CN110105428B - Leu-Arg-Ala-Pro-Leu-Tyr-Val heptapeptide, synthesis, activity and application thereof - Google Patents
Leu-Arg-Ala-Pro-Leu-Tyr-Val heptapeptide, synthesis, activity and application thereof Download PDFInfo
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract
The invention discloses a Leu-Arg-Ala-Pro-Leu-Tyr-Val heptapeptide, discloses a preparation method thereof, discloses analgesic activity thereof, discloses anti-inflammatory activity thereof, discloses anti-tumor activity thereof, discloses anti-thrombotic activity thereof and discloses thrombolytic activity thereof, and thus the invention discloses the application thereof in preparing analgesics, anti-inflammatory drugs, anti-tumor drugs, antithrombotic drugs and thrombolytic drugs.
Description
Technical Field
The invention relates to Leu-Arg-Ala-Pro-Leu-Tyr-Val heptapeptide, relates to a preparation method thereof, relates to analgesic activity thereof, relates to anti-inflammatory activity thereof, relates to anti-tumor activity thereof, relates to anti-thrombotic activity thereof and relates to thrombolytic activity thereof, so that the invention relates to application thereof in preparing analgesics, anti-inflammatory drugs, anti-tumor drugs, antithrombotic drugs and thrombolytic drugs. The invention belongs to the field of biological medicine.
Background
The invention relates to oligopeptide with the effects of resisting tumor, thrombus, blood coagulation and pain, which is a field of long-term attention of the inventor. Although the inventors have disclosed a series of oligopeptides having these activities, no oligopeptides having these activities as a whole have been obtained. The present inventors have found that heptapeptides of the general formula Leu-Arg-Ala-Pro-Leu-Tyr-Val are oligopeptides having an analgesic effect, an anti-inflammatory effect, an antitumor effect, an antithrombotic effect and a thrombolytic effect, and have made the present invention based on these findings.
Disclosure of Invention
The first aspect of the present invention is to provide a Leu-Arg-Ala-Pro-Leu-Tyr-Val heptapeptide.
The second content of the invention is to provide a synthesis method of Leu-Arg-Ala-Pro-Leu-Tyr-Val heptapeptide, which comprises the following steps:
(1) preparing Boc-Tyr-Val-OBzl under the catalysis of DCC and HOBt according to a standard method;
(2) Boc-Tyr-Val-OBzl is removed from Boc at 0 ℃ in 4N hydrogen chloride-ethyl acetate solution and converted into Tyr-Val-OBzl; (3) preparing Boc-Ala-Pro-OBzl under the catalysis of DCC and HOBt;
(4) Boc-Ala-Pro-OBzl is converted into Boc-Ala-Pro by hydrogenolysis under the catalysis of Pd/C;
(5) preparing Boc-Leu-Tyr-Val-OBzl under the catalysis of DCC and HOBt;
(6) Boc-Leu-Tyr-Val-OBzl is subjected to Boc removal at 0 ℃ in a hydrogen chloride-ethyl acetate solution with the concentration of 4N and converted into Leu-Tyr-Val-OBzl;
(7) preparing Boc-Ala-Pro-Leu-Tyr-Val-OBzl under the catalysis of DCC and HOBt;
(8) Boc-Ala-Pro-Leu-Tyr-Val-OBzl in 4N hydrogen chloride-ethyl acetate solution at 0 ℃ to remove Boc and convert into Ala-Pro-Leu-Tyr-Val-OBzl;
(9) preparation of Boc-Leu-Arg (NO) under catalysis of DCC and HOBt 2 )-OBzl；
(10)Boc-Leu-Arg(NO 2 ) Conversion of-OBzl to Boc-Leu-Arg (NO) at 0 ℃ in 2N NaOH solution 2 )；
(11) Preparation of Boc-Leu-Arg (NO) under catalysis of DCC and HOBt 2 )-Ala-Pro-Leu-Tyr-Val-OBzl；
(12)Boc-Leu-Arg(NO 2 ) Deprotection of-Ala-Pro-Leu-Tyr-Val-OBzl in trifluoroacetic acid and trifluoromethanesulfonic acid at 0 ℃ to convert to Leu-Arg-Ala-Pro-Leu-Tyr-Val.
The third aspect of the present invention is to evaluate the analgesic effect of the Leu-Arg-Ala-Pro-Leu-Tyr-Val heptapeptide.
The fourth aspect of the present invention is to evaluate the anti-inflammatory effect of the Leu-Arg-Ala-Pro-Leu-Tyr-Val heptapeptide.
The fifth aspect of the present invention is to evaluate the antitumor effect of the Leu-Arg-Ala-Pro-Leu-Tyr-Val heptapeptide.
The sixth aspect of the present invention is to evaluate the antithrombotic effect of the Leu-Arg-Ala-Pro-Leu-Tyr-Val heptapeptide.
The seventh content of the present invention is to evaluate the thrombolytic effect of Leu-Arg-Ala-Pro-Leu-Tyr-Val heptapeptide.
Drawings
FIG. 1 Synthesis of Glu-Thr-Ala-Pro-Tyr-Val heptapeptide route i) Dicyclohexylcarbodiimide (DCC), 1-hydroxybenzotriazole (HOBt), N-methylmorpholine (NMM), Tetrahydrofuran (THF); ii) H 2 Pd/C; iii)4N HCl/EA,0 ℃; iv)2N NaOH, 0 ℃; v) trifluoroacetic acid (TFA), and three-fold methanesulfonic acid (TFMSA).
Detailed Description
To further illustrate the invention, a series of examples are given below. These examples are purely illustrative and are intended to be a detailed description of the invention only and should not be taken as limiting the invention.
EXAMPLE 1 preparation of Boc-Ala-Pro-OBzl
Under ice-bath, 1.89g (10mmol) of Boc-Ala was dissolved in a small amount of anhydrous Tetrahydrofuran (THF), 1.36g (10mmol) of HOBt was added, a solution of 2.47g (12mmol) of DCC and a small amount of anhydrous THF was added, activation was carried out for 30 minutes, 2.03g (10mmol) of Pro-OBzl was added, pH was adjusted to 9 with NMM, and Dicyclohexylurea (DCU) was removed by filtration after completion of the reaction. Concentrating the filtrate under reduced pressure, dissolving the residue with ethyl acetate, filtering DCU again, and filtering the filtrate with NaHCO 3 Washing with saturated solution for 3 times, washing with NaCl saturated solution for 3 times, and washing with 5% KHSO 4 Washing with NaCl saturated solution 3 times, 5% NaHCO 3 Extracting and washing with NaCl saturated solution for 3 times, and extracting ethyl acetate layer with anhydrous Na 2 SO 4 Drying for 12 hours, filtering Na 2 SO 4 The filtrate was concentrated under reduced pressure to give 2.04g (54.3%) of the title compound as a colorless oilAnd (4) forming a substance. ESI + -MS(m/e):377[M+H] + 。
EXAMPLE 2 preparation of Boc-Ala-Pro
3.76g (10mmol) of Boc-Ala-Pro-OBzl was dissolved in methanol, and 488mg of 10% Pd/C was added. Connecting the three-way valve, decompressing and pumping the air in the eggplant bottle, and filling the reaction bottle with H 2 This operation was repeated 3 times. The starting material point disappeared after 20h of reaction. The Pd/C was filtered off and the methanol was rotary dried. 2.83g (99%) of the title compound are obtained as a colorless powder. ESI + -MS(m/e):287[M+H] + 。
EXAMPLE 3 preparation of Boc-Leu-Tyr-Val-OBzl
From 2.31g (10mmol) Boc-Leu and 3.7g (10mmol) Tyr-Val-OBzl, 3.67g (63.0%) of the title compound were obtained as colorless powder according to the method of example 1. ESI + -MS(m/e):491[M+H] + 。
EXAMPLE 4 preparation of Leu-Tyr-Val-OBzl
5.83g (10mmol) of Boc-Leu-Tyr-Val-OBzl was dissolved in a small amount of dried ethyl acetate in ice bath, stirred for 10min, and 50mL of hydrogen chloride-ethyl acetate solution (4N) was added to react for 4h, and the starting material point disappeared. The reaction mixture was concentrated to dryness under reduced pressure, the residue was dissolved in 40mL of dried ethyl acetate, and the resulting solution was concentrated to dryness under reduced pressure. The residue was repeated 3 times according to this procedure. The residue was taken up in anhydrous ether, triturated with a plastic spatula and concentrated under reduced pressure to remove the ether. The residue was repeated 3 times according to this procedure. 4.95g (99.9%) of the title compound are obtained as a yellow powder. ESI + -MS(m/e):391[M+H] + 。
EXAMPLE 5 preparation of Boc-Ala-Pro-Leu-Tyr-Val-OBzl
Following the procedure of example 1, from 2.86g (10mmol) Boc-Ala-Pro and 4.83g (10mmol) Leu-Tyr-Val-OBzl, 3.32g (44.5%) of the title compound were obtained as colorless powder. ESI + -MS(m/e):659[M+H] + 。
EXAMPLE 6 preparation of Ala-Pro-Leu-Tyr-Val-OBzl
6.05g (92.5%) of the title compound were obtained as colorless powder from 7.51g (10mmol) of Boc-Ala-Pro-Leu-Tyr-Val-OBzl according to the method of example 4. ESI + -MS(m/e):559[M+H] + 。
EXAMPLE 7 preparation of Boc-Leu-Arg (NO) 2 )-OBzl
Following the procedure of example 1, 2.31g (10mmol) Boc-Leu and 3.09g (10mmol) Arg (NO) 2 ) OBzl gave 3.64g (69.7%) of a white oil. ESI + -MS(m/e):524[M+H] + 。
EXAMPLE 8 preparation of Boc-Leu-Arg (NO) 2 )
5.22g (10mmol) of Boc-Leu-Arg (NO) were added under ice-bath 2 ) -OBzl is dissolved in methanol, stirred for 10min, 2N NaOH solution is added dropwise, and the pH is adjusted to 13-14. The reaction was kept in an ice bath for 4 hours and was complete. The reaction solution was saturated KHSO in ice bath 4 Adjusting pH of the solution to neutral, concentrating under reduced pressure to remove methanol, and adding saturated KHSO 4 The solution was adjusted to pH 2. The reaction solution was extracted 3 times with ethyl acetate. The resulting solution was washed with saturated NaCl solution to neutrality and anhydrous Na 2 SO 4 Drying for 12 h, filtration and concentration of the filtrate under reduced pressure gave 4.89g (100%) of the title compound as a colorless oil. ESI + -MS(m/e):433[M+H] + 。
EXAMPLE 9 preparation of Boc-Leu-Arg (NO) 2 )-Ala-Pro-Leu-Tyr-Val-OBzl
From 4.31g (10mmol) Boc-Leu-Arg (NO) according to example 1 2 ) And 6.51g (10mmol) Ala-Pro-Leu-Tyr-Val-OBzl gave 3.24g (31.6%) of the title compound as a colorless jelly-like compound. ESI + -MS(m/e):973[M+H] + ； 1 H-NMR(300MHz,DMSO-d6):δ/ppm＝9.14(s,1H),8.51(s,1H),8.20(m,2H),7.78(m,4H), 7.36(m,5H),6.93(d,J＝8.4Hz,3H),6.59(d,J＝8.4Hz,2H),5.13(s,2H),4.50(m,2H),4.31.89(m, 2H),4.18(m,2H),3.94(m,1H),3.52(s,2H),3.13(m,2H),2.89(m,1H),2.63(m,1H),2.05(m,2H), 1.89(m,2H),1.72(m,1H),1.50(m,6H),1.37(m,13H),1.16(d,J＝7.5Hz,3H),0.835(m,18H)。
EXAMPLE 10 preparation of Leu-Arg-Ala-Pro-Leu-Tyr-Val (GQ-L)
106mg (0.1mmol) of Boc-Leu-Arg (NO) under ice-bath 2 ) Dissolving the-Ala-Pro-Leu-Tyr-Val-OBzl with 4mL of TFFA (trifluoroacetic acid), stirring for 10min, adding 1mL of TFMSA (trifluoromethanesulfonic acid), reacting for 30min, and basically completing the reaction and eliminating the raw material points. Adding anhydrous diethyl etherAdding into eggplant bottle, grinding and washing with plastic shovel, and pouring ether; the operation was repeated three times. The final product was obtained as a tan powder, dissolved in triple distilled water, adjusted to pH 7 with ammonia, loaded onto Sephdex G10 to yield 78mg (72.9%) of the title compound as a colorless powder. ESI + -MS(m/e):804[M+H] + ；Mp 159.5～16.2℃.
(c ═ 0.09, methanol) IR:3297,2965,1656,1518,1469,1346,1239,1224,1167,1027,831,762,636, 578. 1 H-NMR(300MHz,DMSO-d6):δ/ppm＝8.58(d,J＝7.5Hz,1H),8.22(s,2H),8.06(s,3H), 7.87(m,1H),7.40(m,3H),6.97(d,J＝8.4Hz,2H),6.60(d,J＝8.4Hz,2H),4.61(m,2H),4.32(m,2H), 4.15(m,3H),3.81(m,3H),3.39(m,1H),3.09(d,J＝4.5Hz,2H),2.06(m,1H),1.40-1.95(m,10H), 1.02-1.49(m,9H),0.85(m,18H)。
Example 11 evaluation of the analgesic Activity of Leu-Arg-Ala-Pro-Leu-Tyr-Val (GQ-L)
Male ICR mice (20 + -2 g) were loaded into a mouse holder, and their tails were exposed outside the holder, marked one third from the tail tip, used as sensor points for photoreceptors, and irradiated at two thirds of the distance from the tail tip. Preheating the pain measuring instrument for 30min, and covering the mouse tail with the light sensation instrument at the timing. The time is measured as the time when the mouse feels pain, the time is measured continuously for 3 times, the measurement interval is 5min each time, and the average value is obtained. The pain feeling time of the mice without the medicine is the basic pain feeling time. The pain feeling time change of the mice caused by the medicine taking reflects the analgesic activity of the medicine. The mice are randomly grouped into 14 mice per group, and after the basic pain feeling time is measured, the mice are orally taken with 0.2mL of physiological saline solution of Leu-Arg-Ala-Pro-Leu-Tyr-Val (GQ-L), the dosage is 1 mu mol/kg or orally taken with 0.2mL of physiological saline or oral aspirin, and the dosage is 1200 mu mol/kg. The time to pain development in mice was measured at 30,60,90,120,150 and 180min after dosing. Data are presented as mean ± SD seconds, shown in table 1, analyzed by variance and tested by t. The data indicate that the time for the mice to develop a pain sensation after 30,60,90,120,150 and 180min of normal saline was administered orally is not significantly different from the basal pain sensation time prior to normal saline administration; the time for the mice to generate pain after oral administration of 1200 mu mol/kg aspirin 60,90,120,150 and 180min is significantly longer than the basic pain time before oral administration of the aspirin; the time for the mice to develop pain after 1. mu. mol/kg Leu-Arg-Ala-Pro-Leu-Tyr-Val (GQ-L) oral administration 30,60,90,120,150 and 180min was significantly longer than the basal pain time before it was orally administered. The analgesic activity of Leu-Arg-Ala-Pro-Leu-Tyr-Val (GQ-L) after 120,150 and 180min was comparable to oral 1200. mu. mol/kg aspirin. And the analgesic activity of Leu-Arg-Ala-Pro-Leu-Tyr-Val (GQ-L) after 30,60 and 90min is stronger than that of 1200 mu mol/kg aspirin.
TABLE 1 analgesic Activity of Leu-Arg-Ala-Pro-Leu-Tyr-Val (GQ-L)
n is 14; a) the ratio of the time to basal pain sensation is more than 0.05; b) the ratio of the time to basal pain sensation is p < 0.05; c) the ratio of the time to the basal pain sensation is p <0.01.
EXAMPLE 12 evaluation of anti-inflammatory Activity of Leu-Arg-Ala-Pro-Leu-Tyr-Val (GQ-L)
Male mice weighing 20. + -.were orally administered 1. mu. mol/kg Leu-Arg-Ala-Pro-Leu-Tyr-Val (GQ-L) or 1200. mu. mol/kg aspirin or 0.2mL/20g physiological saline for 30 minutes, then the mouse left ear was coated with xylene (0.04mL), and after 2 hours the mice were anesthetized for cervical dislocation. The left and right ears of the mouse are cut off, round ear pieces are taken at the same positions of the two ears by a puncher with the diameter of 7mm, the round ear pieces are respectively weighed, and the weight difference of the two round ear pieces is calculated to be used as swelling degree. (degree of swelling-left auricle weight-right auricle weight) the activity of the compound is expressed in the degree of swelling. The statistics of the experimental data are all performed by adopting t test and variance analysis, and the swelling degree is expressed by (mean value +/-SD mg). Table 2 shows that the degree of swelling of the ears of mice treated by Leu-Arg-Ala-Pro-Leu-Tyr-Val is significantly different from that of the mice treated by normal saline, and shows that Leu-Arg-Ala-Pro-Leu-Tyr-Val has definite anti-inflammatory activity.
TABLE 2 anti-inflammatory Activity of Leu-Arg-Ala-Pro-Leu-Tyr-Val (GQ-L)
n is 14; a) p <0.05 in the saline group.
EXAMPLE 13 evaluation of the antitumor Activity of Leu-Arg-Ala-Pro-Leu-Tyr-Val (GQ-L)
Taking S180 sarcoma inoculated in ICR mouse for 7-10 days under aseptic condition, adding appropriate amount of normal saline to prepare into tumor cell suspension with cell number of 2 × 10 7 Perml, inoculated subcutaneously in the hind axilla of healthy male ICR mice, 0.2mL per mouse. 24h after tumor inoculation, the mice are intraperitoneally injected with 0.2mL of physiological saline solution of Leu-Arg-Ala-Pro-Leu-Tyr-Val (GQ-L) every day, and the administration is continuously carried out for 10 days, wherein the dose is 1 mu mol/kg/day; or the mice are intraperitoneally injected with 0.2mL of adriamycin physiological saline solution every day, and the administration is continuously carried out for 10 days, wherein the dosage is 2 mu mol/kg/day; or the mice are injected with 0.2mL of normal saline per day in the abdominal cavity and continuously administrated for 10 days. The experiment was performed until day 11, mice were weighed, tumors from each group were dissected under ether anesthesia, weighed and the tumor weight is used to indicate the activity of the compound, and the data are shown in table 3. The results show that the tumor weight of the Leu-Arg-Ala-Pro-Leu-Tyr-Val (GQ-L) treated mice at 1 mu mol/kg/day is obviously smaller than that of the mice treated by the normal saline. Furthermore, the tumor weight of Leu-Arg-Ala-Pro-Leu-Tyr-Val (GQ-L) treated mice at 1. mu. mol/kg/day was not significantly different from that of doxorubicin-treated mice at 2. mu. mol/kg/day. Leu-Arg-Ala-Pro-Leu-Tyr-Val showed definite antitumor activity.
TABLE 3 Effect of Leu-Arg-Ala-Pro-Leu-Tyr-Val (GQ-L) on tumor weight in S180 tumor-bearing mice
n is 15; a) p <0.01 to saline and p >0.05 to doxorubicin.
EXAMPLE 14 evaluation of the antithrombotic Activity of Leu-Arg-Ala-Pro-Leu-Tyr-Val (GQ-L)
1) Drawing a polyethylene tube into a thin tube with one end being an oblique opening, wherein the fixed length is 10.0cm, and the thin tube is respectively used for inserting a right vena cava (with thicker tube diameter) and a left carotid artery (with thinner tube diameter); the length of the middle section polyethylene tube is 8.0cm, the thrombus line is pressed in the carotid intubation direction, and the tube needs to be filled with heparin before intubation.
2) After 1 mu mol/kg Leu-Arg-Ala-Pro-Leu-Tyr-Val (GQ-L) or 167 mu mol/kg aspirin or 0.3mL/100g physiological saline is orally taken by a male rat with the weight of 250 +/-for 30 minutes, 20 percent of urethane is injected into the abdominal cavity for anesthesia. On the supine position was fixed in the rat board with the rat, cut open neck skin, separation right common carotid artery and left jugular vein, line ball under the blood vessel, ligature far away heart end, vein were close to far away heart end department and cut a osculum, were carried out the vein end intubate, and heparin is injected, and the line is fixed, and the artery is pressed from both sides to clip the artery and is close to far away heart end direction and cut a osculum, carries out the artery end ligature, loosens the artery after the line is fixed and presss from both sides, establishes the extrinsic cycle bypass. After 15 minutes of circulation, the venous end is cut off to observe whether the blood circulation is normal, if the blood circulation is normal, a thrombus line is taken out from the arterial end, dry floating blood is stained on paper, then weighing is carried out, the thrombus weight represents the activity of the compound, and the data are listed in Table 4. The result shows that the thrombus weight of the rat treated by Leu-Arg-Ala-Pro-Leu-Tyr-Val (GQ-L) is obviously less than that of the rat treated by normal saline, and the compound shows exact antithrombotic activity.
TABLE 4 influence of Leu-Arg-Ala-Pro-Leu-Tyr-Val (GQ-L) on thrombus weight in SD rats
n is 12; a) p <0.01 to saline.
EXAMPLE 15 evaluation of thrombolytic Activity of Leu-Arg-Ala-Pro-Leu-Tyr-Val (GQ-L)
The rats are kept for one day at rest and are randomly grouped into 10 rats in each group, and the rats are fasted without water prohibition.
1) Male SD rats weighing 250. + -. were anesthetized with 20% urethane solution (6mL/kg abdominal cavity). The anesthetized rat is fixed on a rat board, the right common carotid artery is separated, an artery clamp is clamped at the proximal end, the proximal end and the distal end are respectively introduced into an operation line, a blood vessel is inserted at the distal end, and about 1mL of arterial blood is clamped by loosening the artery clamp. The arterial blood was rapidly injected into vertical embolismic tubes (16 mm in length, 2.5mm in inner diameter, 5mm in outer diameter, 1mL of EP tube base for tube bottom) (note that no air bubbles were present) and 0.1mL of rat arterial blood was injected into each embolismic tube, a thrombus fixing bolt (20 mm in length) was rapidly inserted into the tube, the blood was coagulated for 40min, the thrombus was taken out with an acupuncture needle, and the weight of the thrombus was weighed.
2) The bypass cannula comprises triplex, and wherein the middle section is polyethylene rubber tube, long 60mm, internal diameter 3.5mm, and both ends are the same polyethylene pipe, long 100mm, internal diameter 1mm, outdoor scene 2mm, and one section of this pipe is drawn into the sharp pipe, and the outside of the other end overlaps one section long 7mm, outside diameter 3.5 mm's polyethylene pipe. The inner walls of the three sections of pipes are silanized.
3) And placing the thrombus fixing bolt wrapped by the thrombus into the polyethylene rubber tube at the middle section, sleeving two ends of the rubber tube with the thickened ends of the two polyethylenes respectively, and filling heparin normal saline solution into the rubber tube through the tip end by using an injector. One end of the normal saline solution filled with the heparin sodium is inserted into the left vein, the other end of the normal saline solution is added with the heparin sodium with an accurate amount by using an injector for anticoagulation, and then the injector of the heparin sodium is pulled out and inserted into the arterial end. Physiological saline (3mL/kg) or a physiological saline solution (20000IU/kg) of urokinase or a physiological saline solution (1 mu mol/kg) of Leu-Arg-Ala-Pro-Leu-Tyr-Val (GQ-L) is inserted into the proximal vein far away from the thrombus fixing bolt through the middle section of the bypass tube by using a scalp needle, the artery clamp is opened, the time when blood flows into the vein from the artery through the bypass tube is the circulation starting time, the liquid in the syringe is slowly injected into the blood (about 6min), and the physiological saline, urokinase, Arg-Leu-Val-Cys-Val act on the thrombus in the order of vein-heart-artery through the blood circulation. After 60min, the bolt with thrombus was removed, and the floating blood was dipped and the weight was recorded. Thrombolytic activity is represented by loss of thrombus weight. The data are shown in Table 5. The result shows that the weight loss of the thrombus of the rat treated by Leu-Arg-Ala-Pro-Leu-Tyr-Val (GQ-L) is obviously larger than that of the rat treated by normal saline, and the exact thrombolytic activity is shown.
TABLE 5 thrombolytic Activity of Leu-Arg-Ala-Pro-Leu-Tyr-Val (GQ-L)
n is 10; a) p <0.01 to saline.
Claims (7)
1. A heptapeptide with the sequence of Leu-Arg-Ala-Pro-Leu-Tyr-Val.
2. A method of making the Leu-Arg-Ala-Pro-Leu-Tyr-Val heptapeptide of claim 1, comprising:
(1-1) preparing Boc-Tyr-Val-OBzl under the catalysis of DCC and HOBt according to a standard method;
(1-2) removing Boc from the Boc-Tyr-Val-OBzl in a hydrogen chloride-ethyl acetate solution with the concentration of 4N at 0 ℃ and converting into Tyr-Val-OBzl;
(1-3) preparing Boc-Ala-Pro-OBzl under the catalysis of DCC and HOBt;
(1-4) the Boc-Ala-Pro-OBzl is converted into Boc-Ala-Pro by hydrogenolysis under Pd/C catalysis;
(1-5) preparing Boc-Leu-Tyr-Val-OBzl under the catalysis of DCC and HOBt;
(1-6) Boc-Leu-Tyr-Val-OBzl in 4N hydrogen chloride-ethyl acetate solution at 0 ℃ for removing Boc and converting into Leu-Tyr-Val-OBzl;
(1-7) preparing Boc-Ala-Pro-Leu-Tyr-Val-OBzl under the catalysis of DCC and HOBt;
(1-8) Boc-Ala-Pro-Leu-Tyr-Val-OBzl removing Boc at 0 ℃ in 4N hydrogen chloride-ethyl acetate solution, and converting into Ala-Pro-Leu-Tyr-Val-OBzl;
(1-9) preparation of Boc-Leu-N under catalysis of DCC and HOBt G -NO 2 -Arg-OBzl；
(1-10)Boc-Leu-N G -NO 2 Conversion of-Arg-OBzl to Boc-Leu-N at 0 ℃ in 2N NaOH aqueous solution G -NO 2 -Arg；
(1-11) preparation of Boc-Leu-N under catalysis of DCC and HOBt G -NO 2 -Arg-Ala-Pro-Leu-Tyr-Val-OBzl；
(1-12)Boc-Leu-N G -NO 2 Deprotection of-Arg-Ala-Pro-Leu-Tyr-Val-OBzl in trifluoroacetic acid and triflic acid at 0 ℃ converts to Leu-Arg-Ala-Pro-Leu-Tyr-Val.
3. Use of the Leu-Arg-Ala-Pro-Leu-Tyr-Val heptapeptide of claim 1 for the preparation of an anti-tumor medicament.
4. Use of the Leu-Arg-Ala-Pro-Leu-Tyr-Val heptapeptide of claim 1 for the preparation of an analgesic drug.
5. Use of the Leu-Arg-Ala-Pro-Leu-Tyr-Val heptapeptide of claim 1 for the preparation of an anti-thrombotic agent.
6. Use of the Leu-Arg-Ala-Pro-Leu-Tyr-Val heptapeptide of claim 1 for the preparation of a thrombolytic drug.
7. Use of the Leu-Arg-Ala-Pro-Leu-Tyr-Val heptapeptide of claim 1 for the preparation of an anti-inflammatory medicament.
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