CN102702314A - RGDF-YIGSR with targeted anti-thrombotic activity, preparation and application thereof - Google Patents

RGDF-YIGSR with targeted anti-thrombotic activity, preparation and application thereof Download PDF

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CN102702314A
CN102702314A CN2012101051073A CN201210105107A CN102702314A CN 102702314 A CN102702314 A CN 102702314A CN 2012101051073 A CN2012101051073 A CN 2012101051073A CN 201210105107 A CN201210105107 A CN 201210105107A CN 102702314 A CN102702314 A CN 102702314A
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rgdf
yigsr
preparation
ome
boc
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彭师奇
赵明
王超
赵婧华
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Capital Medical University
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Abstract

The invention discloses RGDF-YIGSR with targeted anti-thrombotic activity, further discloses a preparation process thereof and application thereof as an anti-thrombotic agent, and belongs to the field of biomedicine. The polypeptide with targeted anti-thrombotic activity is prepared by conjugating RGDF with YIGSR. According to tests of animal models, the RGDF-YIGSR has higher anti-thrombotic activity.

Description

RGDFYIGSR, preparation and application with target antithrombotic activity
The application is that the application number of on November 30th, 2006 application is 200610144234.9, and denomination of invention is divided an application for the patent of " polypeptide, its preparation method and application with target antithrombotic activity ".
Technical field
The present invention relates to have the polypeptide RGDFYIGSR of target antithrombotic activity.The preparation method and it that the invention still further relates to it belong to biomedicine field as the application of pharmaceutical preparations having antithrombotic activity.
Background technology
Cell adhesion plays a crucial role in the evolution of cell adhesion property disease (metastasis of cancer, thrombosis, chemistry cause inflammation and osteoporosis).Modulability gp for example laminine, Fibrinogen, RGD peptide, YIGSR and YIGSK etc. can be participated in the cell adhesion process.They and integrin receptor have very strong binding ability.For example in the platelet aggregation process, RGDF has combined crucial effects with activatory platelet surface acceptor GP IIb/IIIa.RGDF combines with the specificity of activatory platelet surface acceptor GP IIb/IIIa, has given RGDF a critical nature, and promptly containing RGDF can be to the enrichment of the position of platelet activation.Under such prerequisite, put together RGDF and anti-cell adherent YIGSR, just can obtain the target anti-cell and stick polypeptide.
Summary of the invention
One of the object of the invention is that RGDF and YIGSR are puted together, and prepares the polypeptide with target antithrombotic activity.
Two of the object of the invention provides a kind of method for preparing the RGDFYIGSR of antithrombotic acitivity.This method comprises:
1. employing liquid-phase synthesis process is through progressively connecing the protection midbody of synthetic respectively RGDF of peptide and YIGSR;
2. slough the C end protection base of RGDF protection midbody;
3. slough the N end protection base of YIGSR protection midbody;
4. put together the YIGSR protection midbody of the RGDF of C end dissociative protection midbody and N end dissociative, slough the protection base again and obtain RGDFYIGSR.
Wherein, described N end protection base is the blocking group that the N end of polypeptide is used always when protecting, and for example can be tertbutyloxycarbonyl (Boc); Described C end protection base is the blocking group that the C end of polypeptide is used always when protecting, and for example can be benzyloxy (OBzl), methoxyl group (OMe) etc.
Above-described liquid phase synthetic intermediate and the method for protecting are the conventional and technique known of this area.
Animal model test proves that RGDFYIGSR of the present invention has stronger antithrombotic acitivity.
In order further to set forth the present invention, provide a series of embodiment below.These embodiment are illustrative fully, and they only are used for the present invention is specifically described, and are not to be understood that to be limitation of the present invention.
The explanation of the shortenings that is occurred among the present invention:
The THF THF
DCC dicyclohexyl imide
The DCU NSC 30023
The OBzl benzyloxy
The Boc tertbutyloxycarbonyl
The OMe methoxyl group
HOBt N-hydroxybenzotriazole
The NMM N-methylmorpholine
Embodiment
Embodiment 1 HClTyr-Ile-Gly-Ser (Bzl)-Arg (NO 2The preparation of)-OMe
1) Boc-Ser (Bzl)-Arg (NO 2The preparation of)-OMe
0.59g (2.0mmol) Boc-Ser (Bzl) is dissolved among the anhydrous THF of 6ml, and 0 ℃ adds 0.27g (2.0mmol) N-hydroxybenzotriazole (HOBt) and 0.45g (2.2mmol) dicyclohexyl carbonyl diimine (DCC) down.Stir and add 0.539g (2.0mmol) HClArg (NO after 10 minutes 2The anhydrous THF solution of)-OMe.Reaction mixture is regulated pH 8-9 with N-methylmorpholine (NMM), and 0 ℃ was stirred 24 hours.Stopped reaction removes by filter the NSC 30023 (DCU) that is settled out.Filtrate decompression concentrates, and residue is dissolved in the ETHYLE ACETATE, and the solution that obtains is used saturated NaHCO successively 3The aqueous solution, 5%KHSO 4The aqueous solution and the saturated NaCl aqueous solution are washed.Ethyl acetate layer is used anhydrous Na SO 4Dry 3 hours.Filtering NaSO 4, filtrate decompression concentrates removes ETHYLE ACETATE.Residue uses column chromatography (CHCl 3: CH 3OH, 30: 1), obtain 0.969g (95%) target compound.ESI-MS(m/z)511[M+H] +。
2) HClSer (Bzl)-Arg (NO 2The preparation of)-OMe
With 0.969g (1.9mmol) Boc-Ser (Bzl)-Arg (NO 2)-OMe is dissolved in 15ml hydrogenchloride-ethyl acetate solution (6mol/l), stirring at room 2 hours, and TLC detects raw material point and disappears, and reduces pressure and takes out ETHYLE ACETATE, adds a small amount of ether repeatedly and reduces pressure and bleed to remove the acid gas in the product.Add a small amount of ether at last product is ground to form pressed powder, directly be used for next step reaction.ESI-MS(m/z)411[M+H] +。
3) preparation of Boc-Ile-Gly-OMe
With 0.498g (2.0mmol) Boc-IleH 2O is dissolved among the anhydrous THF of 5mL, and 0 ℃ adds 0.27g (2.0mmol) HOBt and 0.45g (2.18mmol) DCC down.Stir the anhydrous THF solution that adds 0.251g (2.0mmol) HClGly-OMe after 10 minutes.Reaction mixture is regulated pH 8-9 with NMM, and 0 ℃ was stirred 24 hours.Stopped reaction removes by filter the DCU that is settled out.Filtrate decompression concentrates, and residue is dissolved in the ETHYLE ACETATE, and the solution that obtains is used saturated NaHCO successively 3The aqueous solution, 5%KHSO 4The aqueous solution and the saturated NaCl aqueous solution are washed.Ethyl acetate layer is used anhydrous Na SO 4Dry 3 hours.Filtering NaSO 4, filtrate decompression concentrates removes ETHYLE ACETATE.Residue uses column chromatography (CHCl 3: CH 3OH, 60: 1).Obtain 0.567g (94%) target compound.ESI-MS(m/z)303[M+H] +。
4) preparation of HClIle-GlyOMe
0.567g (1.87mmol) Boc-Ile-Gly-OMe is dissolved in 15ml hydrogenchloride-ethyl acetate solution (6mol/l); Stirring at room 2 hours; TLC detects raw material point and disappears, and reduces pressure and takes out ETHYLE ACETATE, adds a small amount of ether repeatedly and reduces pressure and bleed to remove the acid gas in the product.Add a small amount of ether at last product is ground to form pressed powder, directly be used for next step reaction.ESI-MS(m/z)203[M+H] +。
5) preparation of Boc-Tyr-Ile-Gly-OMe
0.525g (1.87mmol) Boc-Tyr is dissolved among the anhydrous THF of 5ml, and 0 ℃ adds 0.27g (2.0mmol) HOBt and 0.45g (2.18mmol) DCC down.Stir after 10 minutes, add the anhydrous THF solution of 0.377g (1.87mmol) HClIle-Gly-OMe.Reaction mixture is regulated pH 8-9 with NMM, and 0 ℃ was stirred 24 hours.Stopped reaction removes by filter the DCU that is settled out.Filtrate decompression concentrates, and residue is dissolved in the ETHYLE ACETATE, and the solution that obtains is used saturated NaHCO successively 3The aqueous solution, 5%KHSO 4The aqueous solution and the saturated NaCl aqueous solution are washed.Ethyl acetate layer is used anhydrous Na SO 4Dry 3 hours.Filtering NaSO 4, filtrate decompression concentrates removes ETHYLE ACETATE.Residue uses column chromatography (CHCl 3: CH 3OH, 60: 1).Obtain 0.808g (93%) target compound.ESI-MS(m/z)466[M+H] +。
6) preparation of Boc-Tyr-Ile-Gly
0.808g (1.87mmol) Boc-Tyr-Ile-Gly-OMe is dissolved in the 10ml methyl alcohol, and 0 ℃ of NaOH (1.5mol/l) aqueous solution that adds is down regulated pH value to 11, stirring reaction 0.5h, and the TLC detection reaction finishes.Add saturated KHSO 4Regulate pH value to 6～7, the salt that filtering is separated out, whole methyl alcohol are removed in the filtrate decompression distillation, and residuary water solution continues to use KHSO 4Regulate pH value to 2, with ethyl acetate extraction three times, ethyl acetate layer merges, give a baby a bath on the third day after its birth time with saturated NaCl collection, and dry 3 hours of anhydrous Na SO4, filtration, filtrate decompression is concentrated removes ETHYLE ACETATE, obtains 0.834g (99%) target compound.ESI-MS(m/z)452[M+H] +。
7) Boc-Tyr-Ile-Gly-Ser (Bzl)-Arg (NO 2The preparation of)-OMe
0.857g (1.9mmol) Boc-Tyr-Ile-Gly is dissolved among the anhydrous THF of 5ml, and 0 ℃ adds 0.257g (1.9mmol) HOBt and 0.45g (2.18mmol) DCC down.Stir after 10 minutes, add 0.848g (1.9mmol) HClSer-Arg (NO 2The anhydrous THF solution of)-OMe.Reaction mixture is regulated pH 8-9 with NMM, and 0 ℃ was stirred 24 hours.Stopped reaction removes by filter the DCU that is settled out.Filtrate decompression concentrates, and residue is dissolved in the ETHYLE ACETATE, and the solution that obtains is used saturated NaHCO successively 3The aqueous solution, 5%KHSO 4The aqueous solution and the saturated NaCl aqueous solution are washed.Ethyl acetate layer is used anhydrous Na SO 4Dry 3 hours.Filtering NaSO 4, filtrate decompression concentrates removes ETHYLE ACETATE.Residue uses column chromatography (CHCl 3: CH 3OH, 30: 1).Obtain 1.44g (90%) target compound.ESI-MS(m/z)844[M+H] +。
8) HClTyr-Ile-Gly-Ser (Bzl)-Arg (NO 2The preparation of)-OMe
With 1.44g (1.70mmol) Boc-Tyr-Ile-Gly-Ser (Bzl)-Arg (NO 2)-OMe is dissolved in 20ml hydrogenchloride-ethyl acetate solution (6mol/l), stirring at room 2 hours, and TLC detects raw material point and disappears, and reduces pressure and takes out ETHYLE ACETATE, adds a small amount of ether repeatedly and reduces pressure and bleed to remove the acid gas in the product.Add a small amount of ether at last product is ground to form pressed powder, directly be used for next step reaction.ESI-MS(m/z)743[M+H] +。
The preparation of embodiment 2 Boc-Arg (Tos)-Gly-Asp (OMe)-Phe
1) preparation of Boc-Asp (OMe)-Phe-OBzl
0.494g (2.0mmol) Boc-Asp (OMe) is dissolved among the anhydrous THF of 5ml, and 0 ℃ adds 0.27g (2.0mmol) HOBt and 0.45g (2.18mmol) DCC down.Stir after 10 minutes, add the anhydrous THF solution of 0.854g (2.0mmol) TosPhe-OBzl.Reaction mixture is regulated pH 8-9 with NMM, and 0 ℃ was stirred 24 hours.Stopped reaction removes by filter the DCU that is settled out.Filtrate decompression concentrates, and residue is dissolved in the ETHYLE ACETATE, and the solution that obtains is used saturated NaHCO successively 3The aqueous solution, 5%KHSO 4The aqueous solution and the saturated NaCl aqueous solution are washed.Ethyl acetate layer is used anhydrous Na SO 4Dry 3 hours.Filtering NaSO 4, filtrate decompression concentrates removes ETHYLE ACETATE.Residue uses column chromatography (CHCl 3: CH 3OH, 30: 1).Obtain 0.96g (99%) target compound.ESI-MS(m/z)485[M+H] +。
2) preparation of HClAsp (OMe)-Phe-OBzl
0.960g (1.98mmol) Boc-Asp (OMe)-Phe-OBzl is dissolved in 10ml hydrogenchloride-ethyl acetate solution (6mol/l); Stirring at room 2 hours; TLC detects raw material point and disappears, and reduces pressure and takes out ETHYLE ACETATE, adds a small amount of ether repeatedly and reduces pressure and bleed to remove the acid gas in the product.Add a small amount of ether at last product is ground to form pressed powder, directly be used for next step reaction.ESI-MS(m/z)385[M+H] +。
3) preparation of Boc-Arg (Tos)-Gly-OMe
0.856g (2.0mmol) Boc-Arg (Tos) is dissolved in the 5ml dry DMF, and 0 ℃ adds 0.27g (2.0mmol) HOBt and 0.45g (2.18mmol) DCC down.Stir after 10 minutes, add the anhydrous DMF solution of 0.251g (2.0mmol) HClGly-OMe.Reaction mixture is regulated pH 8-9 with NMM, and 0 ℃ was stirred 24 hours.Stopped reaction removes by filter the DCU that is settled out.Filtrate decompression concentrates, and residue is dissolved in the ETHYLE ACETATE, and the solution that obtains is used saturated NaHCO successively 3The aqueous solution, 5%KHSO 4The aqueous solution and the saturated NaCl aqueous solution are washed.Ethyl acetate layer is used anhydrous Na SO 4Dry 3 hours.Filtering NaSO 4, filtrate decompression concentrates removes ETHYLE ACETATE.Residue uses column chromatography (CHCl 3: CH 3OH, 30: 1).Obtain 0.96g (96%) target compound.ESI-MS(m/z)500[M+H] +。
4) preparation of Boc-Arg (Tos)-Gly
0.960g (1.9mmol) Boc-Arg (Tos)-Gly-OMe is dissolved in the 10ml methyl alcohol, and 0 ℃ of NaOH aqueous solution (1.5mol/l) that adds is down regulated pH value to 11, stirring reaction 0.5h, and the TLC detection reaction finishes.Add saturated KHSO 4Regulate pH value to 6～7, the salt that filtering is separated out, whole methyl alcohol are removed in the filtrate decompression distillation, and residuary water solution continues to use KHSO 4Regulate pH value to 2, with ethyl acetate extraction three times, ethyl acetate layer merges, with saturated NaCl come together give a baby a bath on the third day after its birth inferior, anhydrous Na SO 4Dry 3 hours, to filter, filtrate decompression concentrates and removes ETHYLE ACETATE, obtains 0.903g (98%) target compound.ESI-MS(m/z)484[M-H] -。
5) preparation of Boc-Arg (Tos)-Gly-Asp (OMe)-Phe-OBzl
0.903g (1.86mmol) Boc-Arg (Tos)-Gly is dissolved among the anhydrous THF of 5ml, and 0 ℃ adds 0.252g (1.86mmol) HOBt and 0.428g (2.08mmol) DCC down.Stir after 10 minutes, add the anhydrous THF solution of 0.784g (1.86mmol) HClAsp (OMe)-Phe-OBzl.Reaction mixture is regulated pH 8-9 with NMM, and 0 ℃ was stirred 24 hours.Stopped reaction removes by filter the DCU that is settled out.Filtrate decompression concentrates, and residue is dissolved in the ETHYLE ACETATE, and the solution that obtains is used saturated NaHCO successively 3The aqueous solution, 5%KHSO 4The aqueous solution and the saturated NaCl aqueous solution are washed.Ethyl acetate layer is used anhydrous Na SO 4Dry 3 hours.Filtering NaSO 4, filtrate decompression concentrates removes ETHYLE ACETATE.Residue uses column chromatography (CHCl 3: CH 3OH, 30: 1).Obtain 1.47g (93%) target compound.ESI-MS(m/z)852[M+H] +。
6) preparation of Boc-Arg (Tos)-Gly-Asp (OMe)-Phe
0.852g (1.0mmol) Boc-Arg (Tos)-Gly-Asp (OMe)-Phe-OBzl is dissolved in the 10ml methyl alcohol, and 0 ℃ adds the NaOH aqueous solution (1.5mol/l) down and regulates pH value to 11, stirring reaction 0.5h, the end of TLC detection reaction.Add saturated KHSO 4Regulate pH value to 6～7, the salt that filtering is separated out, whole methyl alcohol are removed in the filtrate decompression distillation, and residuary water solution continues to use KHSO 4Regulate pH value to 2, with ethyl acetate extraction three times, ethyl acetate layer merges, with saturated NaCl come together give a baby a bath on the third day after its birth inferior, anhydrous Na SO 4Dry 3 hours, to filter, filtrate decompression concentrates and removes ETHYLE ACETATE, obtains 0.731g (96%) target compound.ESI-MS(m/z)760[M-H] -。
The preparation of embodiment 3 RGDFYIGSK
200mg (0.123mmol) Boc-Arg (Tos)-Gly-Asp (OMe)-Phe-Tyr-Ile-Gly-Ser (Bzl)-Lys (Z)-OBzl is dissolved in the 4mL trifluoracetic acid; Add 1mL trifluoromethanesulfonic acid and 1mL methyl-phenoxide; 0 ℃ of following stirring reaction 1 hour, disposable adding 100mL ether was bled in decompression 5 minutes; The product pressed powder of separating out uses Sephadex G 10 to purify, and obtains product 114mg (89%). 1HNMR (BHSC-300, CDCl 3-d 3) δ=11.0 (s, 2H), 7.80 (d, J=5.0Hz, 8H), 7.21 (d, J=7.0Hz, 2H), 7.12 (m, 2H), 7.08 (t; J=7.0Hz, 1H), 6.95 (d, J=7.0Hz, 2H), 6.68 (d, J=7.0Hz, 2H), 5.7 (s, 1H), 5.0 (s; 1H), 4.92 (q, J=6.0Hz, 2H), 4.86 (q, J=6.0Hz, 1H), 4.62 (s, 1H), 4.50 (t, J=6.0Hz; 2H), 4.09 (d, J=6.0Hz, 4H), 4.03 (d, J=7.0Hz, 2H), 3.56 (m, 1H), 3.05 (d; J=6.0Hz, 4H), 2.73 (t, J=6.0Hz, 2H), 2.65 (q, J=6.0Hz, 4H), 2.5 (m, 1H); 2.0 (s, 8H), 1.79 (q, J=7.0Hz, 4H), 1.55 (m, 4H), 0.8-1.3 (m, J=8.0Hz, 10H).ESI-MS(m/z)1042[M+H] +。Ultimate analysis C 47H 71N 13O 14Theoretical value C 54.17, and H 6.87, N 17.47. measured value C 60.80, and H 6.67, and N 11.38.
The antithrombotic acitivity test of Test Example 1 RGDFYIGSR
1) rat operation and apparatus
(male, 220～230g) press 1200mgkg to the SD rat -1Dosage abdominal injection urethane solution is anaesthetized.The anesthetized rat dorsal position is fixed, and separates RCCA, and in proximal part folder bulldog clamp, proximal part and distal end penetrate surgical thread respectively, and the surgical thread of distal end is clamped with mosquito forceps in fur, and preparation is in the distal end intubate.
2) intubate
Intubate is the polyethylene rubber tube that silylanization is crossed, and divides three sections, and the stage casing is a polyethylene rubber tube, long 60.0mm, internal diameter 3.5mm; Two ends are identical polyethylene tube, and pipe range 100.0mm, the end that internal diameter 1.0mm, external diameter 2.0mm should manage pull into point pipe (being used to insert rat carotid artery or vein), and external diameter is 1.0mm.Be respectively charged into the long black surgical thread of 6cm in the clean penicillium mould bottle with the number of finishing, weigh; Take out silk thread then, put into the thicker intubate in stage casing of ready intubate according to numbering.
Open rat right side bulldog clamp, fill with heparin-saline solution (50IUkg in will managing through sharp pipe end with syringe -1), then the arterial end of intubate is inserted the rat right carotid, the heparin of calculated amount is slowly injected in the rat body.
3) administration
Medicine: saline water (3mlkg -1), the physiological salt soln of the physiological salt soln of Asprin (dosage is 30mg/kg), RGDFYIGSR (dosage is 10 μ mol/kg).
Folder closes rat right carotid artery folder, pulls up the syringe of intubate vein end, has the water-soluble medical fluid injector of medicine of calculated amount to insert the vein end of intubate suction, opens rat right carotid artery folder, and medicine is slowly pushed in the rat body.Folder closes right carotid artery folder, and the vein end in teahouse is inserted the rats with left jugular vein of separator well, opens bulldog clamp, makes blood begin circulation.And pick up counting simultaneously.Can produce thrombus because of blood circulation on the silk thread in this process in the extra heavy pipe of intubate central authorities.
4) thrombus is weighed
Timing is cut off venous incubation after beginning 15 minutes, stops circulation, carefully takes out silk thread with the ophthalmology tweezer, on filter paper, dips in drop of blood gently, puts into the penicillium mould bottle of weighing in advance, accurately weighs and record.Calculate the weight in wet base of thrombus.Each medicine repeats 11 administrations.The wet weight of thrombus
Figure BSA00000699271300071
of each group of statistics is also done the t check.
5) result
RGDFYIGSR has good anti-thrombus activity.The result lists table 1 in.
The antithrombotic acitivity of table 1RGDFYIGSR on rat model
Figure BSA00000699271300072
N=11; A. compare P＜0.001 with saline water.

Claims (3)

1. the polypeptide RGDFYIGSR that has target antithrombotic activity.
2. method for preparing the RGDFYIGSR of claim 1 comprises:
(1) adopts liquid-phase synthesis process, synthesize the protection midbody of RGDF and the protection midbody of YIGSR respectively through progressively connecing peptide;
(2) the C end of sloughing the protection midbody of RGDF is protected base;
(3) the N end of sloughing the protection midbody of YIGSR is protected base;
(4) put together the protection midbody that obtains RGDFYIGSR to the RGDF protection midbody of the YIGSR of N end dissociative protection midbody and C end dissociative;
(5) slough the protection base to the protection midbody of RGDFYIGSR, obtain RGDFYIGSR.
3. the RGDFYIGSR of claim 1 is in the purposes of preparation in the antithrombotic reagent.
CN2012101051073A 2006-11-30 2006-11-30 RGDF-YIGSR with targeted anti-thrombotic activity, preparation and application thereof Pending CN102702314A (en)

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Application publication date: 20121003