CN104478995A - Method for synthetizing fullerene bis-addition polypeptide by combining liquid phase and solid phase - Google Patents
Method for synthetizing fullerene bis-addition polypeptide by combining liquid phase and solid phase Download PDFInfo
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Abstract
The invention discloses a method for synthetizing fullerene bis-addition polypeptide by combining a liquid phase and a solid phase. N-substitutive fullerene bis-addition pyrrolidine and Fmoc-Asp-OtBu with protected alfa-amino and beta-carboxyl have a condensation reaction with a liquid-phase synthesis method in the presence of DCC (dicyclohexylcarbodiimide), HOBt (hydroxybenzotriazole ) and DMAP (dimethylaminopyridine); after the reaction, separation and purification are conducted through silica-gel column chromatography, and fullerene bis-addition aspartic acid is obtained after deprotection of a product; an alpha-carboxyl of fullerene bis-addition aspartic acid and activated amino on arginine in Wang resin-polypeptide have a condensation reaction with a solid-phase synthesis method, and fullerene bis-addition polypeptide is obtained after deprotection and decomposition of a product. Fullerene bis-addition polypeptide has good anti-tutor activity and capacity for scavenging free radicals, improves the stability of peptide and water solubility of fullerene, can be used for connecting different polypeptide and obtains different biological activity with changing of functional peptide.
Description
Technical field
The invention belongs to field of medicaments, be specifically related to the preparation method that a kind of liquid-solid phase combines the two addition polypeptide of soccerballene of synthesis, this compound improves the solubleness of soccerballene in polar solvent greatly, improves biology availability and the targeting problem to cell thereof.
Background technology
Soccerballene C
60cause has special physics, chemical property shows unique biologic activity, can be summarized as photosensitivity effect and nonphotosensitive effect.The former and fullerene ball cage produce the free radicals such as singlet oxygen by photoinduction when oxygen exists relevant, comprise light activated DNA break, cell membrane damage and cytotoxicity etc.Ever-increasing research data display fullerene derivate has application prospect quite widely at biomedicine field, as as the photosensitizers in photodynamic therapy, antiaging agent, antisense nucleic acid medicament and pharmaceutical carrier, the research and apply of its photosensitization becomes the forward position of soccerballene research and popular direction gradually.Increasing research shows that soccerballene quantum yield is high, more much better than the photosensitizers effect of current clinical application, and impact be there is no, for soccerballene provides theoretical foundation as the photosensitizers in tumour photodynamic therapy to some enzyme content in normal skin, Mouse Weight and blood; But also there is different research conclusions, also need deeply systematically to study further to confirm.
Different polypeptide has different biological functions and purposes, conventional functional peptides has RGD peptide, PHLATLF peptide and TISWPPR peptide etc., small peptide PHLATLF has growth-inhibiting effect to ovarian cancer A2780 cell, this seven peptide (TR-7) of TISWPPR has specificity affinity interaction to large bowel cancer, mainly there is specific high affinity interaction to the specific marker molecule CD133 of tumor stem cell, the multiplication capacity of tumour cell and adhesive capacity are had no significant effect, has significant restraining effect to the locomotory movement ability of tumour cell.Wherein RGD peptide is that a class contains arginine-glycine-aspartic acid (Arg-Gly-Asp) 3 amino acid whose micromolecule polypeptides, can with the integrin alpha at some tumour cell high expression level
vβ
3molecule generation specific binding, α
vβ
3seldom express in healthy tissues system and even do not express, also become the target spot that neoplasm targeted therapy is desirable.Part RGD and α
vβ
3the high specificity of receptors bind, avidity is high, is effective pharmaceutical carrier.
Based on above series of studies basis, we intend the nanometric photosensitizer of a kind of novel fullerene derivate of design and synthesis.RGD peptide for soccerballene is modified: FBP(RGD), the stability of peptide and the water-soluble of soccerballene can be increased so on the one hand, give full play to the biological activity of RGD peptide, thus obtain the photosensitizers of cancer target; On the other hand, the experimental technique of foundation can also be used to connect different polypeptide (as antibody or surface receptor), obtains different biologic activity along with the conversion of functional peptides.The research of soccerballene photodynamics has many reports, but the compound structure of synthesis is complicated, seldom has further systematic research in biology, and the antitumor activity such as photosensitivity for the nano particle of this fullerene derivate has no report especially.
Summary of the invention
The object of the invention is body for the method for a kind of liquid-solid phase in conjunction with the two addition polypeptide of fullerene synthesis, substantially increase the solubleness of soccerballene in polar solvent, and there is good antitumour activity and the ability of scavenging free radicals.
For achieving the above object, the present invention by the following technical solutions: the two addition polypeptide of a kind of soccerballene, structural formula is as follows:
Wherein P is RGD peptide, TISWPPR peptide or PHLATLF peptide.
A preparation method for the two addition polypeptide of soccerballene, comprises the following steps:
(1) the two addition tetramethyleneimine (preparation method is shown in patent 201410114391.X) of N-substituted fullerene with only have the acidic amino acid of a pendant carboxylic group under the existence of dicyclohexylcarbodiimide (DCC), I-hydroxybenzotriazole (HOBT), DMAP (DMAP), under nitrogen protection, condensation reaction is carried out with liquid phase synthesizing method, room temperature lucifuge stirring reaction 24 ~ 72 hours, after reaction terminates, silica gel column chromatography separating purification obtains the amino and two addition amino acid of all protected soccerballene of carboxyl;
(2) the two addition amino acid of the amino and all protected soccerballene of carboxyl adds in the mixing solutions of trifluoroacetic acid (TFA)/methylene dichloride (DCM), stirring at room temperature reaction 0.5 ~ 12h, removes carboxyl-protecting group through remove-insurance and obtains only containing the two addition amino acid of soccerballene of amino protecting group;
(3) the two addition amino acid of soccerballene only containing amino protecting group is dissolved in N, in N-dimethylformamide (DMF)/DCM mixed solvent, then add resin-polypeptide and (only have an active amino, and end position), benzotriazole-N, N, N', N'-tetramethyl-urea hexafluorophosphate (HBTU), I-hydroxybenzotriazole (HOBT) and N, N-diisopropylethylamine (DIEA), at room temperature carry out condensation reaction with solid-phase synthesis, product obtains the two addition polypeptide of soccerballene through remove-insurance, cracking;
Each step is all carried out under the condition of anhydrous and oxygen-free above;
The acidic amino acid of a pendant carboxylic group that only has in described step (1) is aspartic acid or L-glutamic acid;
Resin-polypeptide in described step (3) is resin-RGD peptide, resin-TISWPPR peptide or resin-PHLATLF peptide.
The two addition tetramethyleneimine of N-substituted fullerene in described step (1), only have the acidic amino acid of a pendant carboxylic group, the ratio of the amount of substance of DCC, HOBT and DMAP is 0.05-0.2:2:2:2:0.2.
The eluent that in described step (1), silica gel column chromatography is used is toluene and ethyl acetate is that 3:1 mixes according to volume ratio.
In the mixing solutions of middle trifluoroacetic acid (the TFA)/methylene dichloride (DCM) of described step (2), the volume ratio of TFA and DCM is 0.2-9:1.
The ratio of the amount of substance of the two addition amino acid of soccerballene only containing amino protecting group in described step (3), resin-polypeptide, HBTU, HOBT and DIEA is 2:1-6:4:4:8.
In described step (3), in DMF/DCM mixed solvent, the volume ratio of DMF and DCM is 1:1.
It is the 8-24 h that vibrates under the condition of 140 r/min that described step (3) at room temperature carries out condensation reaction with solid-phase synthesis.
In described step (3), remove-insurance agents useful for same is the mixing solutions of piperidines/DMF, and wherein the volume ratio of piperidines and DMF is 1:4, and vibrate 15 ~ 30 min under the condition of room temperature, 140 r/min.
In described step (3), cracking agents useful for same is TFA/ tri isopropyl silane (TIS)/H
2the mixing solutions of O, wherein TFA, TIS and H
2the volume ratio of O is 95:2:3, and vibrate 2-4 h under the condition of room temperature, 140 r/min.
In described step (3) after cracking, obtain the two addition polypeptide of soccerballene by the cold diethyl ether precipitator method.
Beneficial effect of the present invention: the polypeptide that (1) soccerballene is modified is as RGD peptide: FBP(RGD), the stability of peptide and the water-soluble of soccerballene can be increased on the one hand, give full play to the biological activity of RGD peptide, thus obtain the photosensitizers of cancer target; On the other hand, the experimental technique of foundation can also be used to connect different polypeptide (as antibody or surface receptor), obtains different biologic activity along with the conversion of functional peptides; (2) the two addition polypeptide of soccerballene, substantially increases the solubleness of soccerballene in polar solvent, and has good antitumour activity and the ability of scavenging free radicals; (3) the two addition polypeptide of soccerballene has many application well at biomedical sector.
figure of description
Fig. 1 is the IR figure of the two addition RGD peptide of soccerballene that embodiment 1 prepares;
Fig. 2 is the MALDI-TOF mass spectrum of the two addition RGD peptide of soccerballene that embodiment 1 prepares.
Embodiment
Following examples for illustration of the present invention, but are not used for limiting the scope of the invention.
Embodiment 1
The synthetic route of the two addition RGD peptide of soccerballene of the present embodiment is:
Wherein, 1 is the two addition tetramethyleneimine of N-substituted fullerene, and 2 is the two addition aspartic acid (containing Fmoc and OtBu) of soccerballene, and 3 is the two addition aspartic acid (containing Fmoc) of soccerballene, and 4 is the two addition RGD peptide of soccerballene.
The preparation method of the two addition RGD peptide of soccerballene of the present embodiment is as follows:
(1) 0.24mmol alpha-amino group and all protected Fmoc-Asp-OtBu of β-carboxyl is got, 0.24mmol HOBT 4mLDCM dissolves, dropwise add DMF until solution clarification, after adding 0.24mmolDCC mixing again, nitrogen protection ice bath lucifuge reacts 30min, filter out white DCU, then the two addition tetramethyleneimine of 0.012mmol soccerballene and 3mgDMAP is added, after nitrogen protection lucifuge reaction 72h, revolve steaming, silica gel column chromatography separating purification, eluent is toluene/ethyl acetate=3:1, be separated the primary product that obtains revolve steam final vacuum dry product 2;
(2) product 2 with 50% TFA/DCM decarboxylation protecting group, room temperature reaction 3h, finally purifies by the cold diethyl ether precipitator method and obtains the two addition aspartic acid FBPD(of soccerballene containing Fmoc);
(3) two for the soccerballene of 0.01mmol addition aspartic acid (FBPD) is dissolved in the DCM/DMF(1:1 of 1 mL), add Wang-Asp (OtBu)-Gly-Arg (the Pbf)-NH of 0.005mmol
2, the HBTU of 0.02mmol, the DIEA of HOBT and 0.04mmol of 0.02 mmol, room temperature 25 DEG C, vibrate under 140 r/min 8 h, fully washs successively with DCM, DMF, each 1 min, obtains Wang-Asp (OtBu)-Gly-Arg (Pbf) (Fmoc).In this resin, add the 20% piperidines/DMF of 2 mL, react 15 min, the abundant washing resin of DMF, elimination solvent; In resin, add trifluoroacetic acid (TFA)/tri isopropyl silane (the TIS)/H of 3 mL
2o(95:2:3) (volume ratio), vibrate under room temperature 25 DEG C, 140 r/min 2 h, and collecting by filtration filtrate, adds a large amount of anhydrous diethyl ethers in filtrate, and freezing spending the night removes excessive TFA, centrifugal collecting precipitation, obtains the two addition RGD peptide of soccerballene after drying.
Fig. 1 is the infrared spectrogram of the two addition RGD peptide of soccerballene that the present embodiment obtains: ν max/ (cm
-1): 3426.88 is the stretching vibration absorption peak of O-H, 2926.37 is the C-H stretching vibration absorption peak on CH2,1650.54 be the stretching vibration absorption peak of C=O, 1542.70,799.01 is the flexural vibration absorption peak of C-N on acid amides, and 1110.94 is the stretching vibration absorption peak of C-N, 1387.69,622.53 is the charateristic avsorption band of C60, and the absorption peak of 516.05 is the marks replacing C60.Fig. 2 is the mass spectrum of the two addition RGD peptide of the present embodiment soccerballene: theoretical molecular is be 1869 [M+H] in 1868, figure
+.
Fourier transform infrared spectrum of the present invention adopts IR-200 Spectrometer infrared spectrometer, the sample preparation of Potassium Bromide KBr pressed disc method; Mass spectrum adopts Bruker Daltonics Inc.BIFLEX III type MALDI-TOF mass spectrograph.
Embodiment 2
The preparation method of the two addition TISWPPR peptide of soccerballene of the present embodiment is as follows:
(1) 0.24mmol alpha-amino group and all protected Fmoc-Glu-OtBu of β-carboxyl is got, 0.24mmol HOBT 4mLDCM dissolves, dropwise add DMF until solution clarification, after adding 0.24mmolDCC mixing again, nitrogen protection ice bath lucifuge reacts 30min, filter out white DCU, then the two addition tetramethyleneimine of 0.024mmol soccerballene and 3mgDMAP is added, after nitrogen protection lucifuge reaction 48h, revolve steaming, silica gel column chromatography separating purification, eluent is toluene/ethyl acetate=3:1, be separated the primary product that obtains revolve steam final vacuum dry product 2;
(2) product 2 with 90% TFA/DCM decarboxylation protecting group, room temperature reaction 0.5h, finally purifies by the cold diethyl ether precipitator method and obtains the two addition L-glutamic acid FBPG(of soccerballene containing Fmoc);
(3) two for the soccerballene of 0.01mmol addition L-glutamic acid (FBPG) is dissolved in the DCM/DMF(1:1 of 1 mL), add the resin-TISWPPR of 0.01mmol (only containing an active amino, and on end position R), the HBTU of 0.02mmol, the DIEA of HOBT and 0.04mmol of 0.02 mmol, room temperature 25 DEG C, vibrate under 140 r/min 16 h, fully wash with DCM, DMF successively, each 1 min, obtain resin-TISWPPR peptide (non-activity amino and carboxyl).In this resin, add the 20% piperidines/DMF of 2 mL, react 20 min, the abundant washing resin of DMF, elimination solvent; In resin, add trifluoroacetic acid (TFA)/tri isopropyl silane (the TIS)/H of 3 mL
2o(95:2:3) (volume ratio), vibrate under room temperature 25 DEG C, 140 r/min 3 h, collecting by filtration filtrate, a large amount of anhydrous diethyl ethers is added in filtrate, freezing spending the night removes excessive TFA, centrifugal collecting precipitation, obtains the two addition TISWPPR peptide of soccerballene after drying.
Embodiment 3
The preparation method of the two addition PHLATLF peptide of soccerballene of the present embodiment is as follows:
(1) 0.24mmol alpha-amino group and all protected Fmoc-Asp-OtBu of β-carboxyl is got, 0.24mmol HOBT 4mLDCM dissolves, dropwise add DMF until solution clarification, after adding 0.24mmolDCC mixing again, nitrogen protection ice bath lucifuge reacts 30min, filter out white DCU, then the two addition tetramethyleneimine of 0.006mmol soccerballene and 3mgDMAP is added, after nitrogen protection lucifuge reaction 24h, revolve steaming, silica gel column chromatography separating purification, eluent is toluene/ethyl acetate=3:1, be separated the primary product that obtains revolve steam final vacuum dry product 2;
(2) product 2 with 17% TFA/DCM decarboxylation protecting group, room temperature reaction 12h, finally purifies by the cold diethyl ether precipitator method and obtains the two addition aspartic acid FBPD(of soccerballene containing Fmoc);
(3) two for the soccerballene of 0.01mmol addition aspartic acid (FBPD) is dissolved in the DCM/DMF(1:1 of 1 mL), add the resin-PHLATLF peptide of 0.03mmol (only containing an active amino, and on end position F), the HBTU of 0.02mmol, the DIEA of HOBT and 0.04mmol of 0.02 mmol, room temperature 25 DEG C, vibrate under 140 r/min 24 h, fully wash with DCM, DMF successively, each 1 min, obtain resin-PHLATLF peptide (non-activity amino and carboxyl).In this resin, add the 20% piperidines/DMF of 2 mL, react 30 min, the abundant washing resin of DMF, elimination solvent; In resin, add trifluoroacetic acid (TFA)/tri isopropyl silane (the TIS)/H of 3 mL
2o(95:2:3) (volume ratio), vibrate under room temperature 25 DEG C, 140 r/min 4 h, collecting by filtration filtrate, a large amount of anhydrous diethyl ethers is added in filtrate, freezing spending the night removes excessive TFA, centrifugal collecting precipitation, obtains the two addition PHLATLF peptide of soccerballene after drying.
Claims (10)
1. the two addition polypeptide of soccerballene, is characterized in that structural formula is as follows:
Wherein P is RGD peptide, TISWPPR peptide or PHLATLF peptide.
2. the preparation method of the two addition polypeptide of soccerballene according to claim 1, is characterized in that comprising the following steps:
(1) the two addition tetramethyleneimine of N-substituted fullerene with only have the acidic amino acid of a pendant carboxylic group under the existence of DCC, HOBT and DMAP, under nitrogen protection, condensation reaction is carried out with liquid phase synthesizing method, room temperature lucifuge stirring reaction 24 ~ 72 hours, after reaction terminates, silica gel column chromatography separating purification obtains the amino and two addition amino acid of all protected soccerballene of carboxyl;
(2) amino and the two addition amino acid of all protected soccerballene of carboxyl are added in the mixing solutions of TFA/DCM, stirring at room temperature reaction 0.5 ~ 12h, remove carboxyl-protecting group through remove-insurance and obtain only containing the two addition amino acid of soccerballene of amino protecting group;
(3) the two addition amino acid of soccerballene only containing amino protecting group is dissolved in DMF/DCM mixed solvent, then resin-polypeptide, HBTU, HOBT and DIEA is added, at room temperature carry out condensation reaction with solid-phase synthesis, product obtains the two addition polypeptide of soccerballene through remove-insurance, cracking;
Each step is all carried out under the condition of anhydrous and oxygen-free above;
The acidic amino acid of a pendant carboxylic group that only has in described step (1) is aspartic acid or L-glutamic acid;
Resin-polypeptide in described step (3) is resin-RGD peptide, resin-TISWPPR peptide or resin-PHLATLF peptide.
3. the preparation method of the two addition polypeptide of soccerballene according to claim 1, is characterized in that: the two addition tetramethyleneimine of N-substituted fullerene in described step (1), only have the acidic amino acid of a pendant carboxylic group, the ratio of the amount of substance of DCC, HOBT and DMAP is 0.05-0.2:2:2:2:0.2.
4. the preparation method of the two addition polypeptide of soccerballene according to claim 1, is characterized in that: in the mixing solutions of the middle TFA/DCM of described step (2), the volume ratio of TFA and DCM is 0.2-9:1.
5. the preparation method of the two addition polypeptide of soccerballene according to claim 1, is characterized in that: the ratio of the amount of substance of the two addition amino acid of soccerballene only containing amino protecting group in described step (3), resin-polypeptide, HBTU, HOBT and DIEA is 2:1-6:4:4:8.
6. the preparation method of the two addition polypeptide of soccerballene according to claim 1, is characterized in that: in described step (3), in DMF/DCM mixed solvent, the volume ratio of DMF and DCM is 1:1.
7. the preparation method of the two addition polypeptide of soccerballene according to claim 1, is characterized in that: it is the 8-24h that vibrates under the condition of 140 r/min that described step (3) at room temperature carries out condensation reaction with solid-phase synthesis.
8. the preparation method of the two addition polypeptide of soccerballene according to claim 1, it is characterized in that: in described step (3), remove-insurance agents useful for same is the mixing solutions of piperidines/DMF, wherein the volume ratio of piperidines and DMF is 1:4, and vibrate 15 ~ 30min under the condition of room temperature, 140 r/min.
9. the preparation method of the two addition polypeptide of soccerballene according to claim 1, is characterized in that: in described step (3), cracking agents useful for same is TFA/TIS/H
2the mixing solutions of O, wherein TFA, TIS and H
2the volume ratio of O is 95:2:3, and vibrate 2-4 h under the condition of room temperature, 140 r/min.
10. the preparation method of the two addition polypeptide of soccerballene according to claim 1, is characterized in that: in described step (3) after cracking, obtains the two addition polypeptide of soccerballene by the cold diethyl ether precipitator method.
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