CN101704878A - Polypeptide derivatives for generating stable micro-molecular hydrogel - Google Patents
Polypeptide derivatives for generating stable micro-molecular hydrogel Download PDFInfo
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Abstract
The invention discloses polypeptide derivatives for generating stable micro-molecular hydrogel and relates to a compound library containing polypeptides. The molecular composition and structure are represented by a compound structural formula below, wherein in the formula, R1 represents aromatic ring derivatives, R2 represents one side chain group of 20 natural amino acids, R3 may be any of H and halogen, R4 may be OMe group or NHMe group, and n is 0 to 3. The micro-molecular hydrogel generated by the polypeptide derivatives can exist stably in a large amount of an aqueous solution, the shape can be well maintained, the micro-molecular hydrogel has high biocompatibility and is widely applied in the fields of tissue engineering, cosmetic, and the like.
Description
Technical field
Technical scheme of the present invention relates to the compound library that contains polypeptide, specifically is used to generate the polypeptide derivative of stable micro-molecular hydrogel.
Background technology
Micro-molecular hydrogel biophase content height based on polypeptide has high potential using value in fields such as tissue engineering material, makeup.But so far, known micro-molecular hydrogel based on polypeptide can't stable existence in a large amount of aqueous solution, is easy to be dissolved into the solution of homogeneous, thereby makes this class hydrogel can't obtain practical application widely.This is at existing document (Genove E, Shen C, Zhang SG, Semino CE, BIOMATERIALS, 2005,16,3341-3351; Ghanaati S, Webber MJ, Unger RE, Orth C, Hulvat JF, Kiehna SE, BarbeckM, Rasic A, Stupp SI, Kirkpatrick CJ, BIOMATERIALS, 2009,31, report had been arranged in 6202-6212).So far do not see about being used to generate the polypeptide of stable micro-molecular hydrogel bibliographical information that in other words can stable existence in a large amount of aqueous solution as yet based on the micro-molecular hydrogel of polypeptide.
Summary of the invention
Technical problem to be solved by this invention is: the polypeptide derivative that is provided for generating stable micro-molecular hydrogel, based on the micro-molecular hydrogel of this polypeptide derivative can be in a large amount of aqueous solution after the formation stable existence, profile can be kept well, have biophase content height, obtain practical application widely in fields such as organizational project and makeup.
The present invention solves this technical problem the technical scheme that is adopted: be used to generate the polypeptide derivative of stable micro-molecular hydrogel, shown in the following structural formula of compound of its molecular composition and structure:
In this formula, R
1Be aromatic derivatives, R
2Be a kind of side-chain radical in 20 kinds of natural amino acids, R
3Be in H or the halogen any one, R
4Be OMe base or NHMe base, n=1～3.
The above-mentioned polypeptide derivative that is used to generate stable micro-molecular hydrogel, described R
1Be
The above-mentioned polypeptide derivative that is used to generate stable micro-molecular hydrogel, described R
2It is the side-chain radical of glycine or Methionin.
The invention has the beneficial effects as follows: use the polypeptide derivative that the present invention is used for generating stable micro-molecular hydrogel and can obtain at aqueous solution stable existence, be difficult for dissociating and micro-molecular hydrogel that the biophase content is high.Its reason is: because the amino acid of polypeptide of the present invention with phosphorylation, and the good dissolving in the aqueous solution of such molecular energy.Under the situation that adds Phosphoric acid esterase, phosphate radical is with cut, thereby acquisition can be assembled gelatigenous molecule in vain, finally causes the generation of micro-molecular hydrogel.Because the amino and the carboxyl of polypeptide are all removed by derivatize, and the micro-molecular hydrogel for preparing by this method can well keep its initial profile, be difficult under the situation that a large amount of aqueous solution exist, being dissociated into the aqueous solution of homogeneous again.Therefore, the polypeptide derivative that the present invention is used to generate stable micro-molecular hydrogel can obtain high application prospect as the carrier of bionts such as cell in the tissue engineering material field, and obtains practical application widely in fields such as organizational project and makeup.
Embodiment
Embodiment 1
The synthetic method step of the polypeptide that is used to generate stable micro-molecular hydrogel of the present invention is as follows:
Wherein, DIPEA is N, and N-diisopropyl ethyl amine, Acetone are acetone, I
2Be iodine, triethyl phosphite is a triethyl-phosphite, and DCM is a methylene dichloride, and pyridine is a pyridine, and TFA is a trifluoroacetic acid, and spps is that the English of " polypeptide solid phase synthesis " is called for short, and TMSBr is a bromotrimethylsilane, and MeOH is a methyl alcohol.
The first step, Fmoc-L-Tyr-O
tBu's is synthetic
N with 10mmolL-tyrosine tert-butyl ester and 10 molecules, the N-diisopropyl ethyl amine is dissolved in the acetone of 75ml, the acetone soln that under stirring condition, adds the 75ml of the Fmoc-OSu that contains 9.8mmol, stirred 12 hours under the room temperature, separate with silica gel chromatographic column then, obtain 4.4g product Fmoc-L-Tyr-O
tBu (being the compound 3 in the above-mentioned synthetic method step), its productive rate is 95.8%,
1H NMR (300MHz, DMSO-d
6) δ 8.03-8.05 (d, 2H), 7.81-7.85 (t, 2H), 7.56-7.59 (t, 2H), 7.46-7.48 (m, 2H), and 7.19-7.21 (d, 2H), 6.81-6.83 (d, 2H), 4.30-4.40 (m, 3H), 4.2-4.24 (m, 1H), 3.30-3.36 (m, 2H), 1.50 (s, 9H), MS:calc.M
+=459.2, obsvd. (M+1)
+=459.78.
Second step, Fmoc-L-Tyr (PO (OEt)
2)-O
tBu's is synthetic
The 8mmol triethyl-phosphite is dissolved in the 80ml methylene dichloride, add 7.5mmol iodine, place ice bath, make it temperature behind the reaction 10min and return to room temperature, be added drop-wise to then in the methylene dichloride that contains 5.0mmol by the 50ml of synthetic compound 3 that obtains of the first step and 20.0mmol pyridine, place ice bath, reaction 2h uses 100ml ether and 300ml ethyl acetate extraction then, and organic phase is given a baby a bath on the third day after its birth time with 5% the sal enixum of each 100ml, wash one time with saturated sodium-chloride again, this organic phase anhydrous magnesium sulfate drying filters then, concentrates, silica gel chromatographic column separates, and obtains Fmoc-L-Tyr (PO (OEt)
2)-O
tBu (being the compound 4 in the above-mentioned synthetic method step), its productive rate is 85.5%.
1H?NMR(300MHz，DMSO-d
6)δ8.03-8.05(d，2H)，7.82-7.84(d，2H)，7.57-7.59(t，2H)，7.42-7.48(m，4H)，7.25-7.28(d，2H)，4.10-4.40(m，8H)，3.11-3.13(m，1H)，3.03-3.07(m，1H)，1.49(s，9H)，1.37-1.41(t，6H).
31P?NMR(δ-6.366ppm).MS：calc.M
+＝595.2，obsvd.(M+1)
+＝596.01。
The 3rd step, Fmoc-L-Tyr (PO (OEt)
2-OH's is synthetic
In the mixed solution of 5ml methylene dichloride and 10ml trifluoroacetic acid, add the 1mmol synthetic compound 4 that obtains of second step, place ice bath again, stirred 4 hours, rotate evaporate to dryness then, change evaporation twice with the toluene corotation again, obtain Fmoc-L-Tyr (PO (OEt)
2-OH (being the compound 5 in the above-mentioned synthetic method step), its productive rate is 98.3%,
1H NMR (300MHz, DMSO-d
6) δ 8.23-8.25 (d, 2H), 8.01-8.05 (t, 2H), 7.76-7.79 (t, 2H), 7.59-7.62 (m, 4H), 7.47-7.52 (d, 2H), 4.30-4.60 (m, 8H), 3.45-3.48 (m, 1H), 3.21-3.27 (m, 1H), 1.58-1.61 (t, 6H).
31P NMR (the .MS:calc.M of δ-6.348ppm)
+=539.2, obsvd. (M+H)
+=540.14.
The 4th step, the compound 6 in the above-mentioned synthetic method step shown in the following structural formula synthetic
Go on foot the synthetic compound that obtains 5 by the compound 6 in the synthetic above-mentioned steps of the method for polypeptide solid phase synthesis commonly used at normal temperatures with the 3rd.The method of this solid phase synthesis is seen Fmoc solid phase peptide synthesis-A practicalapproach edited by Weng c.chan and peterd.white OXFORD UNIVERSITY PRESS; wherein; polypeptide synthetic raw material is the 20 kinds of natural amino acids and the aromatic derivatives of Fmoc protection; the condensing agent that uses is the HBTU of 1 molar equivalent, and the DIEA that adds 2 molar equivalents makees catalyzer.
In the 5th step, being used for shown in the following structural formula generates polypeptide derivative (being the compound 1 of above-mentioned synthetic method step) synthetic of stable micro-molecular hydrogel
The compound 6 that the 4th step of 0.4mmol is made is dissolved in the 10ml dry methylene chloride, adds the 10mmol bromotrimethylsilane, stirs 24 hours under the room temperature, rotates evaporate to dryness then and obtains solid, adds the 10ml anhydrous methanol again, the R that this method obtains
4Be the OMe group, or add again and contain the methanol solution that mass percent is 20% methyl ammonia, the R that this method obtains
4Be the NHMe group, at room temperature stirring reaction is 2 hours, rotates evaporate to dryness again, uses the high performance liquid chromatography separated product, obtains the polypeptide derivative (being the compound 1 of above-mentioned synthetic method step) that being used for shown in top structural formula generates stable micro-molecular hydrogel.
Embodiment 2
Polypeptide compound Nap-GFFY (p)-OMe's shown in the following structural formula (I) is synthetic.
The first step～the 3rd step is all with embodiment 1.
The 4th step, compound N ap-GFFY (PO (OFt)
2)-OMe (promptly in compound 6 general formulas of embodiment 1, R
1For
Group, R
2Be H, R
3Be H) synthetic
Adopt the method for Fmoc solid phase synthesis, step is:
The 1st step took by weighing 0.5mmol 2-chlorine trityl chloride resin in the solid phase synthesis device, added the anhydrous methylene chloride of 2.5mL, fed nitrogen 5min, made the abundant swelling of 2-chlorine trityl chloride resin;
In the 2nd step, methylene dichloride is pressed from the solid phase synthesis device that 2-chlorine trityl chloride resin is housed except that clean with nitrogen;
The 3rd step, the 1mmol synthetic compound 5 that obtains of the 3rd step is dissolved in the anhydrous methylene chloride of 2mL, get wherein 1mL (being 0.5mmol), add the N of 0.5mmol, the N-diisopropyl ethyl amine is transferred in the above-mentioned solid phase synthesizer then, add the N of 0.5mmol again, the N-diisopropyl ethyl amine feeds nitrogen, at room temperature reacts 1h;
The 4th step, liquid Ex-all in this solid phase synthesis device, then with the washing of 5mL anhydrous methylene chloride, each 1min, wash altogether 5 times, adding the volume ratio prepare is anhydrous methylene chloride: N, the N-diisopropyl ethyl amine: the solution 3mL of anhydrous methanol=17: 1: 2, feed nitrogen, at room temperature react 10min;
The 5th step, liquid in this solid phase synthesis device is pressed clean, with the washing of 5mL anhydrous methylene chloride, each 1min washes 5 times altogether, use 5mL N again, the dinethylformamide washing, each 1min washes 5 times altogether, add 5mL and contain the N that volume percent is 20% piperidines, dinethylformamide solution feeds nitrogen reaction 30min, contains the N that volume percent is 20% piperidines with 5mL again, the dinethylformamide solution washing once, use 5mL N then, dinethylformamide washing, each 1min, wash altogether 5 times, carry out next step reaction;
The 6th step, get polypeptide synthetic raw material Fmoc-phenylalanine 2.5mmol, benzotriazole-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester 2.5mmol, N, the anhydrous N of N-diisopropyl ethyl amine 5mmol and 3ml, dinethylformamide is mixed with solution, the solution for preparing is joined in the above-mentioned solid phase synthesizer, feed nitrogen reaction 2h;
The 7th step, replace polypeptide synthetic raw material Fmoc-phenylalanine with polypeptide synthetic raw material Fmoc-phenylalanine, Fmoc-glycine and polypeptide synthetic raw naphthalene material acetate successively, repeat the 5th step and the operation of the 6th step, final Nap-GFFY (PO (OEt) the 2)-COO that obtains to be connected on the 2-chlorine trityl chloride resin;
The 8th step, volume ratio by trifluoroacetic acid and anhydrous methylene chloride is 1: 99, be mixed with concentration of volume percent and be 1% trifluoroacetic acid solution, get the each 3mL of this trifluoroacetic acid solution and join in the above-mentioned solid phase synthesizer, add altogether ten times, each reaction times is 1min, product is downcut from 2-chlorine trityl chloride resin, concentrate, add twice toluene to remove residual trifluoroacetic acid, drain with oil pump, obtain compound N ap-GFFY (PO (OEt) 2)-COOH;
In the 5th step, be used to generate the synthetic of polypeptide Nap-GFFY (p)-OMe shown in the structural formula (I) of stable micro-molecular hydrogel
0.4mmol the 4th is gone on foot the compound N ap-GFFY (PO (OEt) that makes
2)-COOH is dissolved in the 10ml dry methylene chloride, add the 10mmol bromotrimethylsilane, stirred 24 hours under the room temperature, rotate evaporate to dryness then and obtain solid, add the 10ml anhydrous methanol again, at room temperature stirring reaction is 2 hours, rotate evaporate to dryness again, use the high performance liquid chromatography separated product, syntheticly thus obtain polypeptide Nap-GFFY (p)-OMe shown in top structural formula (I), its productive rate is 95.0%
1H NMR (400MHz, DMSO-d
6) δ 8.48 (d, 1H, NH), 8.19-8.28 (m, 2H, NH), 8.06 (d, 1H, NH), 7.75-7.88 (m, 3H), 7.754 (s, 1H), 7.41-7.48 (m, 3H), 7.07-7.25 (m, 14H), and 4.46-4.58 (m, 3H), 3.70-3.76 (m, 1H), 3.6-3.68 (s, 4H), 3.58 (s, 3H), 2.92-3.03 (m, 4H), 2.76-2.81 (m, 1H), 2.63-2.69 (m, 1H).
31P NMR (the .MS:calc.M of δ-6.008ppm)
+=794.27, obsvd. (M+Na)
+=817.30and (M+2Na)
+=839.25, (M-H)
-=793.25.
Polypeptide Nap-GFFY (p)-OMe molecular energy shown in top structural formula (I) that present embodiment makes well is dissolved in the aqueous solution, and phosphate radical is cut under the effect of Phosphoric acid esterase, thereby obtains hydrogel.This hydrogel good stability, minimum one-tenth gum concentration is extremely low-reach ten thousand/.It can be as the carrier of three-dimensional cell cultivation, owing to used the lower polypeptide derivative of solubleness as becoming xanthan molecule, the consumption of compound reduces greatly when obtaining colloid, therefore can improve the biophase content of prepared micro-molecular hydrogel, cell can well be grown in such hydrogel.
Embodiment 3
Polypeptide Nap-FFY (p)-OMe's shown in the following structural formula (II) is synthetic.
Except that the polypeptide synthetic raw material in the 6th～7 step in the 4th step replaces with Fmoc-phenylalanine and the naphthylacetic acid, the working method of other synthesis steps and parameter are with embodiment 2.
Synthetic as to obtain polypeptide Nap-FFY (p)-OMe shown in top structural formula (II) thus, its productive rate is 94%,
1H NMR (400MHz, DMSO-d
6) δ 8.63 (d, J=7.324,1H), 8.39 (d, J=8.518,1H), 8.28 (d, J=8.216,1H), 7.90-8.00 (m, 3H), 7.74 (s, 1H), 7.62 (m, 2H), 7.35-7.40 (m, 3H), and 7.25-7.40 (m, 10H), 7.23-7.25 (m, 2H), 4.6-4.8 (m, 3H), 3.745 (s, 3H), 3.60-3.72 (m, 3H), and 3.000-3.120 (m, 3H), 2.3-2.80 (m, 2H) .MS:calc.M
+=737.25, obsvd. (M+Na)
+=760.35.
Polypeptide Nap-FFY (p)-OMe molecular energy shown in top structural formula (II) that present embodiment makes well is dissolved in the aqueous solution, and phosphate radical is cut under the effect of Phosphoric acid esterase, thereby obtains hydrogel.This hydrogel good stability can be prepared into different shape.
Embodiment 4
Polypeptide Nap-GGFFY (p)-OMe's shown in the following structural formula (III) is synthetic.
Except that polypeptide synthetic raw material replacement in the 6th～7 step in the 4th step is followed successively by Fmoc-phenylalanine, Fmoc-glycine, Fmoc-glycine and the naphthylacetic acid, the working method of other synthesis steps and parameter are with embodiment 2.
Synthetic as to obtain polypeptide Nap-GGFFY (p)-OMe shown in top structural formula (III) thus, its productive rate is 88%,
1H NMR (400MHz, DMSO-d
6) δ 8.587 (d, J=7.287,1H), 8.495-8.520 (m, 1H) 8.227-8.280 (m, 2H), 8.147 (d, J=8.348,1H), and 7.970-8.030 (m, 3H), 7.922 (s, 1H), 7.590-7.650 (m, 3H), and 7.400-7.420 (m, 4H), 7.320-7.360 (m, 8H), 7.234 (d, J=8.3022H), 4.614-4.741 (m, 4H) 3.881-3.890 (m, 4H), 3.819 (m, 3H), 3.075-3.186 (m, 5H), 2.936-2.975 (m, 1H), 2.813-2.853 (m, 1H) .MS:calc.M
+=851.29, obsvd. (M+Na)
+=874.35.
Polypeptide Nap-GGFFY (p)-OMe molecular energy shown in top structural formula (III) that present embodiment makes well is dissolved in the aqueous solution, and phosphate radical is cut under the effect of Phosphoric acid esterase, thereby obtains hydrogel.This hydrogel good stability can be prepared into different shape.
Embodiment 5
Polypeptide Nap-GFY (p)-OMe's shown in the following structural formula (IV) is synthetic.
Except that polypeptide synthetic raw material replacement in the 6th～7 step in the 4th step is followed successively by Fmoc-glycine and the naphthylacetic acid, the working method of other synthesis steps and parameter are with embodiment 2.
Synthetic as to obtain polypeptide Nap-GFY (p)-OMe shown in top structural formula (IV) thus, its productive rate is 96%,
1H NMR (400MHz, DMSO-d
6) δ 8.46 (d, 1H), 8.16-8.25 (m, 1H), 8.02 (d, 1H), 7.65-7.90 (m, 2H), 7.754 (s, 1H), 7.41-7.48 (m, 3H), 7.13-7.32 (m, 10H), 4.42-4.56 (m, 2H), 3.63 (s, 3H), 3.58 (s, 4H), 2.89-3.01 (m, 2H), 2.67-2.78 (m, 1H), 2.62-2.67 (m, 1H) .MS:calc.M
+=647.20, obsvd. (M+Na)
+=670.35.
Polypeptide Nap-GFY (p)-OMe molecular energy shown in top structural formula (IV) that present embodiment makes well is dissolved in the aqueous solution, and phosphate radical is cut under the effect of Phosphoric acid esterase, thereby obtains hydrogel.This hydrogel good stability can be prepared into different shape.
Embodiment 6
Polypeptide Nap-GFFFY (p)-OMe's shown in the following structure formula V is synthetic.
Except that polypeptide synthetic raw material replacement in the 6th～7 step in the 4th step is followed successively by Fmoc-phenylalanine, Fmoc-phenylalanine, Fmoc-glycine and the naphthylacetic acid, the working method of other synthesis steps and parameter are with embodiment 2.
Synthetic as to obtain polypeptide Nap-GFY (p)-OMe shown in top structural formula (V) thus, its productive rate is 92%,
1HNMR (400MHz, DMSO-d
6) δ 8.641 (d, J=6.998,1H), 8.373 (s, 1H), 8.234-8.373 (m, 2H), and 8.143-8.157 (m, 1H), 7.965-8.025 (m, 3H), 7.902 (s, 1H), 7.564-7.638 (m, 4H), 7.210-7.561 (m, 18H), and 4.623-4.766 (m, 4H), 3.735-3.887 (m, 3H), 3.731 (s, 3H), 2.979-3.163 (m, 5H), 2.889-2.917 (m, 2H), and 2.803-2.876 (m, 1H), 2.650-2.763 (m, 1H) .MS:calc.M
+=941.34, obsvd. (M+Na)
+=964.44.
Polypeptide Nap-GFY (p)-OMe molecular energy shown in top structural formula (V) that present embodiment makes well is dissolved in the aqueous solution, and phosphate radical is cut under the effect of Phosphoric acid esterase, thereby obtains hydrogel. and this hydrogel good stability can be prepared into different shape.
Embodiment 7
Polypeptide Nap-GFFY (p)-NHMe's shown in the following structural formula (VI) is synthetic.
Be that the methanol solution of 20% methyl ammonia is replaced the anhydrous methanol with containing mass percent in the 5th step, the working method of other synthesis steps and parameter are with embodiment 2.
Synthetic as to obtain polypeptide Nap-GFFY (p)-NHMe shown in top structural formula (VI) thus, its productive rate is 85%,
1H NMR (400MHz, DMSO-d
6) δ 8.45 (d, 1H), 8.16-8.25 (m, 2H), 8.03 (d, 1H), 7.72-7.85 (m, 4H), 7.751 (s, 1H), 7.38-7.45 (m, 3H), 7.04-7.22 (m, 14H), 4.43-4.55 (m, 3H), 3.67-3.73 (m, 1H), 3.60 (s, 2H), 3.55 (s, 4H), 2.88-3.29 (m, 4H), 2.73-2.78 (m, 1H), 2.60-2.66 (m, 1H).
31P NMR (the .MS:calc.M of δ-6.008ppm)
+=793.29, obsvd. (M+2Na)
+=838.22.
Polypeptide Nap-GFFY (p)-NHMe molecular energy shown in top structural formula (VI) that present embodiment makes well is dissolved in the aqueous solution, and phosphate radical is cut under the effect of Phosphoric acid esterase, thereby obtains hydrogel.This hydrogel good stability can be prepared into different shape.
Embodiment 8
Polypeptide Nap-GF (f) F (f) Y (p)-OMe's shown in the following structural formula (VII) is synthetic.
The Fmoc-amino acid that removes in the 3rd step is Fmoc-4-fluoro-phenylalanine, polypeptide synthetic raw material is replaced and is followed successively by outside Fmoc-4-fluoro-phenylalanine, Fmoc-glycine and the naphthylacetic acid in the 6th～7 step in the 4th step, and the working method of other synthesis steps and parameter are with embodiment 2.
Synthetic as to obtain polypeptide Nap-GF (f) F (f) Y (p)-OMe shown in top structural formula (VII) thus, its productive rate is 92%,
1H NMR (400MHz, DMSO-d
6) δ 8.48 (d, 1H), 8.21-8.26 (m, 2H), 8.10 (d, 1H), 7.70-7.81 (m, 3H), 7.76 (s, 1H), 7.40-7.48 (m, 3H), 7.10-7.25 (m, 12H), 4.47-4.58 (m, 3H), 3.71-3.76 (m, 1H), 3.65 (s, 2H), 3.60 (s, 4H), 2.95-3.03 (m, 4H), 2.80-2.85 (m, 1H), 2.65-2.70 (m, 1H).
31P NMR (the .MS:calc.M of δ-6.012ppm)
+=830.25, obsvd. (M+2Na)
+=853.35.
Polypeptide Nap-GF (f) F (f) Y (p)-OMe molecular energy shown in top structural formula (VII) that present embodiment makes well is dissolved in the aqueous solution, and phosphate radical is cut under the effect of Phosphoric acid esterase, thereby obtains hydrogel.This hydrogel good stability can be prepared into different shape.
Embodiment 9
Polypeptide biPhenyl-GFFY (p)-OMe's shown in the following structural formula (VIII) is synthetic.
Except that polypeptide synthetic raw material replacement in the 6th～7 step in the 4th step is followed successively by Fmoc-phenylalanine, Fmoc-glycine and the felbinac, the working method of other synthesis steps and parameter are with embodiment 2.
Synthetic as to obtain polypeptide biPhenyl-GFFY (p)-OMe shown in top structural formula (VIII) thus, its productive rate is 93%,
1H NMR (600MHz, DMSO-d
6) δ 8.590 (d, J=7.011,1H), 8.303-8.367 (m, 2H), 8.171 (d, J=8.301,1H), 7.771-7.785 (d, 2H), 7.707-7.722 (d, 2H), 7.602 (m, 2H), 7.486-7.501 (m, 3H), 7.301-7.402 (m, 11H), 7.227-7.242 (m, 2H), 4.620-4.720 (m, 3H), 3.857-3.895 (m, 1H), 3.729 (m, 4H), 3.649 (m, 2H), and 3.143-3.178 (m, 2H), 3.086-3.113 (m, 2H), 2.930-2.980 (m, 1H), 2.80-2.85 (m, 1H) .MS:calc.M
+820.29, obsvd. (M+Na)
+=843.39.
Polypeptide biPhenyl-GFFY (p)-OMe molecular energy shown in top structural formula (VIII) that present embodiment makes well is dissolved in the aqueous solution, and phosphate radical is cut under the effect of Phosphoric acid esterase, thereby obtains hydrogel.This hydrogel good stability can be prepared into different shape.
Embodiment 10
Polypeptide biOMePhenyl-GFFY (p)-OMe's shown in the following structural formula (IX) is synthetic.
Except that polypeptide synthetic raw material replacement in the 6th～7 step in the 4th step is followed successively by Fmoc-phenylalanine, Fmoc-glycine and 3, outside the 4-dimethoxyphenylacetic acid, the working method of other synthesis steps and parameter are with embodiment 2.
Synthetic as to obtain polypeptide biOMePhenyl-GFFY (p)-OMe shown in top structural formula (IX) thus, its productive rate is 82%,
1H NMR (600MHz, DMSO-d
6) δ 8.298 (d, 1H), 8.11-8.16 (m, 3H), 7.308-7.451 (m, 10H), 7.226-7.242 (m, 3H), 6.912-7.029 (m, 2H), 6.775-6.847 (m, 2H), 4.705-4.713 (m, 1H), 4.61-4.65 (m, 2H), 3.852-3.884 (m, 8H), 3.730-3.775 (m, 5H), 3.084-3.175 (m, 4H), 2.283-2.289 (d, 2H) .MS:calc.M
+=804.28, obsvd. (M+Na)
+=827.39.
Polypeptide biOMePhenyl-GFFY (p)-OMe molecular energy shown in top structural formula (IX) that present embodiment makes well is dissolved in the aqueous solution, and phosphate radical is cut under the effect of Phosphoric acid esterase, thereby obtains hydrogel.This hydrogel good stability can be prepared into different shape.
Embodiment 11
Polypeptide NitroPhenyl-GFFY (p)-OMe's shown in the following structural formula (X) is synthetic.
Except that polypeptide synthetic raw material replacement in the 6th～7 step in the 4th step is followed successively by Fmoc-phenylalanine, Fmoc-glycine and the 4-nitrophenyl-acetic acid, the working method of other synthesis steps and parameter are with embodiment 2.
Synthetic as to obtain polypeptide NitroPhenyl-GFFY (p)-OMe shown in top structural formula (X) thus, its productive rate is 80%,
1H NMR (600MHz, DMSO-d
6) δ 8.402 (d, and 2H) 8.293 (d, 1H), 8.124-8.162 (m, 3H), 7.942 (d, 2H), 7.551-7.675 (m, 10H), 7.372-7.386 (m, 2H), and 6.908-7.027 (m, 2H), 4.452-4.621 (m, 3H), 3.682-3.758 (m, 1H), 3.626 (s, 2H), 3.579 (s, 4H), 2.918-3.032 (m, 4H), 2.758-2.805 (m, 1H), 2.629-2.685 (m, 1H) .MS:calc.M
+=789.24, obsvd. (M+Na)
+=811.34.
Polypeptide NitroPhenyl-GFFY (p)-OMe molecular energy shown in top structural formula (X) that present embodiment makes well is dissolved in the aqueous solution, and phosphate radical is cut under the effect of Phosphoric acid esterase, thereby obtains hydrogel.This hydrogel good stability can be prepared into different shape.
Embodiment 12
Polypeptide biClPhenyl-GFFY (p)-OMe's shown in the following structural formula (XI) is synthetic.
Except that polypeptide synthetic raw material replacement in the 6th～7 step in the 4th step is followed successively by Fmoc-phenylalanine, Fmoc-glycine and 3, outside the 4-fenac, the working method of other synthesis steps and parameter are with embodiment 2.
Synthetic as to obtain polypeptide biClPhenyl-GFFY (p)-OMe shown in top structural formula (XI) thus, its productive rate is 81%,
1H NMR (600MHz, DMSO-d
6) δ 8.304 (d, 1H), 8129-8.172 (m, 3H), 7.312-7.458 (m, 10H), 7.230-7.245 (m, 3H), 6.909-7.034 (m, 2H), 6.772-6.851 (m, 2H), 4.701-4.716 (m, 1H) 4.609-4.634 (m, 2H), 3.848-3.875 (m, 7H), 3.728 (s, 3H), 3.124-3.180 (m, 4H), 2.281-2.287 (d, 2H) .MS:calc.M
+=812.18, obsvd. (M+2Na)
+=857.20, (M-H)
-=811.30.
Polypeptide biClPhenyl-GFFY (p)-OMe molecular energy shown in top structural formula (XI) that present embodiment makes well is dissolved in the aqueous solution, and phosphate radical is cut under the effect of Phosphoric acid esterase, thereby obtains hydrogel.This hydrogel good stability can be prepared into different shape.
Embodiment 13
Polypeptide Nap-KFFY (p)-NHMe's shown in the following structural formula (XII) is synthetic.
Except that polypeptide synthetic raw material replacement in the 6th～7 step in the 4th step is followed successively by Fmoc-phenylalanine, Fmoc-Methionin and naa; And be that the methanol solution of 20% methyl ammonia is replaced outside the anhydrous methanol with containing mass percent in the 5th step, the working method of other synthesis steps and parameter are with embodiment 2.
Synthetic as to obtain polypeptide Nap-KFFY (p)-NHMe shown in top structural formula (XII) thus, its productive rate is 78%,
1H NMR (600MHz, DMSO-d
6) δ 8.478 (d, 1H), 8.182-8.276 (m, 2H), 8.053 (d,, 1H), 7.746-7.875 (m, 3H), 7.754 (s, 1H), 7.387-7.462 (m, 3H), and 7.065-7.243 (m, 15H), 4.923 (m, 2H), and 4.458-4.575 (m, 3H), 3.689-3.754 (m, 1H), 3.625 (s, 2H), 3.564 (s, 4H), and 2.910-3.018 (m, 4H), 2.724-2.791 (m, 1H), and 2.673-2.715 (m, 2H), 1.953-1.976 (m, 2H), and 1.435-1.468 (m, 2H), 1.258-1.360 (m, 2H) .MS:calc.M-=863.50, obsvd. (M+Na) +=887.45.
Polypeptide Nap-KFFY (p)-NHMe molecular energy shown in top structural formula (XII) that present embodiment makes well is dissolved in the aqueous solution, and phosphate radical is cut under the effect of Phosphoric acid esterase, thereby obtains hydrogel.
The Full Name in English of used condensing agent HBTU is O-Benzotriazole-N in the foregoing description, N, and N ', N '-tetramethyl-uronium-hexafluoro-phosphate is polypeptide synthetic technician and knows.The Chinese of catalyzer DIEA is a di-isopropyl second class amine.The amino acid that these two chemical and all Fmoc protect all obtains from biochemical purchase of gill.
Claims (3)
1. be used to generate the polypeptide derivative of stable micro-molecular hydrogel, it is characterized in that shown in the following structural formula of compound of its molecular composition and structure:
In this formula, R
1Be aromatic derivatives, R
2Be a kind of side-chain radical in 20 kinds of natural amino acids, R
3Be in H or the halogen any one, R
4Be Ome base or NHMe base.n＝1～3。
2. the polypeptide derivative that is used to generate stable micro-molecular hydrogel according to claim 1 is characterized in that: described R
1Be
3. the polypeptide derivative that is used to generate stable micro-molecular hydrogel according to claim 1 is characterized in that: described R
2It is the side-chain radical of glycine or Methionin.
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