CN101870732A - Method for synthesizing mono pegylation-thymopentin by solid phase and liquid phase combination - Google Patents
Method for synthesizing mono pegylation-thymopentin by solid phase and liquid phase combination Download PDFInfo
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Abstract
The invention relates to a method for synthesizing mono pegylation-thymopentin (mPEG-TP5) by solid phase and liquid phase combination. The method comprises the following steps of: connecting modified polyethylene glycol (mPEG-SCM) to side chain amino of lysine protected by amino by adopting liquid-phase synthesis technology; synthesizing mPEG-TP5 by adopting solid-phase synthesis technology; analyzing and purifying high-efficiency liquid phase through dialysis; and identifying the product structure through nuclear magnetism and mass spectrum. The mono pegylation-thymopentin synthesized by the method improves the defect that the conventional parent medicament thymopentin has quick biodegradation, poor digesting stability, short biological half-life and the like, and has good application prospect.
Description
Technical field
The synthetic technology that the present invention relates to adopt liquid phase and solid phase to combine is carried out thymopeptide-5 synthetic of Pegylation.
Background technology
(Thymopentin TP5) is a kind of synthetic small-molecular peptides by 5 amino-acid residues to thymopeptide-5, has identical adjusting immunity of organism equilibrated biological activity with endogenic thymopoietin II.For panimmunity dysfunction or low, TP5 can both make immunologic function be tending towards normal by the dual regulation that promotes or suppress.At present, it has been widely used in clinical, can be used for treatment: (1) malignant tumour; (2) chronic hepatitis; (3) operation and severe infections; (4) diabetes; (5) autoimmune disorder; (6) climacteric syndrome; (7) old and feeble weak etc.It is very fast by proteolytic enzyme and aminopeptidase degraded that but TP5 is injected in behind the human body, and the transformation period of medicine prototype only is 30 seconds.Yet the disease of TP5 treatment generally all needs long-term prescription, and at present can be for clinical application lyophilized injectable powder and solution type injection agent only arranged.So TP5 can only take the mode administration of frequent injection or intravenous drip, has brought very big misery and stress to the patient.Urgent need will be developed new prolonged action preparation product.
The polyoxyethylene glycol of medicine (polyethylene glycol, PEG) modify, be that PEGization (pegylaytion) is that activated polyglycol is coupled on protein, polypeptide, small molecules organic drug and the liposome by chemical process, thereby improve the character of medicine.Purpose medicine aspect such as transformation period in conveying, curative effect and body all is significantly improved, thereby improves its clinical value and commercial value.Abuchowski in 1977 etc. at first use polyethyleneglycol modified pharmaceutical protein, and (J.Biol.Chem.252,3582-3586.), the protein curative effect after the result modifies is better than the prototype medicine of unmodified, obviously obtains its biological half-life prolonging.After this, polyethyleneglycol modified technology has obtained development rapidly and has successfully developed many polyethyleneglycol modified pharmaceutical grade proteins (or polypeptide drugs).
Summary of the invention
Thymopeptide-5 is as a kind of medicine with two-way immunoregulation effect, uses very extensively, has the value and the research background of further development and use.Fast in order to improve in its body biodegradation rate, the problem that biological half-life is short the invention provides a kind of employing solid phase and liquid phase combining method synthesizing polyethylene glycol thymopeptide-5 new technology.
Purpose of the present invention can be achieved through the following technical solutions:
A. adopt liquid-phase synthesis process mono methoxy polyethylene glycol modifier (mPEG-SCM) to be connected to the side chain amino (ε-NH of the Methionin of α amido protecting
2) on; The lysine hydrochloride (Fmoc-lys-OH.HCl) and mono methoxy polyethylene glycol modifier (mPEG-SCM) mol ratio of the protection of reactant fluorenylmethyloxycarbonyl are 7: 1, and reaction system is chloroform and dioxane, and volume ratio is 1: 4; , normal temperature drips diisopropylethylamine (N, N '-Diisopropylsilane are called for short DIEA) down, makes PH keep 9.0, and under the magnetic agitation, reaction is spent the night; Reaction system decompression rotation is drained, and reactant is dissolved in water, and filters out water-insoluble, and with dialysis tubing (MW, 3500) dialysis 48 hours, lyophilize got white powder (Fmoc-lys (PEG)-OH);
Reaction equation is as follows:
B. adopt the thymopeptide-5 of solid-phase synthesis synthesizing polyethylene glycolization, concrete steps are as follows:
1. Fmoc-Tyr (tBu)-Wang resin joins methylene dichloride (DCM)) soaked 30 minutes, vacuum pump is drained, dimethyl formamide (DMF) washing, it is inferior to give a baby a bath on the third day after its birth, each three minutes; With the dimethyl formamide that contains 20% piperidines (DMF) solution mechanical stirring 0.5 hour, take off the Fmoc protecting group; Dimethyl formamide (DMF) solution is given a baby a bath on the third day after its birth inferior, each three minutes; Add 5% triketohydrindene hydrate alcoholic solution indenes check reagent, heating is three minutes in the boiling water, shows blue;
2. with Xie Ansuan (Fmoc-Val-OH), the benzotriazole-N of Fmoc protection, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (HBTU), I-hydroxybenzotriazole (HoBt) are dissolved in dimethyl formamide (DMF) respectively, add diisopropylethylamine (DIEA) and start Acibenzolar; Carry out under the reaction normal temperature, the system argon shield, Fmoc-Arg (OtBu)-OH usage quantity is 2.5～3 times of Fmoc-Tyr (tBu)-Wang resin, N '-tetramethyl-urea phosphofluoric acid ester (HBTU) and I-hydroxybenzotriazole (HoBt) are amino acid whose 2 times, diisopropylethylamine (DIEA) is amino acid whose 2 times, after the startup system joined and add in the solid phase synthetic instrument of handling resin well, mechanical stirring 45 minutes, wash out resin on the wall with dimethyl formamide (DMF), restir was taken out after 15 minutes; Dimethyl formamide (DMF) solution is given a baby a bath on the third day after its birth inferior, each three minutes; The indenes check reagent detects colourless, and circulation is so far finished;
3. more respectively with Fmoc-Asp (OtBu)-OH, Fmoc-Lys (PEG)-OH, and Fmoc-Arg (pbf)-OH is an amino acid starting material, more than the repetition 1., 2. step, finish the synthetic of mPEG-TP5 in turn, get product, the structure of product is: H-Arg-Lys (mPEG)-Asp-Val-Tyr-OH;
4. 1. take off the Fmoc protection by above-mentioned b, the indenes check reagent detects and is blue, and system is washed earlier 2 times with methylene dichloride (DCM), and methyl alcohol (MeOH) is washed once, each three minutes; Use methylene dichloride (DCM) to wash again 1 time, MeOH washes 2 times, each three minutes; Remove agitator,, use vacuum pump (SHB-III) to take out 2 hours more with the circulation ability of swimming with plug sealing synthesizer upper end, add cutting reagent, reacted 3 hours, and, collected cutting agent every 15 minutes mechanical stirring 1 minute, use trifluoroacetic acid (TFA) washing 2 times again, merge cutting agent and trifluoroacetic acid (TFA), system is under 40 ℃, and the decompression rotation is drained, add the aqueous solution dissolving of 20% Glacial acetic acid, freeze-drying; With distilled water lyophilized powder is dissolved, filter out water-insoluble, dialyse 48 hours (dialysis tubing, MW, 3500), freeze-drying; Rp-hplc (RP-HPLC) is further purified, and elutriant is acetonitrile and the water that contains 0.1%TFA.
Reaction equation is as follows:
The beneficial effect of advantage of the present invention and generation:
1, the present invention adopts the polyoxyethylene glycol (mPEG-SCM) that the liquid phase synthetic technology will modification to be connected on the lysine side-chain amino of amido protecting earlier; Adopt solid phase synthesis technique to synthesize mPEG-TP5 again.By dialysis, high performance liquid phase is analyzed and purifying, synthetic thymopeptide-5 with Pegylation of potential long-acting.
Be difficult on this composite structure by the hydrolysis of body endoproteinase,, can reduce renal clearance because molecular weight is big, extension body internal recycle time greatly, thus reach the significant prolongation transformation period, improve the purpose of bioavailability.
2, a kind of method that adopts solid phase and liquid phase to combine provided by the invention, synthetic mPEG-TP5 with potential long-acting.The target product structure is accurate, and the synthetic route maturation is stable.Provided by the invention synthetic relative simple with the operation of analysis purification process, required cost is low.Scale operation basis is preferably arranged.
Description of drawings
Fig. 1 is the MALDI-TOF mass spectrum of synthetic product of the present invention.
Embodiment
A kind of method with solid-liquid phase method synthesizing polyethylene glycol thymopeptide-5, its step is divided into:
A. adopt liquid-phase synthesis process mono methoxy polyethylene glycol modifier (mPEG-SCM) to be connected to the side chain amino (ε-NH of the Methionin of α amido protecting
2) on; The lysine hydrochloride (Fmoc-lys-OH.HCl) of 400mg fluorenylmethyloxycarbonyl protection and 700mg mono methoxy polyethylene glycol modifier (mPEG-SCM) reaction, reaction system is 6ml chloroform and 24ml dioxane; , normal temperature drips diisopropylethylamine (N, N-Diisopropylsilane are called for short DIEA) 800 μ l down, makes PH keep 9.0, magnetic agitation, and reaction is spent the night; Reaction system decompression rotation is drained, and reactant adds the 40mL water dissolution, filters out water-insoluble, and with dialysis tubing (MW, 3500) dialysis 48 hours, lyophilize got white powder 600mg (Fmoc-lys (PEG)-OH), productive rate 78.5%.
The product nuclear magnetic data is as follows:
1H-NMR(DMSO)7.31-7.77(8H，Fmoc-aromatics)，0.85(2H，-OCH
2CH
2-)，3.60(3H，-OCH
3)。HPLC detects: mPEG-SCM (not absorbing under the ultraviolet), Fmoc-lys-OHHCL (t
R=17.06), product (t
R=20.35).By the judgement of nuclear-magnetism and HPLC, product structure is Fmoc-Lys (PEG)-OH as can be known.
B. adopt the thymopeptide-5 of solid-phase synthesis synthesizing polyethylene glycolization, concrete steps are as follows:
1. Fmoc-Tyr (tBu)-Wang resin 0.2g is with methylene dichloride 10ml (DCM)) soaked 30 minutes, drain with vacuum pump then, with dimethyl formamide (DMF) 5ml washing, totally three times, each three minutes; With the DMF solution 15ml mechanical stirring that contains 20% piperidines 0.5 hour, take off the Fmoc protecting group; 5mlDMF solution is given a baby a bath on the third day after its birth inferior, each three minutes; Add 4 5% triketohydrindene hydrate alcoholic solutions (indenes check reagent), heating is three minutes in the boiling water, shows blue.
2. with Fmoc-Val-OH 75.34mg, benzotriazole-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (HBTU) 84.14mg, I-hydroxybenzotriazole (HoBt) 30mg are dissolved in DMF respectively, add diisopropylethylamine 73.4 μ l (DIEA) and start Acibenzolar; Reaction is carried out under the normal temperature, and the system argon shield after the startup joins system and adds in the solid phase synthetic instrument of handling resin well, and mechanical stirring 45 minutes is washed out resin on the wall with dimethyl formamide (DMF) 2ml, and restir was taken out after 15 minutes; Dimethyl formamide (DMF) solution 5ml gives a baby a bath on the third day after its birth inferior, each three minutes; The indenes check reagent detects colourless, and circulation is so far finished.
3. respectively with Fmoc-Asp (OtBu)-OH 91.35mg, Fmoc-Lys (PEG)-OH 588mg (1.5 times excessive), Fmoc-Arg (pbf)-OH 144mg is an amino acid starting material, repeats above step, finishes the synthetic of mPEG-TP5 in turn, target product.The structure of product is: H-Arg-Lys (mPEG)-Asp-Val-Tyr-OH.
4. take off the Fmoc protection by above-mentioned b (1), the indenes check reagent detects and is blue, and system is washed earlier 2 times with methylene dichloride (DCM) 5ml, and methyl alcohol (MeOH) 5ml washes once, each three minutes; Use methylene dichloride (DCM) 5ml to wash again 1 time, MeOH5ml washes 2 times, each three minutes; Remove agitator,, use vacuum pump (SHB-III) to take out 2 hours more, add cutting reagent 10ml with the circulation ability of swimming with plug sealing synthesizer upper end.The cutting reagent proportioning is: trifluoroacetic acid (TFA): distilled water: tri isopropyl silane=95: 2.5: 2.5, reacted 3 hours, every 15 minutes mechanical stirring 1 minute, collect cutting agent, use trifluoroacetic acid (TFA) 5ml washing 2 times again, merge cutting agent and trifluoroacetic acid (TFA), system is under 40 ℃, the decompression rotation is drained, and adds the aqueous solution dissolving of 5ml 20% Glacial acetic acid, freeze-drying; 5ml dissolves lyophilized powder with distilled water, filters out water-insoluble, dialyse 48 hours (dialysis tubing, MW, 3500), freeze-drying.Rp-hplc (RP-HPLC) is further purified, and elutriant is acetonitrile and the water that contains 0.1%TFA.Get white sprills 8.2mg, product overall yield 2%.
The synthetic target product checks order (seeing Fig. 1, table 1) through ground substance assistant laser parsing mass spectrum survey molecular weight and Protein Sequencer, judges that the structure of product is H-Arg-Lys (mPEG)-Asp-Val-Tyr-OH.
Table 1: amino acid N end sequencing result such as following table that Jikang Biotechnology Co Ltd, Shanghai provides:
Totally 5 of table 1 explanation institute amino acid number of surveying and sequences (holding C to hold from N), second amino acid of sample is modified.
Claims (1)
1. method with solid-liquid phase method synthesizing polyethylene glycol thymopeptide-5, its step is divided into:
A. adopt liquid-phase synthesis process mono methoxy polyethylene glycol modifier (mPEG-SCM) to be connected to the side chain amino (ε-NH of the Methionin of α amido protecting
2) on; The lysine hydrochloride (Fmoc-lys-OH.HCl) and mono methoxy polyethylene glycol modifier (mPEG-SCM) mol ratio of the protection of reactant fluorenylmethyloxycarbonyl are 7: 1, and reaction system is chloroform and dioxane, and volume ratio is 1: 4; , normal temperature drips diisopropylethylamine (N, N '-Diisopropylsilane are called for short DIEA) down, makes PH keep 9.0, and under the magnetic agitation, reaction is spent the night; Reaction system decompression rotation is drained, and reactant is dissolved in water, and filters out water-insoluble, dialyses 48 hours, and lyophilize gets white powder (Fmoc-lys (PEG)-OH);
B. adopt the thymopeptide-5 of solid-phase synthesis synthesizing polyethylene glycolization, concrete steps are as follows:
1. Fmoc-Tyr (tBu)-Wang resin joins methylene dichloride (DCM)) soaked 30 minutes, vacuum pump is drained, dimethyl formamide (DMF) washing, it is inferior to give a baby a bath on the third day after its birth, each three minutes; With the dimethyl formamide that contains 20% piperidines (DMF) solution mechanical stirring 0.5 hour, take off the Fmoc protecting group; Dimethyl formamide (DMF) solution is given a baby a bath on the third day after its birth inferior, each three minutes; Add 5% triketohydrindene hydrate alcoholic solution indenes check reagent, heating is three minutes in the boiling water, shows blue;
2. with Xie Ansuan (Fmoc-Val-OH), the benzotriazole-N of Fmoc protection, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (HBTU), I-hydroxybenzotriazole (HoBt) are dissolved in dimethyl formamide (DMF) respectively, add diisopropylethylamine (DIEA) and start Acibenzolar; Carry out under the reaction normal temperature, the system argon shield, Fmoc-Arg (OtBu)-OH usage quantity is 2.5～3 times of Fmoc-Tyr (tBu)-Wang resin, N '-tetramethyl-urea phosphofluoric acid ester (HBTU) and I-hydroxybenzotriazole (HoBt) are amino acid whose 2 times, diisopropylethylamine (DIEA) is amino acid whose 2 times, after the startup system joined and add in the solid phase synthetic instrument of handling resin well, mechanical stirring 45 minutes, wash out resin on the wall with dimethyl formamide (DMF), restir was taken out after 15 minutes; Dimethyl formamide (DMF) solution is given a baby a bath on the third day after its birth inferior, each three minutes; The indenes check reagent detects colourless, and circulation is so far finished;
3. more respectively with Fmoc-Asp (OtBu)-OH, Fmoc-Lys (PEG)-OH, and Fmoc-Arg (pbf)-OH is an amino acid starting material, more than the repetition 1., 2. step, finish the synthetic of mPEG-TP5 in turn, get product, the structure of product is: H-Arg-Lys (mPEG)-Asp-Val-Tyr-OH;
4. 1. take off the Fmoc protection by above-mentioned b, the indenes check reagent detects and is blue, and system is washed earlier 2 times with methylene dichloride (DCM), and methyl alcohol (MeOH) is washed once, each three minutes; Use methylene dichloride (DCM) to wash again 1 time, MeOH washes 2 times, each three minutes; Remove agitator,, use vacuum pump (SHB-III) to take out 2 hours more with the circulation ability of swimming with plug sealing synthesizer upper end, add cutting reagent, reacted 3 hours, and, collected cutting agent every 15 minutes mechanical stirring 1 minute, use trifluoroacetic acid (TFA) washing 2 times again, merge cutting agent and trifluoroacetic acid (TFA), system is under 40 ℃, and the decompression rotation is drained, add the aqueous solution dissolving of 20% Glacial acetic acid, freeze-drying; With distilled water lyophilized powder is dissolved, filter out water-insoluble, with dialysis tubing dialysis 48 hours, freeze-drying; Rp-hplc (RP-HPLC) is further purified, and elutriant is acetonitrile and the water that contains 0.1%TFA.
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