CN101906140B - Aliphatic chain and YIGSR pentapeptide conjugate, and synthesizing method and application thereof - Google Patents
Aliphatic chain and YIGSR pentapeptide conjugate, and synthesizing method and application thereof Download PDFInfo
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- CN101906140B CN101906140B CN200910085124A CN200910085124A CN101906140B CN 101906140 B CN101906140 B CN 101906140B CN 200910085124 A CN200910085124 A CN 200910085124A CN 200910085124 A CN200910085124 A CN 200910085124A CN 101906140 B CN101906140 B CN 101906140B
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- ile
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- tyr
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- 108010052768 tyrosyl-isoleucyl-glycyl-seryl-arginine Proteins 0.000 title claims abstract description 29
- MWOGMBZGFFZBMK-LJZWMIMPSA-N (2s)-2-[[(2s)-2-[[2-[[(2s,3s)-2-[[(2s)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]-3-methylpentanoyl]amino]acetyl]amino]-3-hydroxypropanoyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound NC(N)=NCCC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H](N)CC1=CC=C(O)C=C1 MWOGMBZGFFZBMK-LJZWMIMPSA-N 0.000 title claims abstract description 26
- 238000000034 method Methods 0.000 title claims description 63
- 125000001931 aliphatic group Chemical group 0.000 title description 10
- 230000002194 synthesizing effect Effects 0.000 title 1
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- 230000002785 anti-thrombosis Effects 0.000 claims abstract description 12
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 7
- 239000000463 material Substances 0.000 claims abstract description 6
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- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 8
- 239000003146 anticoagulant agent Substances 0.000 claims description 7
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- 229910021529 ammonia Inorganic materials 0.000 claims description 4
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- 239000000969 carrier Substances 0.000 abstract 1
- 238000001338 self-assembly Methods 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 88
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 78
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 72
- 239000002994 raw material Substances 0.000 description 55
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- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 12
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- 229940079593 drug Drugs 0.000 description 8
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- 238000012546 transfer Methods 0.000 description 8
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- 239000004698 Polyethylene Substances 0.000 description 6
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- 239000001257 hydrogen Substances 0.000 description 6
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
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- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
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- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 2
- 241000255925 Diptera Species 0.000 description 2
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 2
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 2
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- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
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- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
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- DMBKPDOAQVGTST-GFCCVEGCSA-N (2r)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylmethoxypropanoic acid Chemical compound CC(C)(C)OC(=O)N[C@@H](C(O)=O)COCC1=CC=CC=C1 DMBKPDOAQVGTST-GFCCVEGCSA-N 0.000 description 1
- CNBUSIJNWNXLQQ-NSHDSACASA-N (2s)-3-(4-hydroxyphenyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 CNBUSIJNWNXLQQ-NSHDSACASA-N 0.000 description 1
- QJCNLJWUIOIMMF-YUMQZZPRSA-N (2s,3s)-3-methyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]pentanoic acid Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)OC(C)(C)C QJCNLJWUIOIMMF-YUMQZZPRSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
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- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229910000071 diazene Inorganic materials 0.000 description 1
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- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 1
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- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- MVEAAGBEUOMFRX-UHFFFAOYSA-N ethyl acetate;hydrochloride Chemical compound Cl.CCOC(C)=O MVEAAGBEUOMFRX-UHFFFAOYSA-N 0.000 description 1
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- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 1
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- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
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- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical class [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
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- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention discloses fatty alkyl, YIGSR pentapeptide conjugate, and a preparation method and medical application thereof. The conjugate has a general formula of Tyr-Ile-Gly-Ser-Arg-X, Tyr-Ile-Gly-Ser-Arg-Y or Z-Tyr-Ile-Gly-Ser-Arg, wherein X is CH3(CH2)nCH2OH; Y is CH3(CH2)nCH2NH2; Z is CH3(CH2)nCO2H; and n is equal to 6, 8, 10, 12, 14 or 16. The conjugate has excellent antithrombotic activity and excellent self-assembly performance, and can be used as a preparation material for preparing micro-emulsion, liposome and other medicinal carriers.
Description
Technical field
The present invention relates to one type of conjugate; Relate in particular to aliphatic alkyl chain and put together the target cationic pharmacome that obtains through the carboxylic end or the ammonia end of carbonyl, methylamino-and methoxyl group and YIGSR pentapeptide; The preparation method and this conjugate that the invention still further relates to this conjugate belong to biomedicine field as the application of pharmaceutical preparations having antithrombotic activity, pharmaceutical carrier or drug targeting formulation materials.
Background technology
Gene might be sent to the ideal carrier of cell in the gene therapy meetings in 5 years to 10 years in future.See that from the position of biotechnological formulation the gene transfer system is exactly drug delivery system (DDS).The gene transfer system that has number of chemical synthetic small molecules to make up receives publicity, and wherein the gene transfer system of cation lipid formation is the focus of attention.Cation lipid at pharmaceutical field all over being used to make up liposomal delivery small molecules (comprising polypeptide) medicine.With the same in DDS; Cationic-liposome has obvious benefit in the gene transfer system, for example can through electric charge absorption form mixture with DNA and effectively avoid by lysosome degraded in the cell, can be with the efficient transfered cell of DNA, to the not restriction of size of DNA, easy and simple to handle etc.The essential structure of cation lipid comprises hydrophobic arm and the hydrophilic cationic head that senior aliphatic chain constitutes.
The essential structure of cation lipid
Cell adhesion plays a crucial role in the evolution of cell adhesion property disease (metastasis of cancer, thrombosis, chemistry cause inflammation and osteoporosis); The pentapeptide YIGSR that derives from ln B1 chain is the polypeptide that sticks of a quasi-representative; It is also such relevant with the integrin family of cell receptor unlike RGD, but with the adhesion of 67kDa layer conjugated protein relevant (LBP).Be transplanted to when on glass when it, find to promote to stick and a large amount of cell migrations, comprise vascular endothelial cell, inoblast and smooth muscle cell.This effect of YIGSR pentapeptide has given the compound that contains the YIGSR sequence a kind of critical nature, can be to thrombus, cancer and osteoporotic disease sites enrichment.Under such prerequisite, put together YIGSR peptide and aliphatic chain just and can obtain the target pharmacome.
Summary of the invention
One of the object of the invention is that YIGSR peptide and senior aliphatic chain are puted together the one type of conjugate that has antithrombotic acitivity and have target property to obtain;
Two of the object of the invention provides a kind of method for preparing above-mentioned conjugate;
Three of the object of the invention is that above-mentioned conjugate is applied to pharmaceutical preparations having antithrombotic activity, pharmaceutical carrier or drug targeting formulation materials;
Above-mentioned purpose of the present invention realizes by the following technical programs:
One type of aliphatic chain and YIGSR pentapeptide conjugate, the general formula of this conjugate is Tyr-Ile-Gly-Ser-Arg-X, Tyr-Ile-Gly-Ser-Arg-Y, Z-Tyr-Ile-Gly-Ser-Arg, wherein X is CH
3(CH
2)
nCH
2OH, Y are CH
3(CH
2)
nCH
2NH
2, Z is CH
3(CH
2)
nCO
2H; N=6 wherein, 8,10,12,14 or 16.
A kind of method for preparing above-mentioned aliphatic chain and YIGSR pentapeptide may further comprise the steps:
(1) synthetic Tyr-Ile-Gly-Ser-Arg;
(2) with CH
3(CH
2)
nCO
2H, CH
3(CH
2)
nCH
2OH puts together with carboxylic end or the ammonia end of the basic Tyr-Ile-Gly-Ser-Arg that protects of protection respectively, sloughs the protection base, promptly gets; Perhaps with CH
3(CH
2)
nCH
2NH
2Put together with the carboxylic end of the basic Tyr-Ile-Gly-Ser-Arg that protects of protection, slough the protection base, promptly get; N=6 wherein, 8,10,12,14 or 16.
The present invention has combined following understanding or foundation to accomplish technique scheme.The ideal carrier (gene transfer system) that is sent to gene in cell is one of mission critical of gene therapy; See that from the position of biotechnological formulation gene transfer system and drug delivery system (DDS) have identity property; The gene transfer system that cationic-liposome constitutes though the gene transfer system that has number of chemical synthetic small molecules to make up all receives publicity should especially pay close attention; Cationic-liposome can form mixture with DNA through electric charge absorption and also effectively avoid by lysosome degraded in the cell; Cationic-liposome can not limit the efficient transfered cell of DNA, cationic-liposome to the size of DNA; The compound that contains the YIGSR sequence can be to thrombus, inflammation, metastasis of cancer and osteoporotic disease sites enrichment.
The inventor is based on above-mentioned cognition; Put together aliphatic chain through the carboxylic end or the ammonia end of carbonyl, methylamino-and methoxyl group and YIGSR pentapeptide; Make the molecule that makes obtain four kinds of performances, promptly depend on the cationic property and the wetting ability of the hydrophobicity of aliphatic alkyl chain, the amino side-chain base that depends on the YIGSR peptide and the protonated formation of alpha-amino group and depend on the target property that the YIGSR pentapeptide obtains the special affinity interaction of 67kDa layer adhesion binding protein receptor.So, put together the molecule that makes to YIGSR peptide and aliphatic alkyl chain and just become the target cationic pharmacome.
Another purpose of the present invention provides the antithrombotic pharmaceutical composition of the above-mentioned general formula compound of a kind of the present invention of containing, and this pharmaceutical composition is gone up effective dose by treatment conjugate of the present invention is with pharmaceutically acceptable excipient or assist and add agent and form; That is: with the conjugate of the present invention of significant quantity with after pharmaceutically acceptable carrier or thinner cooperate, the formulation method conventional by this area is prepared into any one appropriate drug compsn with it.Usually said composition is suitable for oral administration and drug administration by injection, also is fit to other medication.Said composition can be liquid preparation forms such as tablet, capsule, pulvis, granule, lozenge, suppository, or oral liquid.According to different medications, pharmaceutical composition of the present invention can contain 0.1%-99% weight, the conjugate of the present invention of preferred 10-60% weight.
The evaluation that forms on the model at rat suppository shows that conjugate of the present invention has outstanding antithrombotic acitivity, can be used as pharmaceutical preparations having antithrombotic activity and uses; They can be self-assembled into and be nano particle at water and biota, can be used as the formulation materials of preparation micro emulsion and liposome.
Description of drawings
Fig. 1 fatty alkyl and YIGSR peptide are puted together the synthetic route chart of preparation target cationic pharmacome through carbonyl, methylamino-and methoxyl group.
Fig. 2 conjugate of the present invention is in the test of aqueous phase assembling becoming nanometer ball.
The nanometer ball that Fig. 3 is assembled at water by the of the present invention representative conjugate that transmission electron microscope is described.
The nanometer ball that Fig. 4 is assembled at water by the of the present invention representative conjugate that ESEM is described.
Embodiment
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.
1)Boc-Ser(Bzl)-Arg(NO
2)-OBzl
0.36g (1.20mmol) Boc-Ser (Bzl) is dissolved among the anhydrous THF of 6ml, and 0 ℃ adds 0.155g (1.14mmol) N-hydroxybenzotriazole (HOBt) and 0.26g (1.20mmol) dicyclohexyl carbonyl diimine (DCC) down.Stir and add 0.255g (1.14mmol) HClArg (NO after 10 minutes
2The anhydrous THF solution of)-OBzl.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, 80: 1), obtain 0.55g (83%) target compound.ESI-MS(m/z)586[M+H]
+。
2)HCl·Ser(Bzl)-Arg(NO
2)-OBzl
With 0.59g (1.00mmol) Boc-Ser (Bzl)-Arg (NO
2)-OBzl is dissolved in 50ml 6M hydrogenchloride-ethyl acetate solution, stirring at room 3 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)486[M+H]
+。
3)Boc-Ile-Gly-OBzl
Use and prepare Boc-Ser (Bzl)-Arg (NO
2The method that)-OBzl is identical is with 0.3g (1.29mmol) Boc-Ile and 0.194g (1.17mmol) TosNH
2-Gly-OBzl is a raw material, obtains 0.32g (73%) target compound.ESI-MS(m/z)378[M+H]
+。
4)HCl·Ile-GlyOBzl
Use and prepare HClSer (Bzl)-Arg (NO
2The method that)-OBzl is identical is a raw material with 0.37g (1.0mmol) Boc-Ile-Gly-OMe, obtains target compound.ESI-MS(m/z)278[M+H]
+。
5)Boc-Tyr-Ile-Gly-OBzl
Use and prepare Boc-Ser (Bzl)-Arg (NO
2The method that)-OBzl is identical is a raw material with 0.428g (1.52mmol) Boc-Tyr and 0.38g (1.36mmol) HClH-Ile-Gly-OBzl, obtains 0.64g (86%) target compound.ESI-MS(m/z)542[M+H]
+。
6)Boc-Tyr-Ile-Gly
0.31gBoc-Tyr-Ile-Gly-OBzl is dissolved in the 20ml methyl alcohol, and 0 ℃ of NaOH aqueous solution that adds 1.5mol/l is down regulated pH value to 11, stirring reaction 2.0hr, and the TLC detection reaction finishes.Add saturated KHSO4 and regulate 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 0.23g (89%) target compound.ESI-MS(m/z)451[M-H]
+。
7)Boc-Tyr-Ile-Gly-Ser(Bzl)-Arg(NO
2)-OBzl
Use and prepare Boc-Ser (Bzl)-Arg (NO
2The method that)-OBzl is identical is with 0.496g (1.10mmol) Boc-Tyr-Ile-Gly and 0.48g (1.0mmol) HClSer (Bzl)-Arg (NO
2)-OBzl is a raw material, obtains 0.81g (90%) target compound.ESI-MS(m/z)919[M+H]
+。
8)HCl·Tyr-Ile-Gly-Ser(Bzl)-Arg(NO
2)-OBzl
Use and prepare HClSer (Bzl)-Arg (NO
2The method that)-OBzl is identical is with 0.92gBoc-Tyr-Ile-Gly-Ser (Bzl)-Arg (NO
2)-OBzl is that raw material obtains target compound.ESI-MS(m/z)819[M+H]
+。
9)Tyr-Ile-Gly-Ser-Arg
With 250mg Boc-Tyr-Ile-Gly-Ser (Bzl)-Arg (NO
2)-OBzl is dissolved in the 4ml trifluoracetic acid, adds 1ml trifluoromethanesulfonic acid and 1ml methyl-phenoxide, and stirring reaction is 1 hour under the ice bath; Decompression was bled 5 minutes; Disposable adding 100ml ether, the product pressed powder of separating out use Sephadex G 10 to purify, and obtain 160mg (91%) target compound.ESI-MS(m/z)594[M+H]
+。
10)CH
3(CH
2)
6CO-Tyr-Ile-Gly-Ser(Bzl)-Arg(NO
2)-OBzl
Use and prepare Boc-Ser (Bzl)-Arg (NO
2The method that)-OBzl is identical is with 0.17g (1.2mmol) CH
3(CH
2)
6COOH and 0.82g (1.0mmol) HClTyr-Ile-Gly-Ser (Bzl)-Arg (NO
2)-OBzl is that raw material obtains 0.84g (89.3%) target compound.ESI-MS(m/z)945[M+H]
+。
11)CH
3(CH
2)
6CO-Tyr-Ile-Gly-Ser-Arg[CH
3(CH
2)
6COYIGSR]
With 250mgCH
3(CH
2)
6CO-Tyr-Ile-Gly-Ser (Bzl)-Arg (NO
2)-OBzl is dissolved in the 4ml trifluoracetic acid; Add 1ml trifluoromethanesulfonic acid and 1ml methyl-phenoxide; Stirring reaction is 1 hour under 0 ℃ of condition of ice bath, and 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 150mg (79%) target compound.ESI-MS(m/z)721[M+H]
+。[α]
D 25=-7.60 (c=1.02 methyl alcohol), Mp:164.0～165.0 ℃.
1)CH
3(CH
2)
8CO-Tyr-Ile-Gly-Ser(Bzl)-Arg(NO
2)-OBzl
Use and prepare Boc-Ser (Bzl)-Arg (NO
2The method that)-OBzl is identical is with 0.24g (1.4mmol) CH
3(CH
2)
8-COOH and 0.82g (1.0mml) HClTyr-Ile-Gly-Ser (Bzl)-Arg (NO
2)-OBzl is that raw material obtains 0.87g (89.69%) target compound.ESI-MS(m/z)973[M+H]
+。
2)CH
3(CH
2)
8CO-Tyr-Ile-Gly-Ser-Arg[CH
3(CH
2)
8COYIGSR]
With 250mg CH
3(CH
2)
8CO-Tyr-Ile-Gly-Ser (Bzl)-Arg (NO
2)-OBzl is dissolved in the 4ml trifluoracetic acid; Add 1ml trifluoromethanesulfonic acid and 1ml methyl-phenoxide; Stirring reaction is 1 hour under 0 ℃ of condition of ice bath, and 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 160mg (83%) target compound.ESI-MS(m/z)748[M+H]
+。[α]
D 25=-10.23 (c=1.02 methyl alcohol), Mp:121.0～122.0 ℃.
Embodiment 3 CH
3(CH
2)
10The preparation of COYIGSR
1)CH
3(CH
2)
10CO-Tyr-Ile-Gly-Ser(Bzl)-Arg(NO
2)-OBzl
Use and prepare Boc-Ser (Bzl)-Arg (NO
2The method that)-OBzl is identical is with 0.28g (1.4mmol) CH
3(CH
2)
10COOH and 0.82g (1.0mml) HClTyr-Ile-Gly-Ser (Bzl)-Arg (NO
2)-OBzl is that raw material obtains 0.87g (87.0%) target compound.ESI-MS(m/z)1001[M+H]
+。
2)CH
3(CH
2)
10CO-Tyr-Ile-Gly-Ser-Arg[CH
3(CH
2)
10COYIGSR]
With 250mg CH
3(CH
2)
10CO-Tyr-Ile-Gly-Ser (Bzl)-Arg (NO
2)-OBzl is dissolved in the 4ml trifluoracetic acid; Add 1ml trifluoromethanesulfonic acid and 1ml methyl-phenoxide; Stirring reaction is 1 hour under 0 ℃ of condition of ice bath, and 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 160mg (84%) target compound.ESI-MS(m/z)776[M+H]
+。[α]
D 25=-9.76 (c=1.02 methyl alcohol), Mp:138.50～139.40 ℃.
Embodiment 4 CH
3(CH
2)
12The preparation of COYIGSR
1)CH
3(CH
2)
12CO-Tyr-Ile-Gly-Ser(Bzl)-Arg(NO
2)-OBzl
Use and prepare Boc-Ser (Bzl)-Arg (NO
2The method that)-OBzl is identical is with 0.27g (1.2mmol) CH
3(CH
2)
12COOH and 0.82g (1.0mml) HClTyr-Ile-Gly-Ser (Bzl)-Arg (NO
2)-OBzl is that raw material obtains 0.79g (79.0%) target compound.ESI-MS(m/z)1030[M+H]
+。
2)CH
3(CH
2)
12CO-Tyr-Ile-Gly-Ser-Arg[CH
3(CH
2)
12COYIGSR]
With 250mgCH
3(CH
2)
12CO-Tyr-Ile-Gly-Ser (Bzl)-Arg (NO
2)-OBzl is dissolved in the 4ml trifluoracetic acid; Add 1ml trifluoromethanesulfonic acid and 1ml methyl-phenoxide; Stirring reaction is 1 hour under 0 ℃ of condition of ice bath, and 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 160mg (82%) target compound.ESI-MS(m/z)804[M+H]
+。[α]
D 25=-11.60 (c=1.01 methyl alcohol), Mp:141.50～142.40 ℃.
Embodiment 5 CH
3(CH
2)
14The preparation of COYIGSR
1)CH
3(CH
2)
14CO-Tyr-Ile-Gly-Ser(Bzl)-Arg(NO
2)-OBzl
Use and prepare Boc-Ser (Bzl)-Arg (NO
2The method that)-OBzl is identical is with 0.30g (1.2mmol) CH
3(CH
2)
14COOH and 0.82g (1.0mml) HClTyr-Ile-Gly-Ser (Bzl)-Arg (NO
2)-OBzl is that raw material obtains 0.89g (89.0%) target compound.ESI-MS(m/z)1057[M+H]
+。
2)CH
3(CH
2)
14CO-Tyr-Ile-Gly-Ser-Arg[CH
3(CH
2)
14COYIGSR]
With 250mgCH
3(CH
2)
14CO-Tyr-Ile-Gly-Ser (Bzl)-Arg (NO
2)-OBzl is dissolved in the 4ml trifluoracetic acid; Add 1ml trifluoromethanesulfonic acid and 1ml methyl-phenoxide; Stirring reaction is 1 hour under 0 ℃ of condition of ice bath, and 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 160mg (81.63%) target compound.ESI-MS(m/z)832[M+H]
+。[α]
D 25=-13.60 (c=1.01 methyl alcohol), Mp:140.50～141.40 ℃.
Embodiment 6 CH
2(CH
2)
16The preparation of COYIGSR
1)CH
3(CH
2)
16CO-Tyr-Ile-Gly-Ser(Bzl)-Arg(NO
2)-OBzl
Use and prepare Boc-Ser (Bzl)-Arg (NO
2The method that)-OBzl is identical is with 0.34g (1.2mmol) CH
3(CH
2)
16COOH and 0.82g (1.0mml) HClTyr-Ile-Gly-Ser (Bzl)-Arg (NO
2)-OBzl is that raw material obtains 0.89g (82.40%) target compound.ESI-MS(m/z)1085[M+H]
+。
2)CH
3(CH
2)
16CO-Tyr-Ile-Gly-Ser-Arg[CH
3(CH
2)
16COYIGSR]
With 230mgCH
3(CH
2)
16CO-Tyr-Ile-Gly-Ser (Bzl)-Arg (NO
2)-OBzl is dissolved in the 4ml trifluoracetic acid; Add 1ml trifluoromethanesulfonic acid and 1ml methyl-phenoxide; Stirring reaction is 1 hour under 0 ℃ of condition of ice bath, and 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 150mg (82.41%) target compound.ESI-MS(m/z)860[M+H]
+。[α]
D 25=-19.60 (c=1.03 methyl alcohol), Mp:134.50～135.40 ℃.
Embodiment 7 YIGSRNH (CH
2)
7CH
3Preparation
1)Boc-Arg(NO
2)-NH-(CH
2)
7CH
3
Use and prepare Boc-Ser (Bzl)-Arg (NO
2The method that)-OBzl is identical is with 1.5g (4.7mmol) Boc-Arg (NO
2) and 0.70ml (4.30mmol) CH3 (CH
2)
7NH
2For raw material obtains 1.60g (84.66%) target compound.ESI-MS(m/z)431[M+H]
+。
2)HCl·Arg(NO
2)-NH-(CH
2)
7CH
3
Use and prepare HClNH
2-Ser (Bzl)-Arg (NO
2The method that)-OBzl is identical is with 1.6g (3.7mmol) Boc-Arg (NO
2)-NH-(CH
2)
7CH
3For raw material obtains 1.15g (94.26%) target compound.ESI-MS(m/z)331[M+H]
+。
3)Boc-Tyr-Ile-Gly-Ser-Arg(NO
2)-NH-(CH
2)
7CH
3
With preparation Boc-Ser (Bzl)-Arg (NO
2The method of)-OBzl is with 0.75g (1.4mmol) Boc-Tyr-Ile-Gly-Ser and 0.46g (1.3mmol) HClArg (NO
2)-NH-(CH
2)
7CH
3Be raw material, obtain 1.05g (88.98%) target compound.ESI-MS(m/z)851[M+H]
+。
4)Boc-Tyr-Ile-Gly-Ser-Arg-NH-(CH
2)
7CH
3
Earlier with 0.62g Boc-Tyr-Ile-Gly-Ser-Arg (NO
2)-NH-(CH
2)
7CH
3Be dissolved in 20ml methyl alcohol, add 124mgPd/C (20%) again, the air in the reaction flask is discharged in decompression; Feed hydrogen exchange, replace 5 times repeatedly after, logical hydrogen stirring at room three days; TLC (developping agent CHCl3: MeOH=10: the 1+3d Glacial acetic acid min. 99.5) show the most of disappearance of compound, stopped reaction, filtering Pd/C; Filtrate decompression concentrates to remove and desolvates, and gets 0.45g (77.6%) title compound, is white solid.ESI-MS(m/z)805[M+H]
+。
5) Tyr-Ile-Gly-Ser-Arg-NH-(CH
2)
7CH
3[YIGSRNH(CH
2)
7CH
3]
With 420mg Boc-Tyr-Ile-Gly-Ser-Arg-NH-(CH
2)
7CH
3Be dissolved in the 4ml trifluoracetic acid, stirring reaction is 0.5 hour under 0 ℃ of condition of ice bath, and decompression was bled 5 minutes, and disposable adding 100ml ether is separated out the white solid powder, obtains 330mg (89.91%) target compound.ESI-MS(m/z)705[M+H]
+。[α]
D 25=-10.10 (c=1.03 methyl alcohol), Mp:121.60～122.40 ℃.
Embodiment 8 YIGSRNH (CH
2)
9CH
3Preparation
1)Boc-Arg(NO
2)-NH-(CH
2)
9CH
3
With preparation Boc-Ser (Bzl)-Arg (NO
2The method of)-OBzl is with 1.5g (4.7mmol) Boc-Arg (NO
2) and 0.774g (5.2mmol) CH
3(CH
2)
9NH
2For raw material obtains 2.05g (95.34%) target compound.ESI-MS(m/z)459[M+H]
+。
2)HCl·Arg(NO
2)-NH-(CH
2)
9CH
3
With preparation HClSer (Bzl)-Arg (NO
2The method of)-OBzl is with 1.7g (3.7mmol) Boc-Arg (NO
2)-NH-(CH
2)
9CH
3For raw material obtains 1.21g (91.66%) target compound.ESI-MS(m/z)359[M+H]
+。
3)Boc-Tyr-Ile-Gly-Ser-Arg(NO
2)-NH-(CH
2)
9CH
3
With preparation Boc-Ser (Bzl)-Arg (NO
2The method of)-OBzl is with 0.59g (1.1mmol) Boc-Tyr-Ile-Gly-Ser and 0.36g (1.0mmol) HClArg (NO
2)-NH-(CH
2)
9CH
3Be raw material, obtain 0.72g (81.81%) target compound.ESI-MS(m/z)879[M+H]
+。
4)Boc-Tyr-Ile-Gly-Ser-Arg-NH-(CH
2)
9CH
3
Earlier with 0.70gBoc-Tyr-Ile-Gly-Ser-Arg (NO
2)-NH-(CH
2)
9CH
3Be dissolved in 20ml methyl alcohol, add 140mgPd/C (20%) again, the air in the reaction flask is discharged in decompression; Feed hydrogen exchange, replace 5 times repeatedly after, logical hydrogen stirring at room three days; TLC (developping agent CHCl3: MeOH=10: the 1+3d Glacial acetic acid min. 99.5) show the most of disappearance of compound, stopped reaction, filtering Pd/C; Filtrate decompression concentrates to remove and desolvates, and gets 0.56g (84.8%) title compound, is white solid.ESI-MS(m/z)833[M+H]
+。
5)Tyr-Ile-Gly-Ser-Arg-NH-(CH
2)
9CH
3[YIGSRNH(CH
2)
9CH
3]
With 560mg Boc-Tyr-Ile-Gly-Ser-Arg-NH-(CH
2)
9CH
3Be dissolved in the 5ml trifluoracetic acid, ice bath stirred 0.5 hour, and decompression was bled 5 minutes, and disposable adding 100ml ether is separated out colourless powder, obtains 410mg (83.33%) target compound.ESI-MS(m/z)733[M+H]
+。[α]
D 25=-16.20 (c=1.03 methyl alcohol), Mp:115.60～116.70 ℃.
Embodiment 9 YIGSRNH (CH
2)
11CH
3Preparation
1)Boc-Arg(NO
2)-NH-(CH
2)
11CH
3
With preparation Boc-Ser (Bzl)-Arg (NO
2The method of)-OBzl is with 1.4g (4.4mmol) Boc-Arg (NO
2) and 0.972g (5.3mmol) CH3 (CH
2)
11NH
2For raw material obtains 2.01g (94.36%) target compound.ESI-MS(m/z)487[M+H]
+。
2)HCl·Arg(NO
2)-NH-(CH
2)
9CH
3
With preparation HClSer (Bzl)-Arg (NO
2The method of)-OBzl is with 1.8g (3.7mmol) Boc-Arg (NO
2)-NH-(CH
2)
11CH
3For raw material obtains 1.22g (85.31%) target compound.ESI-MS(m/z)387[M+H]
+。
3)Boc-Tyr-Ile-Gly-Ser(Bzl)-Arg(NO
2)-NH-(CH
2)
11CH
3
With preparation Boc-Ser (Bzl)-Arg (NO
2The method of)-OBzl is with 0.87g (1.4mmol) Boc-Tyr-Ile-Gly-Ser (Bzl) and 0.56g (1.3mmol) HClArg (NO
2)-NH-(CH
2)
11CH
3Be raw material, obtain 1.20g (85.71%) target compound.ESI-MS(m/z)997[M+H]
+。
4)Tyr-Ile-Gly-Ser-Arg-NH-(CH
2)
11CH
3[YIGSRNH(CH
2)
11CH
3]
With 250mg Boc-Tyr-Ile-Gly-Ser (Bzl)-Lys (Z)-NH-(CH
2)
13CH
3Be dissolved in the 4ml trifluoracetic acid, add 1ml trifluoromethanesulfonic acid and 1ml methyl-phenoxide, ice bath stirred 1 hour down; Decompression was bled 5 minutes; Disposable adding 100ml ether, the product pressed powder of separating out use Sephadex G 10 to purify, and obtain 176mg (89.79%) target compound.ESI-MS(m/z)761[M+H]
+。[α]
D 25=-9.56 (c=1.03 methyl alcohol), Mp:120.60～121.50 ℃.
Embodiment 10 YIGSRNH (CH
2)
13CH
3Preparation
1)Boc-Arg(Boc)-NH-(CH
2)
13CH
3
With preparation Boc-Ser (Bzl)-Arg (NO
2The method of)-OBzl is with 1.5g (4.0mmol) Boc-Arg (Boc) and 1.02g (4.8mmol) CH3 (CH
2)
13NH
2For raw material obtains 2.5g (90.90%) target compound.ESI-MS(m/z)569[M+H]
+。
2)HCl·Arg-NH-(CH
2)
13CH
3
With preparation HClSer (Bzl)-Arg (NO
2The method of)-OBzl is with 1.8g (4.9mmol) Boc-Arg (Boc)-NH-(CH
2)
11CH
3For raw material obtains 1.02g (87.93%) target compound.ESI-MS(m/z)369[M+H]
+。
3)Boc-Tyr-Ile-Gly-Ser-Arg-NH-(CH
2)
13CH
3
Use and prepare Boc-Ser (Bzl)-Arg (NO
2The method of)-OBzl is with 1.2g (2.2mmol) Boc-Tyr-Ile-Gly-Ser and 0.9g (2.1mmol) HClArg-NH-(CH
2)
13CH
3Be raw material, obtain 1.90g (88.78%) target compound.ESI-MS(m/z)890[M+H]
+。
4)Tyr-Ile-Gly-Ser-Arg-NH-(CH
2)
13CH
3[YIGSRNH(CH
2)
13CH
3]
With 520mg Boc-Tyr-Ile-Gly-Ser-Arg-NH-(CH
2)
13CH
3Be dissolved in the 5ml trifluoracetic acid, stirring reaction is 0.5 hour under 0 ℃ of condition of ice bath, and decompression was bled 5 minutes, and disposable adding 100ml ether is separated out the white solid powder, obtains 420mg (91.30%) target compound.ESI-MS(m/z)790[M+H]
+。[α]
D 25=-5.93 (c=1.03 methyl alcohol), Mp:149.60～150.50 ℃.
Embodiment 11 YIGSRNH (CH
2)
15CH
3Preparation
1)Boc-Arg(NO
2)-NH-(CH
2)
15CH
3
With preparation Boc-Ser (Bzl)-Arg (NO
2The method of)-OBzl is with 1.5g (4.7mmol) Boc-Arg (NO
2) and 1.25g (5.2mmol) CH3 (CH
2)
15NH
2For raw material obtains 1.90g (91.34%) target compound.ESI-MS(m/z)543[M+H]
+。
2)HCl·Arg(NO
2)-NH-(CH
2)
15CH
3
With preparation HClSer (Bzl)-Arg (NO
2The method of)-OBzl is with 1.8gBoc-Arg (NO
2)-NH-(CH
2)
15CH
3For raw material obtains 1.23g (84.24%) target compound.ESI-MS(m/z)443[M+H]
+。
3)Boc-Tyr-Ile-Gly-Ser-Arg(NO
2)-NH-(CH
2)
15CH
3
With preparation Boc-Ser (Bzl)-Arg (NO
2The method of)-OBzl is with 1.23g (2.3mmol) Boc-Tyr-Ile-Gly-Ser and 1.01g (2.1mmol) HClArg (NO
2)-NH-(CH
2)
15CH
3Be raw material, obtain 1.05g (87.21%) target compound.ESI-MS(m/z)963[M+H]
+。
4)Tyr-Ile-Gly-Ser-Arg-NH-(CH
2)
15CH
3[YIGSRNH(CH
2)
15CH
3]
With preparation YIGSRNH (CH
2)
7CH
3Method, with 0.95g Boc-Tyr-Ile-Gly-Ser-Arg (NO
2)-NH-(CH
2)
15CH
3Be raw material, obtain 0.75g (80.79%) target compound.ESI-MS(m/z)818[M+H]
+。[α]
D 25=-11.60 (c=1.02 methyl alcohol), Mp:124.60～125.50 ℃.
Embodiment 12 YIGSRNH (CH
2)
17CH
3Preparation
1)Boc-Arg(NO
2)-NH-(CH
2)
17CH
3
With preparation Boc-Ser (Bzl)-Arg (NO
2The method of)-OBzl is with 1.5g (4.7mmol) Boc-Arg (NO
2) and 1.25g (5.2mmol) CH3 (CH
2)
17NH
2For raw material obtains 1.90g (91.34%) target compound.ESI-MS(m/z)571[M+H]
+。
2)HCl·Arg(NO
2)-NH-(CH
2)
17CH
3
Use and prepare HClSer (Bzl)-Arg (NO
2The method that)-OBzl is identical is with 1.8gBoc-Arg (NO
2)-NH-(CH
2)
17CH
3For raw material obtains 1.23g (84.24%) target compound.ESI-MS(m/z)471[M+H]
+。
3)Boc-Tyr-Ile-Gly-Ser-Arg(NO
2)-NH-(CH
2)
17CH
3
With preparation Boc-Ser (Bzl)-Arg (NO
2The method of)-OBzl is with 1.01g (1.9mmol) Boc-Tyr-Ile-Gly-Ser and 0.91g (1.8mmol) HClArg (NO
2)-NH-(CH
2)
17CH
3Be raw material, obtain 1.7g (89.47%) target compound.ESI-MS(m/z)991[M+H]
+。
4)Tyr-Ile-Gly-Ser-Arg-NH-(CH
2)
17CH
3[YIGSRNH(CH
2)
17CH
3]
With preparation YIGSRNH (CH
2)
7CH
3Method, with 0.95g Boc-Tyr-Ile-Gly-Ser-Arg (NO
2)-NH-(CH
2)
17CH
3Be raw material, obtain 0.54g (88.52%) target compound.ESI-MS(m/z)846[M+H]
+。[α]
D 25=-14.60 (c=1.03 methyl alcohol), Mp:126.60～127.50 ℃.
Embodiment 13 YIGSRO (CH
2)
7CH
3Preparation
1)Boc-Arg(NO
2)O(CH
2)
7CH
3
With preparation Boc-Ser (Bzl)-Arg (NO
2The method of)-OBzl is with 1.5g (4.7mmol) Boc-Arg (NO
2) and 1.22g (9.40mmol) CH3 (CH
2)
7OH is that raw material obtains 1.80g (90.01%) target compound.ESI-MS(m/z)432[M+H]
+。
2)HCl·Arg(NO
2)O(CH
2)
7CH
3
With preparation HClSer (Bzl)-Arg (NO
2The method of)-OBzl is with 1.6g (3.7mmol) Boc-Arg (NO
2) O (CH
2)
7CH
3For raw material obtains 1.15g (94.26%) target compound.ESI-MS(m/z)332[M+H]
+。
3)Boc-Tyr-Ile-Gly-Ser-Arg(NO
2)O(CH
2)
7CH
3
With preparation Boc-Ser (Bzl)-Arg (NO
2The method of)-OBzl is with 0.64g (1.2mmol) Boc-Tyr-Ile-Gly-Ser and 0.41g (1.2mmol) HClArg (NO
2)-O (CH
2)
7CH
3Be raw material, obtain 0.92g (91.08%) target compound.ESI-MS(m/z)852[M+H]
+。
4)Boc-Tyr-Ile-Gly-Ser-Arg-O(CH
2)
7CH
3
Earlier with 0.62gBoc-Tyr-Ile-Gly-Ser-Arg (NO
2)-O (CH
2)
7CH
3Be dissolved in 20ml methyl alcohol, add 124mgPd/C (20%) again, the air in the reaction flask is discharged in decompression; Feed hydrogen exchange, replace 5 times repeatedly after, logical hydrogen stirring at room three days; TLC (developping agent CHCl3: MeOH=10: the 1+3d Glacial acetic acid min. 99.5) show the most of disappearance of compound, stopped reaction, filtering Pd/C; Filtrate decompression concentrates to remove and desolvates, and gets 0.45g (76.30%) title compound, is colorless solid.ESI-MS(m/z)807[M+H]
+。
5)Tyr-Ile-Gly-Ser-Arg-O(CH
2)
7CH
3[YIGSRO(CH
2)
7CH
3]
With 420mg Boc-Tyr-Ile-Gly-Ser-Arg-O (CH
2)
7CH
3Be dissolved in the 4ml trifluoracetic acid, stirring reaction is 0.5 hour under 0 ℃ of condition of ice bath, and decompression was bled 5 minutes, and disposable adding 100ml ether is separated out the white solid powder, obtains 340mg (92.64%) target compound.ESI-MS(m/z)707[M+H]
+。[α]
D 25=-6.21 (c=1.03 methyl alcohol), Mp:135.60～136.40 ℃.
Embodiment 14 YIGSRO (CH
2)
9CH
3Preparation
1)Boc-Arg(NO
2)O(CH
2)
9CH
3
With preparation Boc-Ser (Bzl)-Arg (NO
2The method of)-OBzl is with 1.5g (4.7mmol) Boc-Arg (NO
2) and 1.49g (9.40mmol) CH3 (CH
2)
9OH is that raw material obtains 1.80g (83.33%) target compound.ESI-MS(m/z)460[M+H]
+。
2)HCl·Arg(NO
2)O(CH
2)
9CH
3
With preparation HClSer (Bzl)-Arg (NO
2The method of)-OBzl is with 1.6g (3.5mmol) Boc-Arg (NO
2) O (CH
2)
9CH
3For raw material obtains 1.15g (92.20%) target compound.ESI-MS(m/z)360[M+H]
+。
3)Boc-Tyr-Ile-Gly-Ser-Arg(NO
2)O(CH
2)
9CH
3
With preparation Boc-Ser (Bzl)-Arg (NO
2The method of)-OBzl is with 0.42g (0.80mmol) Boc-Tyr-Ile-Gly-Ser and 0.28g (0.78mmol) HClArg (NO
2) O (CH
2)
9CH
3Be raw material, obtain 0.59g (86.76%) target compound.ESI-MS(m/z)880[M+H]
+。
4)Tyr-Ile-Gly-Ser-Arg-O(CH
2)
9CH
3[YIGSRO(CH
2)
9CH
3]
With preparation YIGSRO (CH
2)
7CH
3Method, with 1.02g Boc-Tyr-Ile-Gly-Ser-Arg (NO
2)-O (CH
2)
9CH
3Be raw material, obtain 0.69g (81.17%) target compound.ESI-MS(m/z)735[M+H]
+。[α]
D 25=-7.21 (c=1.03 methyl alcohol), Mp:141.60～142.40 ℃.
Embodiment 15 YIGSRO (CH
2)
11CH
3Preparation
1)Boc-Arg(NO
2)O(CH
2)
11CH
3
With preparation Boc-Ser (Bzl)-Arg (NO
2The method of)-OBzl is with 1.5g (4.7mmol) Boc-Arg (NO
2) and 1.75g (9.40mmol) CH3 (CH
2)
11OH is that raw material obtains 2.10g (91.70%) target compound.ESI-MS(m/z)488[M+H]
+。
2)HCl·Arg(NO
2)O(CH
2)
11CH
3
With preparation HClSer (Bzl)-Arg (NO
2The method of)-OBzl is with 1.6g (3.3mmol) Boc-Arg (NO
2) O (CH
2)
9CH
3For raw material obtains 1.15g (90.55%) target compound.ESI-MS(m/z)388[M+H]
+。
3)Boc-Tyr-Ile-Gly-Ser-Arg(NO
2)O(CH
2)
11CH
3
With preparation Boc-Ser (Bzl)-Arg (NO
2The method of)-OBzl is with 0.36g (0.67mmol) Boc-Tyr-Ile-Gly-Ser and 0.26g (0.67mmol) HClArg (NO
2) O (CH
2)
11CH
3Be raw material, obtain 0.55g (91.66%) target compound.ESI-MS(m/z)908[M+H]
+。
4)Tyr-Ile-Gly-Ser-Arg-O(CH
2)
11CH
3[YIGSRO(CH
2)
11CH
3]
With preparation YIGSRO (CH
2)
7CH
3Method, with 1.02g Boc-Tyr-Ile-Gly-Ser-Arg (NO
2) O (CH
2)
11CH
3Be raw material, obtain 0.75g (87.21%) target compound.ESI-MS(m/z)763[M+H]
+。[α]
D 25=-3.90 (c=1.03 methyl alcohol), Mp:145.60～146.40 ℃.
Embodiment 16 YIGSRO (CH
2)
13CH
3Preparation
1)Boc-Arg(NO
2)O(CH
2)
13CH
3
With preparation Boc-Ser (Bzl)-Arg (NO
2The method of)-OBzl is with 1.6g (5.0mmol) Boc-Arg (NO
2) and 2.15g (10.0mmol) CH3 (CH
2)
13OH is that raw material obtains 2.48g (96.12%) target compound.ESI-MS(m/z)516[M+H]
+。
2)HCl·Arg(NO
2)O(CH
2)
13CH
3
With preparation HClSer (Bzl)-Arg (NO
2The method of)-OBzl is with 1.6g (3.1mmol) Boc-Arg (NO
2) O (CH
2)
13CH
3For raw material obtains 1.15g (89.84%) target compound.ESI-MS(m/z)416[M+H]
+。
3)Boc-Tyr-Ile-Gly-Ser-Arg(NO
2)O(CH
2)
13CH
3
With preparation Boc-Ser (Bzl)-Arg (NO
2The method of)-OBzl is with 0.67g (1.20mmol) Boc-Tyr-Ile-Gly-Ser and 0.57g (1.32mmol) HClArg (NO
2) O (CH
2)
13CH
3Be raw material, obtain 1.01g (87.07%) target compound.ESI-MS(m/z)936[M+H]
+。
4)Tyr-Ile-Gly-Ser-Arg-O(CH
2)
13CH
3[YIGSRO(CH
2)
13CH
3]
With preparation YIGSRO (CH
2)
7CH
3Method, with 1.09g Boc-Tyr-Ile-Gly-Ser-Arg (NO
2) O (CH
2)
13CH
3Be raw material, obtain 0.81g (86.95%) target compound.ESI-MS(m/z)791[M+H]
+。[α]
D 25=-8.63 (c=1.03 methyl alcohol), Mp:139.50～140.20 ℃.
Embodiment 17 YIGSRO (CH
2)
15CH
3Preparation
1)Boc-Arg(NO
2)O(CH
2)
15CH
3
With preparation Boc-Ser (Bzl)-Arg (NO
2The method of)-OBzl is with 1.5g (4.7mmol) Boc-Arg (NO
2) and 2.28g (9.4mmol) CH3 (CH
2)
15OH is that raw material obtains 2.41g (94.50%) target compound.ESI-MS(m/z)544[M+H]
+。
2)HCl·Arg(NO
2)O(CH
2)
15CH
3
With preparation HClSer (Bzl)-Arg (NO
2The method of)-OBzl is with 1.6g (2.9mmol) Boc-Arg (NO
2) O (CH
2)
15CH
3For raw material obtains 1.20g (92.30%) target compound.ESI-MS(m/z)444[M+H]
+。
3)Boc-Tyr-Ile-Gly-Ser-Arg(NO
2)-O(CH
2)
15CH
3
With preparation Boc-Ser (Bzl)-Arg (NO
2The method of)-OBzl is with 0.93g (1.70mmol) Boc-Tyr-Ile-Gly-Ser and 0.75g (1.68mmol) HClArg (NO
2) O (CH
2)
15CH
3Be raw material, obtain 1.42g (87.65%) target compound.ESI-MS(m/z)964[M+H]
+。
4)Tyr-Ile-Gly-Ser-Arg-O(CH
2)
15CH
3[YIGSRO(CH
2)
15CH
3]
With preparation YIGSRO (CH
2)
7CH
3Method, with 1.19g Boc-Tyr-Ile-Gly-Ser-Arg (NO
2)-O (CH
2)
15CH
3Be raw material, obtain 0.83g (83.01%) target compound.ESI-MS(m/z)819[M+H]
+。[α]
D 25=-5.76 (c=1.03 methyl alcohol), Mp:149.60～150.40 ℃.
Embodiment 18 YIGSRO (CH
2)
17CH
3Preparation
1)Boc-Arg(NO
2)O(CH
2)
17CH
3
With preparation Boc-Ser (Bzl)-Arg (NO
2The method of)-OBzl is with 1.5g (4.7mmol) Boc-Arg (NO
2) and 2.53g (9.4mmol) CH3 (CH
2)
17OH is that raw material obtains 2.50g (93.28%) target compound.ESI-MS(m/z)572[M+H]
+。
2)HCl·Arg(NO
2)O(CH
2)
17CH
3
With preparation HClSer (Bzl)-Arg (NO
2The method of)-OBzl is with 1.6g (2.8mmol) Boc-Arg (NO
2) O (CH
2)
17CH
3For raw material obtains 1.16g (87.87%) target compound.ESI-MS(m/z)472[M+H]
+。
3)Boc-Tyr-Ile-Gly-Ser-Arg(NO
2)-O(CH
2)
17CH
3
With preparation Boc-Ser (Bzl)-Arg (NO
2The method of)-OBzl is with 0.93g (1.70mmol) Boc-Tyr-Ile-Gly-Ser and 0.89g (1.87mmol) HClArg (NO
2) O (CH
2)
17CH
3Be raw material, obtain 1.61g (93.56%) target compound.ESI-MS(m/z)992[M+H]
+。
4)Tyr-Ile-Gly-Ser-Arg-O(CH
2)
17CH
3[YIGSRO(CH
2)
17CH
3]
With preparation YIGSRO (CH
2)
7CH
3Method, with 1.20g Boc-Tyr-Ile-Gly-Ser-Arg (NO
2) O (CH
2)
17CH
3Be raw material, obtain 0.91g (89.21%) target compound.ESI-MS(m/z)847[M+H]
+。[α]
D 25=-5.93 (c=1.03 methyl alcohol), Mp:156.20～157.10 ℃.
1HNMR(DMSO-d
6)δ/ppm＝8.62(m，2H)，8.34(d，J＝6.20Hz，1H)，8.13(s，2H)，8.01(d，J＝6.40Hz，1H)，7.40(s，1H)，7.29(s，1H)，7.19(s，1H)，7.02(d，J＝4.50Hz，2H)，6.69(d，J＝8.40Hz，2H)，4.28-2.72(m，14H)，1.73-0.8(m，48H)。
The antithrombotic test of Test Example 1 The compounds of this invention intravenously administrable
1) rat operation and apparatus
(male, 220～230g) press 1200mg-kg to the SD rat
-1Dosage abdominal injection urethane solution is anaesthetized.The anesthetized rat dorsal position is fixed, and separates RCCA, proximal part folder bulldog clamp, and 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: the physiological salt soln of saline water (3ml/kg), the physiological salt soln of Asprin (dosage is 30mg/kg), compound of the present invention (dosage is 10nmol/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 12 administrations.The wet weight of thrombus of each group of statistics (X ± SD), and do the t check.
5) result
Through intravenously administrable, compound of the present invention all has good anti-thrombus activity.The result lists table 1 in.
Table 1 compound of the present invention is through the antithrombotic acitivity of intravenously administrable
| Compound (10nmol/Rg) | Wet weight of thrombus (x ± SDmg) |
| YIGSRO(CH 2) 7CH 3 | 14.79±5.96 a |
| YIGSRO(CH 2) 9CH 3 | 19.08±5.25 a |
| YIGSRO(CH 2) 11CH 3 | 18.26±5.59 a |
| YIGSRO(CH 2) 13CH 3 | 17.80±5.29 a |
| YIGSRO(CH 2) 15CH 3 | 20.49±5.42 a |
| YIGSRO(CH 2) 17CH 3 | 18.23±3.87 a |
| YIGSRNH(CH 2) 7CH 3 | 19.45±3.52 a |
| YIGSRNH(CH 2) 9CH 3 | 20.31±5.20 a |
| YIGSRNH(CH 2) 11CH 3 | 17.80±4.33 a |
| YIGSRNH(CH 2) 13CH 3 | 20.28±5.29 a |
| YIGSRNH(CH 2) 15CH 3 | 17.80±4.33 a |
| YIGSRNH(CH 2) 17CH 3 | 18.09±5.80 a |
| CH 3(CH 2) 6COYIGSR | 19.95±5.69 a |
| CH 3(CH 2) 8COYIGSR | 19.57±4.37 a |
| CH 3(CH 2) 10COYIGSR | 17.79±5.09 a |
| CH 3(CH 2) 12COYIGSR | 20.47±5.17 a |
| CH 3(CH 2) 14COYIGSR | 21.14±5.15 a |
| CH 3(CH 2) 16COYIGSR | 17.90±2.65 a |
| YIGSR | 20.47±6.87 a |
| Saline water | 28.66±5.04 |
| Frosst) | 14.50±3.52 a |
N=12; A. compare P＜0.01. with saline water
Test Example 2 The compounds of this invention YIGSRO (CH
2)
7CH
3The dose-effect relationship of oral administration
1) rat operation and apparatus
(male, 220～230g) press 10nmolkg to the SD rat
-1, 1nmolkg
-1And 0.1nmolkg
-1Oral dose YIGSKNC16 presses 1200mg-kg behind the 30min
-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) give drug solns
Medicine: with YIGSRO (CH
2)
7CH
3Press 10nmolkg
-1, 0.1nmolkg
-1And 0.01nmolkg
-1Dosage configuration physiological salt soln, for oral administration.
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 of each group of statistics (X ± SD), and do the t check.
5) result
The oral administration administration is at 10nmolkg
-1, 0.1nmolkg
-1And 0.01nmolkg
-1Under the dosage, YIGSRO (CH
2)
7CH
3Dosage relies on ground performance anti thrombotic action.The result lists table 2 in.
Table 2. orally give YIGSRO (CH
2)
7CH
3Dose-effect relationship
| Dosage | Wet weight of thrombus (
 |
| 10nmol/Kg | 13.77±4.40 a |
| 0.1nmol/Kg | 18.63±3.99 b |
| 0.01nmol/Kg | 24.62±5.68 |
A) organize than p＜0.05 with 0.1nmol/kg; B) organize than p＜0.05 with 0.01nmol/kg
Test Example 3 The compounds of this invention are in the test of aqueous phase assembling becoming nanometer ball
1) 9 kinds of compounds of the present invention are configured as the aqueous solution according to the concentration of mg/ml, go up METHOD FOR CONTINUOUS DETERMINATION 8 days at laser light scattering particle size analyzer (model), observe particle diameter and change of size, and the result sees table 3.The data that obtain show that these 9 kinds of compounds can be self-assembled at aqueous phase and be the stabilized nano ball, thereby are the outstanding micro emulsion and the preparation material of liposome medicament.Can find out that from table 3 particle diameter becomes big behind the aliphatic chain of parent nucleus spreading, particle diameter diminishes behind the aliphatic chain that blocks, and all stable than parent nucleus.
Table 3 partial cation pharmacome (10 of the present invention
-3M) in water, be self-assembled into into the stabilized nano ball the grain warp
| Compound | First day | Second day | The 3rd day | The 4th day | The 5th day | The 6th day | The 7th day | The 8th day |
| YIGSRO(CH2)7CH3 | 134 | 230 | 165 | 124 | 155 | 124 | 102 | 96 |
| YIGSRO(CH2)13CH3 | 290 | 205 | 140 | 320 | 298 | 310 | 241 | 160 |
| YIGSRO(CH2)17CH3 | 268 | 271 | 310 | 250 | 278 | 298 | 245 | 269 |
| YIGSRNH(CH2)7CH3 | 245 | 210 | 310 | 268 | 325 | 245 | 259 | 312 |
| YIGSRNH(CH2)13CH3 | 298 | 236 | 208 | 282 | 361 | 389 | 401 | 415 |
| YIGSRNH(CH2)17CH3 | 297 | 403 | 546 | 589 | 574 | 477 | 610 | 598 |
| CH3(CH2)6COYIGSR | 489 | 398 | 478 | 548 | 512 | 479 | 546 | 452 |
| CH3(CH2)12COYIGSR | 645 | 597 | 698 | 576 | 645 | 697 | 745 | 698 |
| YIGSR | 665 | 427 | 498 | 372 | 553 | 590 | 389 | 448 |
Claims (5)
1. fatty alkyl and YIGSR pentapeptide conjugate, the general formula of this conjugate is Tyr-Ile-Gly-Ser-Arg-X, Tyr-Ile-Gly-Ser-Arg-Y or Z-Tyr-Ile-Gly-Ser-Arg; Wherein X is CH
3(CH
2)
nCH
2O-, Y are CH
3(CH
2)
nCH
2NH-, Z are CH
3(CH
2)
nCO-; N=6,8,10,12,14 or 16.
2. one kind prepares described fatty alkyl of claim 1 and YIGSR pentapeptide conjugate method, may further comprise the steps:
(1) synthetic Tyr-Ile-Gly-Ser-Arg;
(2) with CH
3(CH
2)
nCO
2H, CH
3(CH
2)
nCH
2OH puts together with carboxylic end or the ammonia end of the basic Tyr-Ile-Gly-Ser-Arg that protects of protection respectively, sloughs the protection base, promptly gets; Perhaps with CH
3(CH
2)
nCH
2NH
2Put together with the carboxylic end of the basic Tyr-Ile-Gly-Ser-Arg that protects of protection, slough the protection base, promptly get; N=6 wherein, 8,10,12,14 or 16.
3. antithrombotic pharmaceutical composition is characterized in that: the described fatty alkyl of claim 1 and YIGSR pentapeptide conjugate and pharmaceutically acceptable carrier or the auxiliary material of being gone up significant quantity by treatment or prevention are formed.
4. described fatty alkyl of claim 1 and YIGSR pentapeptide conjugate are in the purposes of preparation in the antithrombotic reagent.
5. described fatty alkyl of claim 1 and YIGSR pentapeptide conjugate prepare the purposes in micro emulsion or the lipidosome drug carrier in conduct.
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| CN103539835A (en) * | 2012-07-15 | 2014-01-29 | 彭莉 | 1-methyl-tetrahydro-beta-carbolinyl-3-formyl YIGS peptides, and synthesis, nano structure, antithrombotic action and application thereof |
| CN105120836B (en) * | 2013-01-08 | 2018-06-05 | 诺娃细胞科技公司 | New peptide with collagen synthesis ability and application thereof |
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| CN105273056A (en) * | 2014-06-11 | 2016-01-27 | 首都医科大学 | YIGSR-modified 5-fluorouracil, preparation, nano-structure, activity and application thereof |
| CN105294836A (en) * | 2014-06-11 | 2016-02-03 | 首都医科大学 | LPNISKP modified 5-fluorouracil, preparation therefor, nanostructure thereof, activity thereof and application thereof |
| CN105294835A (en) * | 2014-06-11 | 2016-02-03 | 首都医科大学 | LDV modified 5-fluorouracil, preparation therefor, nanostructure thereof, vigor thereof and application thereof |
| CN109134659B (en) * | 2017-06-15 | 2022-04-26 | 中国人民解放军军事医学科学院毒物药物研究所 | Nucleic acid vector and application thereof |
| CN107522773B (en) * | 2017-09-30 | 2021-06-01 | 武汉工程大学 | Pentapeptide modified rhodamine B compound and preparation method and application thereof |
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