d, 2H), 7.85~7.36 (m, 4H), 7.36~7.26 (m, 3H), 7.15~
7.05 (m, 3H), 6.87 (d, 2H), 6.28 (s, 1H), 5.83 (s, 1H), 5.52 (dd, J=15.0Hz, J=12.0Hz, 2H),
4.92 (m, 1H), 4.88 (dd, J=12.0Hz, J=12.0Hz, 2H), 3.50 (m, 1H), 3.33 (m, 1H), 3.21 (dd, J=
6.0Hz, J=6.0Hz, 1H), 2.93 (m, 1H), 2.81 (d, J=6.0Hz, 3H), 2.76 (d, J=3.0Hz, 3H), 2.15 (m,
1H), 1.71 (m, 1H), 1.00 (d, J=6.0Hz, 3H), 0.92 (d, J=6.0Hz, 3H).
Embodiment 19 prepares 1- (ethyl-Val-Gln-OBzl)-B-carboline -3- benzyl carboxylates (5p)
According to the method for embodiment 4, by 446mg (1.2mmol) HClVal-Gln-OBzl and 344mg (1mmol) 1- second
Aldehyde radical-B-carboline -3- benzyl carboxylates obtain 25mg (4%) title compound, are 664.0 [M of pale yellow oil .ESI-MS (m/e)
+H]+；IR(KBr)：3439.08,3288.63,3219.19,3207.62,
3192.19,3174.83,3155.54,3088.03,3062.96,3034.03,3010.88,2958.80,2929.87,
2893.22,2872.01,2854.65,2819.93,1716.65,1662.64,1600.92,1568.13,1500.62,
1456.26,1417.68,1379.10,1348.24,1303.88,1251.80,1213.23,1176.58,1155.36,
1136.07,1101.35,1083.99,1028.06,972.12,910.40,852.54,840.96,786.96,738.74,
696.30,675.09cm-1；1HNMR (300MHz, CDCl3) δ/ppm：10.83 (br s, 1H), 8.64 (s, 1H), 8.29 (d, J
=9.0Hz, 1H), 8.12 (d, J=9.0Hz, 1H), 7.54~7.48 (m, 4H), 7.48~7.20 (m, 9H), 6.22 (s, 1H),
5.97 (m, 1H), 5.49 (s, 2H), 5.19 (dd, J=12.0Hz, J=12.0Hz, 2H), 4.69 (m, 1H), 3.41 (m, 2H),
3.08 (d, J=6.0Hz, 1H), 3.06 (d, J=6.0Hz, 1H), 2.97 (d, J=3.0Hz, 1H), 2.35 (m, 1H), 2.32
(m, 1H), 2.16 (m, 1H), 2.10 (m, 2H), 0.92 (d, J=6.0Hz, 3H), 0.90 (d, J=6.0Hz, 3H).
Embodiment 20 prepares 1- (ethyl-Val-Cys (pMeOBzl)-OBzl)-B-carboline -3- benzyl carboxylates (5q)
According to the method for embodiment 4, by 560mg (1.2mmol) HClVal-Cys (pMeOBzl)-OBzl and 344mg
(1mmol) 1- aldehyde-bases-B-carboline -3- benzyl carboxylates obtain 25mg (3%) title compound, are pale yellow oil .ESI-MS
(m/e)760.3[M+H]+；IR(KBr)：3439.08,2951.09,
2360.87,2345.44,1865.17,1824.66,1772.58,1718.58,1701.22,1653.00,1635.64,
1560.41,1541.12,1496.76,1458.18,1375.25,1340.53,1247.94,758.02,727.16,704.02,
621.08em-1；1H NMR (300MHz, CDCl3)δ/ppm：10.36 (br s, 1H), 8.78 (s, 1H), 8.17 (d, J=
9.0Hz, 1H), 7.92 (d, J=9.0Hz, 1H), 7.60~7.50 (m, 4H), 7.45~7.20 (m, 12H), 7.16 (d, J=
6.0Hz, 1H), 6.78 (d, J=9.0Hz, 1H), 5.53 (s, 2H), 5.32 (d, J=12.0Hz, 1H), 5.21 (d, J=
12.0Hz, 1H), 5.03 (m, 1H), 3.75 (s, 2H), 3.70 (s, 1H), 3.66 (s, 1H), 3.51 (m, 1H), 3.40 (m, 1H),
3.13 (m, 2H), 2.99 (d, J=3.0Hz, 1H), 2.91 (d, J=6.0Hz, 2H), 2.11 (m, 1H), 1.03 (d, J=
6.0Hz, 3H), 0.99 (d, J=6.0Hz, 3H).
Experimental example 1 measures inhibiting effect of the compound 5a-q to tumor cell proliferation
1) the compound of the present invention 5a-q is configured to required concentration with the culture medium containing 0.1%DMSO.
2) tumour cell of experiment be HL-60 (human promyelocytic leukemia), A549 (lung carcinoma cell),
Be17402 (liver cancer cells), SH-sy5y (human neuroblastoma), S180 (mouse ascites oncocyte), MCF-7 (human breast carcinomas
Cell).
3) experimental method HL-60, MCF-7, Bel-7402, A549 and S180 cell select RPMI-1640 culture mediums；SH-
Sy5y cells, which are selected, contains 10% fetal calf serum and 1 × 10 through inactivation in DMEM culture medium culture mediums5U/L penicillin and
100mg/L streptomysins.
The culture of attached cell MCF-7, Bel-7402, A549, SH-sy5y and half attached cell S180：It respectively will growth
In good condition, the cell in exponential phase is with 4 × 104The density of a/mL is inoculated in 96 orifice plates, per 100 μ L of hole, is placed in 37
DEG C and 5%CO2Cell incubation case in cultivate 6 hours, the compound of sterilized processing is then added by preset concentration gradient
The solution that 5a-q is configured to the culture medium containing 0.1%DMSO, per 25 μ L of hole, the molten of isometric sample dissolution is added in control group
After matchmaker continues culture 48 hours, the MTT solution of 25 a concentration of 5mg/mL of μ L is added per hole, is placed in 37 DEG C and 5%CO2Cell incubate
It educates and cultivates the DMSO that 4 hours carefully remove 100 μ L of every hole addition after supernatant in case, oscillation about 10min dissolves purple powder
(first a ceremonial jade-ladle, used in libation), immediately in detection O.D. (absorbance) value, wavelength 570nm in microplate reader.
The culture of suspension cell HL60：Respectively that growth conditions are good, the cell in exponential phase is with 5 × 104A/
The density of mL is inoculated in 96 orifice plates, and per 100 μ L of hole, the compound 5a-q of sterilized processing is then added by preset concentration gradient
The solution being configured to the culture medium containing 0.1%DMSO, per 25 μ L of hole, the solvent of isometric sample dissolution is added in control group,
It is placed in 37 DEG C and 5%CO2Cell incubation case in cultivate the MTT solution that 25 a concentration of 5mg/mL of μ L are added per hole by 48 hours, after
The continuous condition that is placed in is 37 DEG C and 5%CO2Cell incubation case in cultivate 4 hours .3000rpm centrifugation 10min, supernatant is carefully sucked out
100 μ L DMSO, oscillation about 10min dissolving purple powders (first a ceremonial jade-ladle, used in libation), immediately in detecting O.D. in microplate reader are added per hole for liquid
(absorbance) value, wavelength 570nn.
The activity that compound 5a-q under each concentration inhibits tumor cell proliferation is found out as the following formula：
Cell Proliferation (%)=(compound 5a-q groups be averaged O.D. values/control group be averaged O.D. values) × 100%, experiment weight
It is 3 times multiple, it is mapped to drug concentration with cell Proliferation, IC is found out by graphing method50(half effective inhibition concentration) value.
4) 1 and table 2 be the results are shown in Table.The result shows that compound 5a-q is to HL-60, MCF-7, Bel-7402, A549 and S180
Specific inhibiting effect is all shown with SH-sy5y tumor cell proliferations.
1 compound 5a-q of table inhibits the IC of tumor cell proliferation50(+SD μM of mean value)
2 compound 5a-q of table inhibits the IC of tumor cell proliferation50(+SD μM of mean value)
Experimental example 2 evaluates the internal antitumor activity of compound 5a-q
1) the compound of the present invention 5a-q is configured to suspension positive control adriamycins with 0.5% sodium carboxymethylcellulose
2 μm of ol/kg normal saline solutions are configured to, it is negative that positive control cytarabine is configured to 8.2 μm of ol/kg normal saline solutions
For 0.5% sodium carboxymethyl cellulose solution.
2) compound 5a-q gastric infusions, dosage are 1 μm of ol/kg, and successive administration 7 days is administered 7 times altogether；Adriamycin abdominal cavity
Injection, dosage are 2 μm of ol/kg, and successive administration 7 days is administered 7 times altogether；Cytarabine is injected intraperitoneally, and dosage is 8.2 μm of ol/kg,
It is administered within continuous 7 days 7 days, is administered 7 times altogether；0.5% sodium carboxymethyl cellulose solution gastric infusion, dosage 0.2mL/20g, even
It is 7 days continuous.
3) experimental animal is ICR male mices (cleaning grade), 20 ± 2g of weight, every group of 12 mouse.
4) knurl source is mouse S 180 sarcoma, is purchased from Department Of Medicine, Peking University's animal experimental center, and voluntarily passage maintains.
5) animal model is inoculated with eugonic S180 ascites tumors tumor liquid with extraction under treatment aseptic condition, uses physiological saline
The liquid for being diluted to (1: 2) is sufficiently mixed, and 0.2% Trypan Blue of tumor cell suspension Fresh is pressed after mixing
White blood cell count(WBC) method counts, and dye blue person is dead cell, and tinter is not living cells, and cell concentration is calculated as follows
And cell survival rate.
Viable count/4 × 10 in the block plaid of cell concentration=44× extension rate=cell number/mL
Cell survival rate=viable count/(viable count+dead cell number) × 100%
Tumor liquid by survival rate more than 90% is prepared into 1.5 × 10 with homogenate method7The cell suspension of a/mL, in mouse armpit skin
Lower inoculation, 0.2mL/ only, after manufacturing S180 tumor-bearing mice tumor inoculations for 24 hours, according to dosage above and give daily by each group mouse
Medicinal strip part is treated experiments and is carried out to the 8th day, and mouse weight, etherization, cervical dislocation is claimed to put to death mouse, then fixed with tweezers
The right armpit tumor location of mouse cuts off skin, exposure tumour, and blunt separation is weighed, and tumour inhibiting rate is calculated as follows：Suppression
Test number in ratio of outflow %=(negative control group average knurl weight-administration group average knurl weight)/negative control group average knurl weight × 100%.
Indicate that the results are shown in Table 3 according to using t inspections and variance analysis, knurl weight with mean value+SD g.As can be seen from Table 3, in 1 μm of ol/kg
Oral dose under, the knurl weight of compound 5a-q treatment groups mouse is significantly less than the treatment of 0.5% sodium carboxymethyl cellulose solution
The knurl weight of group mouse illustrates that they have effective antitumour active.Their this effective dose (1 μm of ol/kg) is than invention
The effective dose (8.9 μm of ol/kg) of 1- (ethyl-AA-OBzl)-B-carboline -3- benzyl carboxylates of human hair table is 8.9 times low.In 1 μ
Under the oral dose of mol/kg, the knurl weight of compound 5e, d treatment groups mouse is treated with the cytarabine that dosage is 8.2 μm of ol/kg
The knurl weight of mouse is suitable, illustrates that its effective dose is 8.2 times lower than the effective dose of cytarabine.In the oral agents of 1 μm of ol/kg
Under amount, knurl weight and the dosage of compound 5e treatment groups mouse are that the knurl weight of doxorubicin mouse of 2 μm of ol/kg is suitable, explanation
Its effective dose is 2 times lower than the effective dose of adriamycin.
Influences (mean value+SD g) of the 3 compound 5a-q of table to S180 tumor weights
N=12；A) with 0.5% sodium carboxymethyl cellulose solution group ratio P ＜ 0.01；B) with 0.5% carboxymethyl cellulose
Sodium water solution group ratio P ＜ 0.01, the P ＞ 0.05, c compared with cytarabine and adriamycin group) and 0.5% sodium carboxymethylcellulose water
Solution group compares P ＜ 0.01, the P ＞ 0.05 compared with cytarabine group.
Experimental example 3 measures the transmission electron microscope photo of compound 5a-q
By compound 5a-q according to 6 × 10-7The pH7.4PBS solution of the concentration configuration compound of M, is uniformly layered on copper mesh
On, the self-assembly property that compound is observed under transmission electron microscope (TEM, JEM-1230, JEOL) obtains the photo results such as Fig. 2
Show that compound 5a-q can form nano particle in pH7.4PBS solution, nanometer particle size is between 63-1045nm.
Claims (4)
1. 1- (ethyl-Val-AA-OBzl)-B-carboline -3- benzyl carboxylates of following formula, AA is Gly, L-Ala, L-Phe, L- in formula
Val,L-Asp(OBzl),L-Trp,L-Ile,L-Leu,L-Thr,L-Ser,L-Met,L-Pro,L-Asn,L-Gln,L-Cys
(pMeOBzl),L-Arg(NG-NO2) and L-Lys residues,
2. the preparation method of 1- (ethyl-Val-AA-OBzl)-B-carboline -3- benzyl carboxylates of claim 1, this method include：
(1) L-Trp benzyl ester is subjected to Pictet- under trifluoroacetic catalysis with 1,1,3,3- tetramethoxy propanes
Spengler is condensed, and obtains 1- (2,2- dimethoxy ethyls) -1,2,3,4- tetrahydro-beta-carboline -3- benzyl carboxylates；
(2) 1- (2,2- dimethoxy ethyls) -1,2,3,4- tetrahydro-beta-carboline -3- benzyl carboxylates in tetrahydrofuran, are used into Gao Meng
Sour aqueous solutions of potassium aoxidizes to obtain 1- (2,2- dimethoxy ethyls)-B-carboline -3- benzyl carboxylates；
(3) 1- (2,2- dimethoxy ethyls)-B-carboline -3- benzyl carboxylates are hydrolyzed to 1- second in glacial acetic acid, concentrated hydrochloric acid, mixed liquor
Aldehyde radical-B-carboline -3- benzyl carboxylates；
(4) it is coupled 1- aldehyde-bases-B-carboline -3- benzyl carboxylates and HClVal-Ala-OBzl to obtain 1- (ethyl-Val-
Ala-OBzl)-B-carboline -3- benzyl carboxylates；
(5) it is coupled 1- aldehyde-bases-B-carboline -3- benzyl carboxylates and HClVal-Phe-OBzl to obtain 1- (ethyl-Val-
Phe-OBzl)-B-carboline -3- benzyl carboxylates；
(6) it is coupled 1- aldehyde-bases-B-carboline -3- benzyl carboxylates and HClVal-Trp-OBzl to obtain 1- (ethyl-Val-
Trp-OBzl)-B-carboline -3- benzyl carboxylates；
(7) it is coupled 1- aldehyde-bases-B-carboline -3- benzyl carboxylates and HClVal-Val-OBzl to obtain 1- (ethyl-Val-
Val-OBzl)-B-carboline -3- benzyl carboxylates；
(8) it is coupled 1- aldehyde-bases-B-carboline -3- benzyl carboxylates and HClVal-Asp (OBzl)-OBzl to obtain 1- (ethyls -
Val-Asp (OBzl)-OBzl)-B-carboline -3- benzyl carboxylates；
(9) it is coupled 1- aldehyde-bases-B-carboline -3- benzyl carboxylates and HClVal-Ile-OBzl to obtain 1- (ethyl-Val-
Ile-OBzl)-B-carboline -3- benzyl carboxylates；
(10) it is coupled 1- aldehyde-bases-B-carboline -3- benzyl carboxylates and HClVal-Leu-OBzl to obtain 1- (ethyl-Val-
Leu-OBzl)-B-carboline -3- benzyl carboxylates；
(11) it is coupled 1- aldehyde-bases-B-carboline -3- benzyl carboxylates and HClVal-Gly-OBzl to obtain 1- (ethyl-Val-
Gly-OBzl)-B-carboline -3- benzyl carboxylates；
(12) it is coupled 1- aldehyde-bases-B-carboline -3- benzyl carboxylates and HClVal-Thr-OBzl to obtain 1- (ethyl-Val-
Thr-OBzl)-B-carboline -3- benzyl carboxylates；
(13) it is coupled 1- aldehyde-bases-B-carboline -3- benzyl carboxylates and HClVal-Ser-OBzl to obtain 1- (ethyl-Val-
Ser-OBzl)-B-carboline -3- benzyl carboxylates；
(14) it is coupled 1- aldehyde-bases-B-carboline -3- benzyl carboxylates and HClVal-Met-OBzl to obtain 1- (ethyl-Val-
Met-OBzl)-B-carboline -3- benzyl carboxylates；
(15) it is coupled 1- aldehyde-bases-B-carboline -3- benzyl carboxylates and HClVal-Pro-OBzl to obtain 1- (ethyl-Val-
Pro-OBzl)-B-carboline -3- benzyl carboxylates；
(16) by 1- aldehyde-bases-B-carboline -3- benzyl carboxylates and HClVal-Lys (Nω- Fmoc)-OBzl is coupled to obtain 1- (second
Base-Val-Lys (Nω- Fmoc)-OBzl)-B-carboline -3- benzyl carboxylates, by 1- (ethyl-Val-Lys (Nω-Fmoc)-OBzl)-
B-carboline -3- benzyl carboxylates are added dropwise hexahydropyridine in anhydrous methylene chloride, under condition of ice bath and obtain 1- (ethyl-Val-Lys-
OBzl)-B-carboline -3- benzyl carboxylates；
(17) by 1- aldehyde-bases-B-carboline -3- benzyl carboxylates and HClVal-Arg (NG-NO2)-OBzl is coupled to obtain 1- (second
Base-Val-Arg (NG-NO2)-OBzl)-B-carboline -3- benzyl carboxylates；
(18) it is coupled 1- aldehyde-bases-B-carboline -3- benzyl carboxylates and HClVal-Asn-OBzl to obtain 1- (ethyl-Val-
Asn-OBzl)-B-carboline -3- benzyl carboxylates；
(19) it is coupled 1- aldehyde-bases-B-carboline -3- benzyl carboxylates and HClVal-Gln-OBzl to obtain 1- (ethyl-Val-
Gln-OBzl)-B-carboline -3- benzyl carboxylates；
(20) it is coupled 1- aldehyde-bases-B-carboline -3- benzyl carboxylates and HClVal-Cys (pMeOBzl)-OBzl to obtain 1- (second
Base-Val-Cys (pMeOBzl)-OBzl)-B-carboline -3- benzyl carboxylates.
3. the nanostructure of 1- (ethyl-Val-AA-OBzl)-B-carboline -3- benzyl carboxylates of claim 1.
4. 1- (ethyl-Val-AA-OBzl)-B-carboline -3- benzyl carboxylates of claim 1 answering in the preparation of antitumor drugs
With.
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| CN1370778A (en) * | 2001-12-20 | 2002-09-25 | 浙江医药股份有限公司新昌制药厂 | Beta-tetrahydro carboline carboxylic acid, its RGD conjugate, their synthesis and medical application |
| CN1743326A (en) * | 2004-09-03 | 2006-03-08 | 首都医科大学 | Carboline carboxylate derivative, and its synthesizing method and use |
| CN101906102A (en) * | 2009-06-02 | 2010-12-08 | 首都医科大学 | Beta-carboline alkaloid derivative, preparation method and application thereof |
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| CN1370778A (en) * | 2001-12-20 | 2002-09-25 | 浙江医药股份有限公司新昌制药厂 | Beta-tetrahydro carboline carboxylic acid, its RGD conjugate, their synthesis and medical application |
| CN1743326A (en) * | 2004-09-03 | 2006-03-08 | 首都医科大学 | Carboline carboxylate derivative, and its synthesizing method and use |
| CN101906102A (en) * | 2009-06-02 | 2010-12-08 | 首都医科大学 | Beta-carboline alkaloid derivative, preparation method and application thereof |
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