CN106317177A - Gly-Phe-Pro, and synthesis, activity and application thereof - Google Patents
Gly-Phe-Pro, and synthesis, activity and application thereof Download PDFInfo
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- CN106317177A CN106317177A CN201510351800.2A CN201510351800A CN106317177A CN 106317177 A CN106317177 A CN 106317177A CN 201510351800 A CN201510351800 A CN 201510351800A CN 106317177 A CN106317177 A CN 106317177A
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Abstract
The invention discloses Gly-Phe-Pro, a preparation method, analgesic activity, anti-inflammatory activity, antitumor activity, anti-thrombotic activity and thrombolysis activity of Gly-Phe-Pro, and application of Gly-Phe-Pro to preparation of analgesic drugs, anti-inflammatory drugs, antitumor drugs, anti-thrombotic drugs and thrombolysis drugs.
Description
Technical field
The present invention relates to Gly-Phe-Pro, relate to its preparation method, relate to its analgesic activity, relate to its antiinflammatory
Effect, relates to its anti-tumor activity, relates to its antithrombotic acitivity and relates to its thrombus dissolving activity, thus this
Bright relate to its application as antalgic and inflammation relieving medicine, antitumor drug, antithrombotic reagent and thrombolytic agent.The invention belongs to
In biomedicine field.
Background technology
Invention antitumor, antithrombotic, thrombus dissolving, anticoagulation, analgesia, antiinflammatory action oligopeptide are that inventor pays close attention to for a long time
Field.Although the most a series of oligopeptide with these activity of inventor's disclosure of the invention, but integrate these activity
Oligopeptide never obtain.Through the sequential designs of nearly 10 years and the experimentation of nearly 5 years, inventor finds
Gly-Phe-Pro is collection analgesic activity, antiinflammatory action, and antitumor action anti thrombotic action and thrombus dissolving act as one
Oligopeptide.
Summary of the invention
First content of the present invention is to provide Gly-Phe-Pro.
Second content of the present invention is to provide the synthetic method of Gly-Phe-Pro, and the method includes:
(1) under the catalysis of DCC, HOBt, Boc-Gly-Phe-OBzl is prepared by standard method；
(2) Boc-Gly-Phe-OBzl is at H2The lower hydrogenolysis of Pd/C catalysis changes into Boc-Gly-Phe；
(3) under the catalysis of DCC, HOBt, Boc-Gly-Phe-Pro-OBzl is prepared；
(4) Boc-Gly-Phe-Pro-OBzl is at H2The lower hydrogenolysis of Pd/C catalysis changes into Boc-Gly-Phe-Pro
(5) Boc-Gly-Phe-Pro is in the hydrogen chloride-ethyl acetate solution of 4N, 0 DEG C of de-Boc, in change into
Gly-Phe-Pro
3rd content of the present invention is to evaluate the analgesic activity of Gly-Phe-Pro.
4th content of the present invention is to evaluate Gly-Phe-Pro antiinflammatory action.
5th content of the present invention is to evaluate Gly-Phe-Pro antitumor action.
6th content of the present invention is to evaluate Gly-Phe-Pro anti thrombotic action.
7th content of the present invention is to evaluate Gly-Phe-Pro thrombus dissolving effect.
Accompanying drawing explanation
Synthetic route .i of Fig. 1 .Gly-Phe-Pro) dicyclohexylcarbodiimide (DCC), I-hydroxybenzotriazole (HOBt), N-
Methyl morpholine (NMM), oxolane (THF)；ii)H2, Pd/C；Iii) ethyl acetate solution of 4N hydrogen chloride, 0 DEG C.
Detailed description of the invention
In order to the present invention is expanded on further, a series of embodiment is given below.These embodiments are entirely illustrative,
They are only used for being specifically described the present invention, are not construed as limitation of the present invention.
Embodiment 1 prepares Boc-Gly-Phe-OBzl
During 1.75g (10mmol) Boc-Gly is dissolved in a small amount of anhydrous tetrahydro furan (THF) under ice bath, add 1.36g
(10mmol) HOBt, 2.47g (12mmol) DCC is in a small amount of anhydrous THF in addition, activates 30 minutes, adds
Entering 2.55g (10mmol) Phe-OBzl, regulate pH=9 with NMM, reaction filters 1,3-Dicyclohexylurea after terminating
(DCU).Filtrate reduced in volume, residue with Ethyl acetate dissolves, again filters DCU, filtrate NaHCO3Full
Wash 3 times with solution, wash 3 times with NaCl saturated solution, the KHSO of 5%4Solution is washed 3 times, NaCl saturated solution
Extraction is washed 3 times, the NaHCO of 5%3Solution extraction is washed 3 times, and NaCl saturated solution extraction is washed 3 times, ethyl acetate layer nothing
Water Na2SO4It is dried 2 hours, filters Na2SO4, filtrate reduced in volume, obtain 3.45g (83.7%) title compound,
For colorless oil.ESI+-MS (m/e): 413 [M+H]+。
Embodiment 2 prepares Boc-Gly-Phe
4.12g (10mmol) Boc-Gly-Phe-OBzl methanol is dissolved, the Pd/C of the 10% of addition 412mg.
Connecting tee, after decompression extracts the air in eggplant bottle, will be full of H in reaction bulb2. it is repeated 3 times by this operation.Reaction
After 20h, raw material point disappears.Filter Pd/C, be spin-dried for methanol.Obtain 3.02g (93.7%) title compound, for without toner
End.ESI+-MS (m/e): 323 [M+H]+。
Embodiment 3 prepares Boc-Gly-Phe-Pro-OBzl
According to the method for embodiment 1,3.22g (10mmol) Boc-Gly and 2.05g (10mmol) Pro-OBzl is marked
Topic compound, for colourless powder.ESI+-MS (m/e): 511 [M+H]+；1H-NMR (300MHz, DMSO-d6):
δ/ppm=8.15 (m, 1H), 7.30 (d, 9H), 6.88 (s, 1H), 5.09 (s, 2H), 4.69 (m, 1H), 4.39 (m, 1H),
3.67 (m, 2H), 3.47 (s, 2H), 2.90 (m, 2H), 1.98 (m, 4H), 1.36 (s, 9H).
Embodiment 4 prepares Boc-Gly-Phe-Pro
According to the method for embodiment 2, obtain 3.95g (94.3%) from 4.19g (10mmol) Boc-Gly-Phe-Pro-OBzl
Title compound, for colourless powder .ESI+-MS (m/e): 420 [M+H]+。
Embodiment 5 prepares Gly-Phe-Pro
Under ice bath, by 4.19g (10mmol) Boc-Gly-Phe-Pro-OBzl with the fewest acetic acid ethyl dissolution, stir
Mixing 10min, add 40mL hydrogen chloride-ethyl acetate solution (4N) reaction 4h, raw material point disappears.Reaction mixing
Thing is evaporated to do, and residue adds the acetic acid ethyl dissolution that 40mL is dried, and the solution decompression obtained is concentrated to dryness.
Residue is repeated 3 times by this operation.Residue adds absolute ether, grinds with plastic spatula, and concentrating under reduced pressure removes ether.
Residue is repeated 3 times by this operation.Obtain finally giving 2.97g (93.1%) title compound, for colourless powder.
ESI-MS (m/e): 320 [M+H]+；Mp 96～97 DEG C.(c=0.12, methanol).1H-NMR(300
MHz, DMSO-d6): δ/ppm=7.21 (m, 5H), 4.70 (m, 1H), 4.25 (m, 1H), 3.60 (m, 2H), 3.28 (m,
2H), 2.85 (m, 2H), 2.07-1.57 (m, 4H).
Embodiment 6 evaluates the analgesic activities of Gly-Phe-Pro
Male ICR mouse (20 ± 2g) installs in mouse fixing device, and rat-tail is exposed to outside holder, in rat-tail distance tail
Labelling at point 1/3rd, as the induction point of light sensation sensor, irradiates the position of rat-tail distance tail point 2/3rds.
Dolorimeter preheating 30min, clocks, mice rat-tail is covered light sensation instrument.Starting to clock during lamp flicker, rat-tail leaves light
Stopping clocking during sense instrument, the time recorded is mice and produces the time of pain, METHOD FOR CONTINUOUS DETERMINATION 3 times, each measurement interval
For 5min, average.Keenly feel the time based on the time that mice of not taking medicine produces pain.The mice caused of taking medicine produces
Raw pain time change reflects the analgesic activities of medicine.Mice, random packet, often group 14, measure basis pain
After time, mice or the normal saline solution of oral 0.2mL Gly-Phe-Pro (GFP), dosage be 1 μm ol/kg or
Oral 0.2mL normal saline or the normal saline solution of oral aspirin, dosage is 1200 μm ol/kg.Measure and be administered
Rear 30,60,90,120,150 and 180min mice produce pain time.The data mean value ± SD second represents, arranges such as table 1,
With variance analysis and carry out t inspection.Data show, oral normal saline 30,60, after 90,120,150 and 180min
The basic pain time before mice produces time and the oral normal saline of pain is not significantly different from；Oral 1200
After μm ol/kg aspirin 60,90,120,150 and 180min mice produce time of pain be considerably longer than oral Ah
The basic pain time before a department woods；Oral 1 μm ol/kg Gly-Phe-Pro 30,60,90,120,150 and 180min
The basic pain time before mice produces the time the most oral Gly-Phe-Pro of pain afterwards.Visible, oral
1 μm ol/kgArg-Leu-Val-Cys-Val60, the analgesic activities after 90,120,150 and 180min and oral 1200
μm ol/kg aspirin is suitable.And analgesic activities 1 μm ol/kg Gly-Phe-Pro 30min after is administered orally than oral
1200 μm ol/kg aspirin are the strongest.
The analgesic activities of table 1Gly-Phe-Pro (GFP)
N=14；A) with the basis pain time than p ＞ 0.05；B) with the basis pain time than p ＜ 0.05；C) with basis pain time ratio
P ＜ 0.05.
Embodiment 7 evaluates the anti-inflammatory activity of Gly-Phe-Pro
Body weight 20 ± male mice is administered orally 1 μm ol/kgGly-Phe-Pro or 1200 μm ol/kg aspirin or 0.2mL/20
After g normal saline 30 minutes, the left ear gabarit toward white mice is coated with dimethylbenzene (0.04mL), by white mice neck after 2 hours
Vertebra dislocation is put to death.By a left side for mice, auris dextra is cut, and with the card punch of diameter 7mm in the same position of two ears, takes
Circular auricle, weighs respectively, obtains the weight difference of two circle auricles as swelling.(swelling=former of left ear weight-
Former weight of auris dextra) activity of compound is represented with swelling.This experimental data statistics all uses t inspection and variance to divide
Analysis, swelling with () represent.Result shows, the Mus ear swelling degree of Gly-Phe-Pro treatment and normal saline
Group is compared has significant difference, shows that compound has definite anti-inflammatory activity.
The anti-inflammatory activity of table 2Gly-Phe-Pro
N=14；A) with normal saline than p ＜ 0.01.
The anti-tumor in vivo activity rating of embodiment 8 compound Gly-Phe-Pro
Take under aseptic condition and be inoculated in the ICR mice S180 sarcoma of 7-10 days, add appropriate normal saline tumor cells
Suspension, cell number is 2 × 107/ mL, is inoculated in healthy male ICR mouse forelimb axil subcutaneous, every injected in mice 0.2mL.
After tumor inoculation 24h, the normal saline solution of mice lumbar injection every day 0.2mL Gly-Phe-Pro, successive administration 10
My god, dosage is 1 μm ol/kg；Or the normal saline solution of mice lumbar injection every day 0.2mL amycin, successive administration
10 days, dosage was 2 μm ol/kg；Or mice lumbar injection every day 0.2mL normal saline, successive administration 10 days.Experiment
Carrying out to the 11st day, claim Mouse Weight, etherization takes the tumor of each group of mice, weighs and heavily represents chemical combination with tumor
The activity of thing, data list table 3 in.Result shows that the tumor of 1 μm ol/kgGly-Phe-Pro treatment mice is heavily significantly less than life
The tumor weight of reason saline-treated mice, Gly-Phe-Pro shows definite anti-tumor activity.
The table 3Gly-Phe-Pro impact on the tumor weight of S180 tumor-bearing mice
N=12；A) with normal saline than p ＜ 0.05.
Embodiment 9 evaluates the anti-thrombus activity of Gly-Phe-Pro
1) polyethylene tube pulling into the tubule that one end is angle, fixed length is 10.0cm, and the rightest through vein, (caliber is relatively
Slightly) and left neck artery (caliber is thinner) intubates；Stage casing polyethylene tube fixed length is 8.0cm, and thrombosis line is pressed in carotid artery
Intubate direction, heparin before intubating, need to be full of in pipe.
2) body weight 250 ± male rat is administered orally 1 μm ol/kg Gly-Phe-Pro or 167 μm ol/kg aspirin or 0.3
After mL/100g normal saline 30 minutes, the urethane of lumbar injection 20% is anaesthetized.Rat is fixed on by dorsal position
On Mus plate, cut off skin of neck, separate right common carotid artery and left jugular vein, line ball under blood vessel, ligature distal end, quiet
Arteries and veins cuts an osculum by distal end, carries out vein end and intubates, and injecting heparin, anchor line (string) is fixed, then clamped with bulldog clamp dynamic
Arteries and veins proximal part, cuts an osculum near distal end direction, carries out arterial end ligation, unclamps bulldog clamp, build after anchor line (string) is fixing
Three-dimensional outer circulation bypass.First cut off vein end after circulating 15 minutes and observe blood circulation the most normally, if normal from tremulous pulse
End removal of thromboses line, weighs after being stained with dry floating blood, heavily represent the activity of compound with bolt on paper, and data list table 4 in.Knot
Fruit shows, the thrombosis of Gly-Phe-Pro treatment rat is heavily significantly less than the thrombosis weight of saline therapy rat,
Gly-Phe-Pro shows definite antithrombotic acitivity.
The anti-thrombus activity of table 4Gly-Phe-Pro
N=12；A) with normal saline than p ＜ 0.05.
Embodiment 10 evaluates the thrombolysis activity of Gly-Phe-Pro
Being raised one day by rat tranquillization, random packet, often group 10, water is can't help in fasting.
1) carry out anaesthetizing (6mL/kg abdominal cavity) with 20% urethane solution by body weight 250 ± male SD rat.Postanesthetic greatly
Mus is fixed on Mus plate, separates right carotid, presss from both sides bulldog clamp in proximal part, and proximal part and distal end pass respectively
Enter surgical thread, insert at distal end and take blood vessel, unclamp tremulous pulse and grip about 1mL arterial blood.Rapidly arterial blood is injected into
Vertical makes in bolt pipe (long 16mm, internal diameter 2.5mm, external diameter 5mm, with 1mL EP pipe base at the bottom of pipe), (note
Meaning can not have bubble) each make in bolt pipe injection 0.1mL rat artery blood, in pipe, it is rapidly inserted into thrombosis fixes
Bolt (long 20mm), blood coagulation 40min, uses acupuncture needle removal of thromboses, weighs thrombus weight.
2) bypass intubates and is made up of three parts, and wherein stage casing is polyethylene rubber tube, long 60mm, internal diameter 3.5mm, and two ends are identical
Polyethylene tube, long 100mm, internal diameter 1mm, outdoor scene 2mm, one section of this pipe pulls into spike tube, the outside of the other end
Overlap a segment length 7mm, the polyethylene tube of external diameter 3.5mm.The inwall of three sections of pipes is silanization.
3) thrombosis that thrombosis wraps up is fixed bolt is placed in the polyethylene rubber tube in stage casing, the two ends of sebific duct respectively with two polyethylene
The butt end that adds be nested, fill heparin-saline solution with syringe by spike tube end.Will be filled with the physiology salt of heparin sodium
Vein on the left of the insertion of aqueous solution one end, after the other end adds the heparin sodium anticoagulant of correct amount with syringe, pulls out heparin sodium
Syringe, insert arterial end.With scalp acupuncture by normal saline (3mL/kg) or the normal saline solution of urokinase
(20000IU/kg) or the normal saline solution (1 μm ol/kg) of Gly-Phe-Pro, by the stage casing of shunt valve, thrusts away from blood
Bolt is fixed at the nearly vein of bolt, opens bulldog clamp, make blood flow by bypass duct from tremulous pulse flow into vein moment be
Circulation initial time, is injected into the liquid in syringe in blood (about 6min) slowly, makes normal saline, urokinase,
Gly-Phe-Pro passes through blood circulation, by the sequential action of vein-heart-tremulous pulse to thrombosis.Take out after 60min and have
The bolt of thrombosis, dips in floating blood, records weight.Thrombolysis activity is represented with thrombosis loss of weight.Data list table 4 in.Result table
Bright, the thrombosis loss of weight of Gly-Phe-Pro treatment rat is significantly greater than the thrombosis loss of weight of saline therapy rat,
Gly-Phe-Pro shows definite thrombus dissolving activity.
The thrombolysis activity of table 5Gly-Phe-Pro
N=10；A) with normal saline than p ＜ 0.01.
Claims (7)
1.Gly-Phe-Pro。
2. the preparation method of the Gly-Phe-Pro of claim 1, the method includes:
(1) under the catalysis of DCC, HOBt, Boc-Gly-Phe-OBzl is prepared by standard method；
(2) Boc-Gly-Phe-OBzl is at H2The lower hydrogenolysis of Pd/C catalysis changes into Boc-Gly-Phe；
(3) under the catalysis of DCC, HOBt, Boc-Gly-Phe-Pro-OBzl is prepared；
(4) Boc-Gly-Phe-Pro-OBzl is at H2The lower hydrogenolysis of Pd/C catalysis changes into Boc-Gly-Phe-Pro；
(5) Boc-Gly-Phe-Pro is in the hydrogen chloride-ethyl acetate solution of 4N, 0 DEG C of de-Boc, in change into
Gly-Phe-Pro。
3. the Gly-Phe-Pro of claim 1 application in preparing antitumor drug.
4. the Gly-Phe-Pro of claim 1 application in preparing analgesic.
5. the Gly-Phe-Pro of claim 1 application in preparing thromboembolism preventing medicine.
6. the Gly-Phe-Pro of claim 1 application in preparing thrombolytic drug.
7. the Gly-Phe-Pro of claim 1 application in preparing anti-inflammatory drug.
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| CN201510351800.2A CN106317177A (en) | 2015-06-23 | 2015-06-23 | Gly-Phe-Pro, and synthesis, activity and application thereof |
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| CN201510351800.2A CN106317177A (en) | 2015-06-23 | 2015-06-23 | Gly-Phe-Pro, and synthesis, activity and application thereof |
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| CN1099799A (en) * | 1993-05-26 | 1995-03-08 | 贝林格尔-英格海姆国际有限公司 | Process for preparing and purifying alpha-interferon |
| CN1541706A (en) * | 1996-04-03 | 2004-11-03 | ͨ��ҽ�ƹ�˾ | Inhibitor and stimulator of stem cell proliferation and uses thereof |
| US20050080016A1 (en) * | 2001-02-05 | 2005-04-14 | Jean Rapin | Tripeptides and tripeptide derivatives for the treatment of postlesional diseases of the nervous system |
| CN101870974A (en) * | 2010-05-26 | 2010-10-27 | 中国科学院昆明动物研究所 | Preparation method of proteinase activated receptors agonist and use thereof |
| CN103992384A (en) * | 2014-05-22 | 2014-08-20 | 浙江海洋学院 | Pseudosciaena crocea fish bone collagen peptide, and preparation method and application thereof |
-
2015
- 2015-06-23 CN CN201510351800.2A patent/CN106317177A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1099799A (en) * | 1993-05-26 | 1995-03-08 | 贝林格尔-英格海姆国际有限公司 | Process for preparing and purifying alpha-interferon |
| CN1541706A (en) * | 1996-04-03 | 2004-11-03 | ͨ��ҽ�ƹ�˾ | Inhibitor and stimulator of stem cell proliferation and uses thereof |
| US20050080016A1 (en) * | 2001-02-05 | 2005-04-14 | Jean Rapin | Tripeptides and tripeptide derivatives for the treatment of postlesional diseases of the nervous system |
| CN101870974A (en) * | 2010-05-26 | 2010-10-27 | 中国科学院昆明动物研究所 | Preparation method of proteinase activated receptors agonist and use thereof |
| CN103992384A (en) * | 2014-05-22 | 2014-08-20 | 浙江海洋学院 | Pseudosciaena crocea fish bone collagen peptide, and preparation method and application thereof |
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Application publication date: 20170111 |