CN105085603B - A kind of load type platinum complex oxidant that can be recycled and its preparation method and application - Google Patents
A kind of load type platinum complex oxidant that can be recycled and its preparation method and application Download PDFInfo
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Abstract
The invention discloses a kind of load type platinum complex oxidant that can be recycled, and it is the silicon dioxide microsphere of load tetravalence platinum complex, and it has such as formula（Ⅰ）Shown structure, formula（Ⅰ）In shown structure：N=3, M Pt4+, Y is 1 valency halogen ion, and silicon dioxide microsphere particle diameter is 100nm ~ 2000nm.Present invention also offers the preparation method of the oxidant, a）Using toluene as solvent, by silicon dioxide microsphere and silicone agent heating reflux reaction, white solid thing is obtained；b）By gained white solid thing divalence platinum complex stirring reaction, pale solid thing is obtained；c）By pale solid thing and H2O2/ hydrochloric acid mixed solution, chlorine or bromine are fully reacted, and obtain support type tetravalence platinum complex oxidant.This support type oxidant is prepared simply, and can be recycled after regeneration treatment, and the yield of synthesized oxidized form polypeptide is not recycled number by oxidant to be influenceed, and the recovery and regeneration treatment of oxidant are simple.
Description
Technical field
The present invention relates to support type oxidant, specifically a kind of load type platinum complex oxidant that can be recycled
And its preparation method and application.
Background technology
Polypeptide drug containing intramolecular disulfide bond has been used to the treatment of various diseases, such as：The life for the treatment of cancer
Long chalone, calcitonin, uterotonics oxytocins, antiplatelet drug eptifibatide, the treating diabetes for treating Paget ' s diseases
The polypeptide drugs such as medicine pramlintide.At present, largely the polypeptide containing intramolecular disulfide bond is developed, and promotes polypeptide
The development of medicine（Nature Chem., 2014, 6, 1009–1016; Eur. J. Med. Chem., 2014, 77,
248–257; Future Med. Chem., 2009, 1, 361–377.）.The generation of polypeptide drug intramolecular disulfide bond is
An important reaction in fine organic chemical industry and pharmaceutical chemistry.
In the building-up process of the polypeptide drug containing intramolecular disulfide bond, the synthesis of disulfide bond is its pass in peptide molecule
Key step, typically using method for oxidation, homogeneous oxidizing synthesizes in the solution at present.
Being presently used for the oxidant that polypeptide drug intramolecular disulfide is bonded to includes：Iodine, thallium trifluoroacetate (III), oxygen
Gas, DMSO, oxidized form of glutathione and Ellman ' s reagents etc..But these oxidants are for synthesis polypeptide intramolecular two
During sulfide linkage, with residues such as the methionine in polypeptide chain, tyrosine, tryptophans side reaction occurs for some meetings, and some meetings give birth to polypeptide
Into dimer or the accessory substance of polymer, yield is caused to reduce, and these oxidants can not all regenerate and be recycled, and have
Oxidant even can produce the larger accessory substance of toxicity (Eur. J. Org. Chem., 2014, 3519–3530; RSC Adv. 2014, 4, 13854–13881; Synthesis, 2008, 16, 2491–2509.) 。
In addition to above-mentioned conventional oxidant, what tetravalence platinum complex oxidant obtained in synthetic drug intramolecular disulfide bond
It is widely applied, and oxidation effectiveness is superior to presently used other oxidants（J. Am. Chem. Soc. 2000, 122,
6809–6815; J. Org. Chem. 1999, 64, 4590–4595; Bioorg.Med. Chem. Lett. 2002,12, 2237–2240.）.But platinum complex due to it is expensive, the reason such as be not easy to prepare and limit its application, therefore,
If a kind of recyclable platinum complex oxidant can be prepared, it can substantially reduce and carry out synthetic drug using such oxidant
Cost payout during intramolecular disulfide bond.
The content of the invention
An object of the present invention is to provide a kind of load type platinum complex oxidant that can be recycled and application, solves
Existing platinum complex oxidant when being used for synthesis polypeptide intramolecular disulfide bond can not recycling the problem of.
The second object of the present invention is to provide a kind of preparation method for the load type platinum complex oxidant that can be recycled.
What an object of the present invention was realized in：
A kind of load type platinum complex oxidant that can be recycled, it is micro- for the silica of load tetravalence platinum complex
Ball, it has such as formula（Ⅰ）Shown structure：
（Ⅰ）
Formula（Ⅰ）In shown structure：N=3, M Pt4+, Y is -1 valency halogen ion, silicon dioxide microsphere particle diameter be 100nm ~
2000nm。
The load type platinum complex oxidant of the present invention that can be recycled, the Y are Cl-Or Br-。
The load type platinum complex oxidant of the present invention that can be recycled, the silicon dioxide microsphere particle diameter are
500nm。
Present invention also offers the load type platinum complex oxidant in the polypeptide containing intramolecular disulfide bond is prepared
Using.
The application can be specifically achieved through the following technical solutions：
Silicon dioxide microsphere and the reduced form polypeptide solution of tetravalence platinum complex concussion reaction at ambient temperature will be loaded
0.5-6 h, after reaction terminates, centrifuge, sediment and the supernatant containing reaction product is separately recovered；Utilize efficient liquid phase
Reaction product in chromatographic isolation supernatant；The silica of load tetravalence platinum complex is regenerated after sediment regeneration treatment
Microballoon, recycle.
The silicon dioxide microsphere of the load tetravalence platinum complex is with the reduced form polypeptide amount ratio with tetravalence platinum with going back
Prototype polypeptide mol ratio is advisable for 1 ~ 1.5: 1.
The reduced form polypeptide solution is using reduced form polypeptide as solute, with NaAc_HAc buffer solution or acetic acid-vinegar
The mixed liquor of sour sodium cushioning liquid and acetonitrile is made up of solvent；In the mixed liquor of the NaAc_HAc buffer solution and acetonitrile
The volume ratio of NaAc_HAc buffer solution and acetonitrile is 1: 1.
The reduced form polypeptide is reduced form polypeptide containing sulfydryl, can to form intramolecular disulfide bond, is specifically included
Reduced form polypeptide (1), reduced form polypeptide (2), reduced form polypeptide (3), reduced form RGD peptide and reduced form oxytocins.The reduction
The amino acid sequence of type polypeptide (1) is：Ac-Cys-Pro-Phe-Cys-NH2；The reduced form polypeptide（2）Amino acid sequence
For：Ac-Thr-Cys-Pro-Phe-Cys-Arg-NH2；The reduced form polypeptide（3）Amino acid sequence be：Ac-Cys-Thr-
Ile-Gln-Asn-Cys-Pro-Leu-Gly-NH2；The amino acid sequence of the reduced form RGD peptide is：Ac-Cys-Arg-Gly-
Asp-Lys-Gly-Pro-Asp-Cys-NH2；The amino acid sequence of the reduced form oxytocins is：Ac-Cys-Tyr-Ile-
Gln-Asn-Cys-Pro-Leu-Gly-NH2。
What the second object of the present invention was realized in：
A kind of preparation method for the load type platinum complex oxidant that can be recycled,
a）Using toluene as solvent, by silicon dioxide microsphere and silicone agent in mass ratio 1: 2 ~ 6, in 110 ~ 130 DEG C of bars
12 ~ 50h of heating reflux reaction under part；
Reaction is finished, and is filtered after reaction system is cooled into room temperature, and gained solid is dried in vacuo after being washed with ethanol, is obtained
White solid thing；
b）By gained white solid thing ultrasonic disperse in water, divalence platinum complex is then added, 40 ~ 50 DEG C are stirred, instead
Answer 15 ~ 20h；
Reaction is finished, and is filtered after being cooled to room temperature, and gained solid is dried in vacuo after being washed with ethanol, obtains pale solid
Thing；
c）By pale solid thing in DMF after ultrasonic disperse, under the conditions of 20 ~ 50 DEG C with H2O2/ hydrochloric acid mixed solution, chlorine
Or bromine is fully reacted；
Reaction finishes, and centrifuges, and is dried in vacuo after the washing of gained solid, and obtained light yellow solid thing is described negative
Load type platinum complex oxidant.
The preparation method of the load type platinum complex oxidant of the present invention that can be recycled, the silicone agent are
N-（Aminoethyl）--aminopropyl trimethoxysilane.
The preparation method of the load type platinum complex oxidant of the present invention that can be recycled, the divalence platinum complex
For cis Pt (en) Cl2；In mol, the dosage of the divalence platinum complex is not less than the dosage of the silicone agent.
The preparation method of the load type platinum complex oxidant of the present invention that can be recycled, the silicon dioxide microsphere
Particle diameter is 100 ~ 2000nm, preferably 300 ~ 600nm.
The preparation method of the load type platinum complex oxidant of the present invention that can be recycled,
Step c）Specifically：Pale solid thing after ultrasonic disperse, is passed through chlorine 0.5 in DMF under the conditions of 20 ~ 50 DEG C
~ 6h is reacted；
Reaction finishes, and centrifuges, and is dried in vacuo after the washing of gained solid, and obtained light yellow solid thing is described negative
Load type platinum complex oxidant.
The preparation method of the load type platinum complex oxidant of the present invention that can be recycled,
Step c）Specifically：Pale solid thing is added into bromine shake in DMF after ultrasonic disperse, under the conditions of 20 ~ 50 DEG C
Swing 1 ~ 3h of reaction；In mol, the dosage of the bromine is not less than the dosage of the divalence platinum complex；
Reaction finishes, and centrifuges, and is dried in vacuo after the washing of gained solid, and obtained light yellow solid thing is described negative
Load type platinum complex oxidant.
The preparation method of the load type platinum complex oxidant of the present invention that can be recycled,
Step c）Specifically：After ultrasonic disperse, H is added under the conditions of 20 ~ 50 DEG C in DMF for pale solid thing2O2- salt
5 ~ 8h of sour mixed liquor concussion reaction；The H2O2H in-hydrochloric acid mixed solution2O2With hydrochloric acid（1.0mol/L）Volume ratio be 1: 1；With
H2O2The molar amount of institute's chloride ion-containing, the H in-hydrochloric acid mixed solution2O2The dosage of-hydrochloric acid mixed solution is not less than the divalence
2 times of platinum complex dosage；
Reaction finishes, and centrifuges, and is dried in vacuo after the washing of gained solid, and obtained light yellow solid thing is described negative
Load type platinum complex oxidant.
The oxidant of the present invention and its preparation have many advantages：
1st, this support type oxidant is prepared simple, and can be recycled after regeneration treatment, and synthesized oxidized form is more
The yield of peptide is not recycled number by this oxidant to be influenceed.
2nd, relative to conventional oxidation agent, have yield high when generating oxidized form polypeptide using this support type is oxidizing
Advantage.
3rd, after synthesis polypeptide intramolecular disulfide bond, the recovery and regeneration treatment of oxidant are simple, this support type oxidant
After being reacted with reduced form polypeptide, by filtering or centrifuging, you can reach the purpose of recovery oxidant, the oxidant reclaimed
Reused after regeneration treatment.
Brief description of the drawings
Fig. 1 is that support type oxidant of the present invention prepares reacting flow chart.
Fig. 2 is the SEM scanning figures of oxidant of the present invention.
Fig. 3 is the distribution diagram of element of oxidant of the present invention.
Fig. 4 is the XPS testing results of oxidant of the present invention.
Fig. 5 is that reduced form RGD peptide contrasts with the chromatogram before and after oxidant reaction of the present invention.
Fig. 6 is chemical formula and the mass spectrogram contrast of reduced form RGD peptide and oxidized form RGD peptide.
Fig. 7 is between the yield of oxidized form RGD peptide and the recycling number of oxidant of the present invention prepared by embodiment 2
Relation.
Embodiment
Fig. 1 gives support type oxidant of the present invention and prepares reacting flow chart.It is as shown in figure 1, of the invention by silica
Microballoon and silicone agent（N-（Aminoethyl）--aminopropyl trimethoxysilane）Reaction, obtains ethylene diamine-modified titanium dioxide
Silicon microballoon（For white solid thing）, such as Fig. 1 Chinese styles（Ⅱ）It is shown；Ethylene diamine-modified silicon dioxide microsphere and cis dichloride second
Diamines closes platinum（Cis Pt（en）Cl2）Reaction, obtain loading the silicon dioxide microsphere of divalence platinum complex（Pale solid thing）,
Such as Fig. 1 Chinese styles（Ⅲ）It is shown；Oxidation reaction occurs for the silicon dioxide microsphere and chlorine for loading divalence platinum complex, obtains load four
The silicon dioxide microsphere of valency platinum complex（Light yellow solid thing）, such as Fig. 1 Chinese styles（Ⅰ）Shown, resulting load tetravalence platinum is matched somebody with somebody
The silicon dioxide microsphere of compound is support type tetravalence platinum complex oxidant of the present invention, its specific preparation process see embodiment 1 ~
3：
Embodiment 1
Silicon dioxide microsphere used in the present embodiment obtains to be purchased in market, particle diameter 500nm.
1. in 250 mL three-neck flasks, 2.0 g silicon dioxide microspheres and 150 mL dry toluenes are added, then add 5
g N-（Aminoethyl）--aminopropyl trimethoxysilane, magnetic agitation, 120oThe h of C back flow reactions 48；Cool down after completion of the reaction
To room temperature, filtering, gained solid washs 3 times with ethanol, and then 50oC is dried in vacuo 12h, obtains the ethylene diamine-modified of white
Silicon dioxide microsphere；
2. the ethylene diamine-modified silicon dioxide microspheres of 1.5g are added in 250mL three-necked bottle, 100mL is then added
Water, 0.3g cis Pt (en) Cl is added after ultrasonic disperse2, stirring, 50oC reacts 20h；Room temperature, mistake are cooled to after completion of the reaction
Filter, solid are washed 3 times with ethanol, are then dried in vacuo, and obtain the silicon dioxide microsphere of canescence load divalence platinum complex；
3. weighing the silicon dioxide microsphere of 0.1g load divalence platinum complexes in test tube, 10mL DMF, ultrasound point are added
Dissipate, then lead to chlorine 4h at room temperature；Centrifuge after completion of the reaction, solid is washed with water 3 times, then washs 3 times with ethanol, Ran Houzhen
Sky is dried overnight, and obtains the silicon dioxide microsphere of light yellow load tetravalence platinum complex.
The SEM results of the silicon dioxide microsphere of prepared load tetravalence platinum complex are as shown in Figure 2.
The silicon dioxide microsphere distribution diagram of element of prepared load tetravalence platinum complex is as shown in Figure 3.It can be known by Fig. 3
Road, tetravalence platinum complex have been loaded on silicon dioxide microsphere.
ICP-MS（Inductivity coupled plasma mass spectrometry）The platinum of the silicon dioxide microsphere of measure load tetravalence platinum complex
Content is 3.9 × 10-4mol/g.XPS results such as Fig. 4 of the silicon dioxide microsphere of tetravalence platinum complex is loaded, is determined using XPS
Divalence platinum and platinic ratio in the silicon dioxide microsphere of tetravalence platinum complex are loaded, tetravalence platinum is determined according to the load capacity of platinum
Content be 2.1 × 10-4mol/g。
Embodiment 2
Silicon dioxide microsphere used in the present embodiment obtains to be purchased in market, particle diameter 100nm.
1. in 250 mL three-neck flasks, 2.0 g silicon dioxide microspheres and 150 mL dry toluenes are added, then add 5
g N-（Aminoethyl）--aminopropyl trimethoxysilane, magnetic agitation, 130oThe h of C back flow reactions 20；Cool down after completion of the reaction
To room temperature, filtering, gained solid washs 3 times with ethanol, and then 50oC is dried in vacuo 12h, obtains the ethylene diamine-modified of white
Silicon dioxide microsphere；
2. the ethylene diamine-modified silicon dioxide microspheres of 1.5g are added in 250mL three-necked bottle, 100mL is then added
Water, 0.3g cis Pt (en) Cl is added after ultrasonic disperse2, stirring, 40oC reacts 20h；Room temperature, mistake are cooled to after completion of the reaction
Filter, solid are washed 3 times with ethanol, are then dried in vacuo, and obtain the silicon dioxide microsphere of canescence load divalence platinum complex；
3. weighing the silicon dioxide microsphere of 0.1g load divalence platinum complexes in test tube, 10mL DMF, ultrasound point are added
Dissipate, then add 10 mL bromines, concussion reaction 2.5h；Centrifuge after completion of the reaction, solid is washed with water 3 times, then is washed with ethanol
Wash 3 times, be then dried in vacuum overnight, obtain the silicon dioxide microsphere of light yellow load tetravalence platinum complex.
Embodiment 3
Silicon dioxide microsphere used in the present embodiment obtains to be purchased in market, particle diameter 2000nm.
1. in 250 mL three-neck flasks, 2.0 g silicon dioxide microspheres and 150 mL dry toluenes are added, then add 5
g N-（Aminoethyl）--aminopropyl trimethoxysilane, magnetic agitation, 110oThe h of C back flow reactions 30；Cool down after completion of the reaction
To room temperature, filtering, gained solid washs 3 times with ethanol, and then 50oC is dried in vacuo 12h, obtains the ethylene diamine-modified of white
Silicon dioxide microsphere；
2. the ethylene diamine-modified silicon dioxide microspheres of 1.5g are added in 250mL three-necked bottle, 100mL is then added
Water, 0.3g cis Pt (en) Cl is added after ultrasonic disperse2, stirring, 40oC reacts 15h；Room temperature, mistake are cooled to after completion of the reaction
Filter, solid are washed 3 times with ethanol, are then dried in vacuo, and obtain the silicon dioxide microsphere of canescence load divalence platinum complex；
3. weighing the silicon dioxide microsphere of 0.1g load divalence platinum complexes in test tube, 10mL DMF, ultrasound point are added
Dissipate, then add 20mL H2O2- hydrochloric acid mixed solution（With 1.0mol/L hydrochloric acid and H2O21: 1 mixing by volume）, concussion is instead
Answer 5h；Centrifuge after completion of the reaction, solid is washed with water 3 times, then is washed 3 times with ethanol, is then dried in vacuum overnight, obtains shallow
Yellow loads the silicon dioxide microsphere of tetravalence platinum complex.
Embodiment 4
The oxidant of the present invention（Load the silicon dioxide microsphere of tetravalence platinum complex）Can be with a variety of going back containing sulfydryl
Prototype polypeptide reacts synthesis polypeptide intramolecular disulfide bond.
The silicon dioxide microsphere of load tetravalence platinum complex is synthesized with the reduced form polypeptide containing sulfydryl by following scheme
Disulfide bond in peptide molecule：By the silicon dioxide microsphere of load tetravalence platinum complex and reduced form polypeptide solution at ambient temperature
Concussion reaction 0.5-6 h, after reaction terminates, centrifuge, sediment and the supernatant containing reaction product is separately recovered；Utilize
Reaction product in high performance liquid chromatography separation supernatant, and reaction product is identified by mass spectrum；At sediment regeneration
The silicon dioxide microsphere of load tetravalence platinum complex is regenerated after reason, is recycled.
The also oxidable a variety of reduced form polypeptides containing sulfydryl of oxidant of the present invention, such as reduced form polypeptide (1), reduced form
Polypeptide (2), reduced form polypeptide (3), reduced form RGD peptide and reduced form oxytocins etc., the reduced form and oxidized form ammonia of these polypeptides
Base acid sequence is as follows：
Specifically, utilize the oxidizing above-mentioned reduced form polypeptide of the support type prepared by embodiment 1, specific course of reaction
It is as follows：
First, the silicon dioxide microsphere and reduced form polypeptide of tetravalence platinum complex are loaded（1）Reaction
The NaAc_HAc buffer solution of pH=4.65 by volume 1:1 ratio adds acetonitrile and obtains mixed solution, mixes
It is standby to close the logical nitrogen 1h of solution；In 20mL reaction bulb, it is 5.3 × 10 to prepare 8mL concentration with the mixed solution of preparation-4mol/
L reduced form polypeptide（1）Solution, the silicon dioxide microsphere of 0.1g load tetravalence platinum complexes, room are then added into reaction bulb
Warm concussion reaction 1h.
Reaction terminates, and reaction system is centrifuged, and gained liquid phase liquid chromatogram separation product, is produced with mass spectroscopy after centrifugation
The molecular weight of thing is：508.1681, the result meets the oxidized form polypeptide to form intramolecular disulfide bond（1）Signal peak；Yield
For 75%；Gained solid phase carries out regeneration treatment after centrifugation, and specific method is by solid phase dispersion into DMF, is completed with chlorine oxidation 4h
Regeneration（Specific non-regenerative operating procedure and step 3 in embodiment 1）Condition is identical）.
By the oxidant after regeneration again with same amount of reduced form polypeptide（1）Reaction, in this way, repeating experiment 5 times, oxidized form
Polypeptide（1）Yield scope be 69-75%.
2nd, the silicon dioxide microsphere and reduced form polypeptide of tetravalence platinum complex are loaded（2）Reaction
The NaAc_HAc buffer solution of pH=5.5 by volume 1:1 ratio adds acetonitrile and obtains mixed solution, mixes
It is standby that solution leads to nitrogen 1h；Weigh 3.1mg reduced form polypeptides（2）It is added in 20mL reaction bulb, it is molten adds 10mL mixing
Liquid dissolves polypeptide, obtains concentration as 4.0 × 10-4Mol/L reduced form polypeptide（2）Solution, 0.1g is then added into reaction bulb
Load the silicon dioxide microsphere of tetravalence platinum complex, room temperature concussion reaction 1.5h.
Reaction terminates, and reaction system is centrifuged, and gained liquid phase liquid chromatogram separation product, is produced with mass spectroscopy after centrifugation
The molecular weight of thing is：765.3161 the result meets oxidized form polypeptide（2）Plus hydrionic mass signal peak；Institute after centrifugation
Obtain solid phase and carry out regeneration treatment, specific method is by solid phase dispersion into DMF, completes to regenerate with chlorine oxidation 4h.
By the oxidant after regeneration again with same amount of reduced form polypeptide（2）Reaction, in this way, repeating experiment 5 times, oxidized form
Polypeptide（2）Yield scope be 73-80%.
3rd, the silicon dioxide microsphere and reduced form polypeptide of tetravalence platinum complex are loaded（3）Reaction
The NaAc_HAc buffer solution of pH=6 by volume 1:1 ratio adds acetonitrile and obtains mixed solution, and mixing is molten
It is standby that liquid leads to nitrogen 1h；Weigh 4.8mg reduced form polypeptides（3）It is added in 20mL reaction bulb, adds 10mL mixed solutions
Polypeptide is dissolved, obtains concentration as 5.0 × 10-4Mol/L reduced form polypeptide（3）Solution, 0.1g is then added into reaction bulb and is born
Carry the silicon dioxide microsphere of tetravalence platinum complex, room temperature concussion reaction 1.5h.
Reaction terminates, and reaction system is centrifuged, and gained liquid phase liquid chromatogram separation product, is produced with mass spectroscopy after centrifugation
The molecular weight of thing is：945.4262 the result meets oxidized form polypeptide（3）Plus hydrionic mass signal peak；Institute after centrifugation
Obtain solid phase and carry out regeneration treatment, specific method is by solid phase dispersion into DMF, completes to regenerate with chlorine oxidation 4h.
By the oxidant after regeneration again with same amount of reduced form polypeptide（3）Reaction, in this way, repeating experiment 5 times, oxidized form
Polypeptide（3）Yield scope be 76-85%.
4th, the silicon dioxide microsphere and reduced form RGD peptide for loading tetravalence platinum complex react
The logical nitrogen 1h of the NaAc_HAc buffer solution of pH=5.5 is standby, weighs 5.0mg reduced form RGD peptides and is added to
In 20mL reaction bulb, 10mL cushioning liquid is added, obtains concentration as 5.2 × 10-4Mol/L reduced form RGD peptide solution,
Then the silicon dioxide microsphere of 0.1g load tetravalence platinum complexes, room temperature concussion reaction 0.5h are added into reaction bulb.
Reaction terminates, and reaction system is centrifuged, and gained liquid phase liquid chromatogram separation product, is produced with mass spectroscopy after centrifugation
The molecular weight of thing is：474.1944, the result meets the mass signal peak of oxidized form RGD peptide；Gained solid phase is carried out again after centrifugation
Raw processing, specific method are by solid phase dispersion into DMF, complete to regenerate with chlorine oxidation 4h.
Oxidant after regeneration is reacted with same amount of reduced form RGD peptide again, in this way, experiment 5 times is repeated, as a result as schemed
Shown in 7, the yield scope of oxidized form RGD peptide is 75-83%.
Silicon dioxide microsphere reaction of the reduced form RGD peptide solution in the present embodiment with loading tetravalence platinum complex is forward and backward
Chromatographic results contrasted, as a result as shown in Figure 5.As seen from Figure 5, reduced form RGD peptide is all oxidized to oxidized form
RG peptides.
Silicon dioxide microsphere reaction of the reduced form RGD peptide solution in the present embodiment with loading tetravalence platinum complex is forward and backward
Mass spectral results contrasted, as a result as shown in Figure 6.As seen from Figure 6, the molecular weight of mass spectroscopy reduced form RGD peptide is
475.20201 the molecular weight of mass spectroscopy reaction products therefrom is：474.1944, the result meets the mass spectrum of oxidized form RGD peptide
Signal peak.
5th, the silicon dioxide microsphere and reduced form oxytocins for loading tetravalence platinum complex react
The logical nitrogen 1h of the NaAc_HAc buffer solution of pH=4 is standby, weighs 5.0mg reduced form oxytocins and is added to 20mL
Reaction bulb in, add 10mL cushioning liquid, obtain concentration as 5.4 × 10-4Mol/L reduced form oxytocins solution, so
The silicon dioxide microsphere of 0.1g load tetravalence platinum complexes, room temperature concussion reaction 0.5h are added in backward reaction bulb.
Reaction terminates, and reaction system is centrifuged, and gained liquid phase liquid chromatogram separation product, is produced with mass spectroscopy after centrifugation
The molecular weight of thing is：1007.4412, the result meets the mass signal peak of oxidized form oxytocins；Gained solid phase is carried out after centrifugation
Regeneration treatment, specific method are by solid phase dispersion into DMF, complete to regenerate with chlorine oxidation 4h.
Oxidant after regeneration is reacted with same amount of reduced form oxytocins again, in this way, repeating experiment 5 times, oxidized form
The yield scope of oxytocins is 73-81%.
Comparative example 1
The NaAc_HAc buffer solution of pH=4.65 by volume 1:1 ratio adds acetonitrile and obtains mixed solution, mixes
It is standby to close the logical nitrogen 1h of solution；In 20mL reaction bulb, it is 5.3 × 10 to prepare 8mL concentration with the mixed solution of preparation-4mol/
L reduced form polypeptide（1）Solution, this solution and the oxygen reaction in air, magnetic agitation reaction 22h, reaction terminate.Yield is
45%。
Comparative example 2
It is standby that acetonitrile leads to nitrogen 1h；In 20mL reaction bulb, it is 5.3 × 10 to prepare 8mL concentration-4Mol/L reduced form
Polypeptide（1）Solution, 50 μ L triethylamines being added, then add the acetonitrile solution that 5mL contains 10mg iodine, react 16h, reaction terminates,
Excessive elemental iodine is removed, separates oxidized form polypeptide（1）, yield 60%.
Above example and experimental data show that support type oxidant of the invention can be used in the polypeptide point of different structure
The synthesis of disulfide bond in son.The oxidant of the present invention is compared with existing support type Ellman ' s oxidising agents, the oxidation of this support type
Agent is prepared simply, and can be recycled, and yield is not influenceed by number is recycled；With traditional oxidant such as iodine, oxygen,
DMSO is compared, and this support type oxidant also has the advantages of yield is high, such as when synthesizing oxidized form polypeptide (1), is made using oxygen
For oxidant, yield only has 45%；And by the use of elemental iodine as yield during oxidant be 60%.Synthesis polypeptide intramolecular disulfide bond
Afterwards, the purification processes of polypeptide are simple, and as well known to those skilled in the art when by the use of DMSO as oxidant, and polypeptide carries after reaction
It is pure to need to carry out multiple freeze-drying process, and DMSO is reduced to the very big dimethyl sulfide of toxicity, and this support type aoxidizes
Agent is led to using the mixed liquor of NaAc_HAc buffer solution or NaAc_HAc buffer solution and acetonitrile as reaction dissolvent after reaction
Filtering or centrifugation, you can reach the purpose of separation product.
Claims (3)
1. a kind of preparation method for the load type platinum complex oxidant that can be recycled, it is characterized in that,
a）Using toluene as solvent, by silicon dioxide microsphere and silicone agent in mass ratio 1: 2 ~ 6, under the conditions of 110 ~ 130 DEG C
12 ~ 50h of heating reflux reaction；
Reaction is finished, and is filtered after being cooled to room temperature, and gained solid is dried in vacuo after being washed with ethanol, obtains white solid thing；
b）By gained white solid thing ultrasonic disperse in water, divalence platinum complex is then added, 40 ~ 50 DEG C are stirred, reaction 15 ~
20h；
Reaction is finished, and is filtered after being cooled to room temperature, and gained solid is dried in vacuo after being washed with ethanol, obtains pale solid thing；
c）By pale solid thing in DMF after ultrasonic disperse, under the conditions of 20 ~ 50 DEG C with H2O2/ hydrochloric acid mixed solution, chlorine or liquid
Bromine fully reacts；
Reaction finishes, and centrifuges, and is dried in vacuo after the washing of gained solids, resulting light yellow solid thing is support type four
Valency platinum complex oxidant.
2. the preparation method for the load type platinum complex oxidant that can be recycled according to claim 1, it is characterized in that, institute
It is N- to state silicone agent（Aminoethyl）--aminopropyl trimethoxysilane.
3. the preparation method for the load type platinum complex oxidant that can be recycled according to claim 1, it is characterized in that, institute
It is Pt (en) Cl to state divalence platinum complex2。
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| CN109912477B (en) * | 2019-03-07 | 2020-12-29 | 河北大学 | Selenomethionine oxide, preparation method thereof and application thereof in synthesis of polypeptide intramolecular disulfide bond |
| WO2023190768A1 (en) * | 2022-03-30 | 2023-10-05 | 日本ゼオン株式会社 | Method for recovering platinum group element |
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