CN108904531A - A kind of organic platinum that can inhibit A beta replaces the preparation method of polyacid - Google Patents
A kind of organic platinum that can inhibit A beta replaces the preparation method of polyacid Download PDFInfo
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Abstract
A kind of organic platinum that can inhibit A beta replaces the preparation method of polyacid, it is related to a kind of preparation method of organic platinum substitution polyacid.The invention aims to solve the problem of that existing drug is only capable of mitigation alzheimer's disease cannot fundamentally treat.Method:One, vacant structure with Keggin polyacid is prepared;Two, (Me is prepared4N)3[PW11O40Si2C6H16N2];Three, (Me is prepared4N)3[PW11O40(SiC3H6NH2)2PtCl2], it can as inhibit the organic platinum of A beta to replace polyacid.It can inhibit the organic platinum of A beta that polyacid is replaced to show to inhibit the bioactivity of A beta in vivo and in vitro synthesized by the present invention;The organic platinum prepared by the present invention that can inhibit A beta replaces polyacid to can be used as the drug candidate for treating AD as a result,.The present invention can get a kind of organic platinum substitution polyacid that can inhibit A beta.
Description
Technical field
The present invention relates to the preparation methods that a kind of organic platinum replaces polyacid.
Background technique
Alzheimer's disease (AD) is one of the great difficult problem that modern medicine is faced.Its pathological characters is in nerve cell
There are neurofibrillary tangles, extracellularly have amyloid senile plaque deposition.To the drug treated, there are two main classes at present, i.e. gallbladder
Alkali esterase inhibitor and N-methyl-D-aspartate receptor antagonist.These drugs are only capable of mitigating the symptom of patient's presentation, without
Disease can fundamentally be treated.It is that AD recognized at present is most main since amyloid beta (A β) is the core component of senile plaque
One of pathogenic factor wanted.Morbid substance A β is reduced and removes to be expected to fundamentally treat AD.
Summary of the invention
The invention aims to solve existing drug to be only capable of mitigating alzheimer's disease, what cannot fundamentally be treated is asked
Topic, and a kind of preparation method of organic platinum substitution polyacid that can inhibit A beta is provided.
A kind of organic platinum that can inhibit A beta replaces the preparation method of polyacid, is completed by the following steps:
One, vacant structure with Keggin polyacid is prepared:
Sodium chloride is added to the phosphotungstic acid aqueous solution that temperature is 65 DEG C~75 DEG C, concentration is 0.1g/mL~0.3g/mL
In, then in the case where temperature is 68 DEG C~71 DEG C and mixing speed is 1000r/min~1200r/min it is stirred to react 3min~5min,
It is cooled to room temperature, obtains reaction solution I;The pH value of reaction solution I is adjusted to using the sodium bicarbonate solution that concentration is 1mol/L
4.5~5.5, then be filtered by vacuum, collect filtrate;Weight is carried out by cooling hot saturated solution crystallisation to the filtrate being collected into
The solid matter obtained after recrystallization is dried in the vacuum oven that temperature is 55 DEG C~60 DEG C 8h~12h, obtained by crystallization
Na7PW11O39·12H2O is denoted as PW11;
The quality and concentration of sodium chloride described in step 1 are the body of the phosphotungstic acid aqueous solution of 0.1g/mL~0.3g/mL
Product is than being (0.4g~1.2g):100mL;
Two, (Me is prepared4N)3[PW11O40Si2C6H16N2]:
1., aminopropyl triethoxysilane is add to deionized water, arrive aminopropyl triethoxysilane solution;
Step 2 1. described in aminopropyl triethoxysilane and deionized water volume ratio be (2~5):(150~
300);
2., by PW11It is dissolved into distilled water, obtains the PW that concentration is 2g/L~5g/L11Solution;
3., low whipping speed be that aminopropyl triethoxysilane solution is added to PW under 700r/min~800r/min11
In solution, reaction solution II is obtained;It reuses the hydrochloric acid that concentration is 1mol/L and the pH value of reaction solution II is adjusted to 1, then stirring
Speed is to be stirred to react for 24 hours~48h under 1000r/min~1200r/min, reuses G4 specification glass sand core funnel and carries out vacuum
It filters, obtains subnatant;
Step 2 3. described in aminopropyl triethoxysilane solution and PW11The volume ratio of solution is (0.1~0.2):
(0.6~1.2);
4., tetramethyl ammonium chloride is added in subnatant, then react 3min~8min at room temperature, then carry out vacuum
It filters, obtains solid matter;Solid matter is cleaned 3 times~5 times using deionized water first, isopropanol is reused and cleans 3 times
It~5 times, is finally cleaned solid matter 3 times~5 times using ether, then dries 8h~12h at being 55 DEG C~60 DEG C in temperature, obtained
(Me4N)3[PW11O40Si2C6H16N2], it is denoted as PW11-APTES;
Step 2 4. described in tetramethyl ammonium chloride quality and subnatant volume ratio be (1g~3g):
1200mL;
Three, (Me is prepared4N)3[PW11O40(SiC3H6NH2)2PtCl2]:
1., by PW11- APTES is dissolved into dimethylformamide, and obtaining concentration is 0.05mmol/L~0.3mmol/L's
PW11- APTES solution;
2., potassium tetrachloroplatinate is dissolved into dimethylformamide, obtaining concentration is 0.05mmol/L~0.15mmol/
Potassium tetrachloroplatinate solution;
3., by concentration be 0.05mmol/L~0.3mmol/L PW11- APTES solution is heated to 70 DEG C~80 DEG C, then plus
Enter the potassium tetrachloroplatinate solution that concentration is 0.05mmol/L~0.15mmol/L, then is reacted at being 70 DEG C~80 DEG C in temperature
40min~50min, then cooled to room temperature reuse Rotary Evaporators and rotate under conditions of temperature is 70 DEG C~80 DEG C
Evaporation, obtains (Me4N)3[PW11O40(SiC3H6NH2)2PtCl2], it is denoted as PtII-PW11, can as inhibit the organic of A beta
Platinum replaces polyacid;
Step 3 3. described in concentration be 0.05mmol/L~0.3mmol/L PW11- APTES solution is with concentration
The volume ratio of the potassium tetrachloroplatinate solution of 0.05mmol/L~0.15mmol/ is (1~5):(0.2~1.5).
The principle of the present invention:
One, organic platinum group is inhibited the fibre of amyloid beta by the present invention in conjunction with Keggin-type polyoxometallate
Dimensionization.Since polyacid has the bioactivity of anti-A beta, and organic group has preferable modification performance, can be with polyacid knot
It closes, helps improve the stability and biocompatibility of polyacid.In addition, platinum complexes can in conjunction with the histidine residues of A β,
Inhibit the fibrosis of A β;
Advantages of the present invention:
One, Keggin-type polyacid can effectively inhibit the fibrosis of amyloid beta, higher but there are toxic side effects,
And internal the disadvantages of stability is low, targeting is poor;Present invention consideration mutually ties it with biologically active organic compound
It closes, forms hybrid inorganic-organic materials, can will have complementary advantages, form low toxicity, stable structure with Keggin polyacid, improve scarce
The structural limitations of position structure with Keggin polyacid;
Two, organic or organometallic group is bonded with polyoxometallic acid anion, and polyacid and target biological molecules can be improved
The activity of interaction, so that the validity of drug and targeting is made to be significantly improved, and platinum complexes are to A beta
Inhibiting effect be also proven;In the present invention organic platinum replace polyacid, the A beta inhibitor being prepared with it is single
The inhibitor of structure is compared, and functional and Molecular interaction ability is stronger;
Three, simple synthetic method of the present invention is easy, and the synthesized organic platinum that can inhibit A beta replaces polyacid in body
The inside and outside bioactivity for showing to inhibit A beta;The organic platinum prepared by the present invention that can inhibit A beta takes as a result,
The drug candidate that can be used as treatment AD for polyacid, is particularly advantageous in that rejection ability is strong, bio-toxicity is low, to AD model mouse
Dysfunction have significant recovery effects.
The present invention can get a kind of organic platinum substitution polyacid that can inhibit A beta.
Detailed description of the invention
Fig. 1 is PW prepared by embodiment one11、PW11- APTES and PtII-PW11Infrared spectrogram;
Fig. 2 is PW prepared by embodiment one11、PW11- APTES and PtII-PW11's31P H NMR spectroscopy;
Fig. 3 is Pt prepared by embodiment oneII-PW11Electrospray ionization mass spectrum;
Fig. 4 is Pt prepared by embodiment oneII-PW11XPS result phenogram;
Fig. 5 is Pt prepared by embodiment oneII-PW11Pt 4f XPS spectrum;
The A β that Fig. 6 is 0.5mL, concentration is 20 μm of ol/L42SEM schemes after solution incubates 48h at being 37 DEG C in temperature;
The A β that Fig. 7 is 0.5mL, concentration is 20 μm of ol/L42Solution and 0.5mL, the Pt that concentration is 10 μm of ol/LII-PW11It is molten
SEM schemes after liquid incubates 48h at 37 DEG C jointly;
The A β that Fig. 8 is 0.5mL, concentration is 20 μm of ol/L42Solution and 0.5mL, the Pt that concentration is 20 μm of ol/LII-PW11It is molten
SEM schemes after liquid incubates 48h at 37 DEG C jointly;
The A β that Fig. 9 is 0.5mL, concentration is 20 μm of ol/L42Solution and 0.5mL, the Pt that concentration is 50 μm of ol/LII-PW11It is molten
SEM schemes after liquid incubates 48h at 37 DEG C jointly.
Specific embodiment
Specific embodiment one:Present embodiment is a kind of preparation side of organic platinum substitution polyacid that can inhibit A beta
Method is completed by the following steps:
One, vacant structure with Keggin polyacid is prepared:
Sodium chloride is added to the phosphotungstic acid aqueous solution that temperature is 65 DEG C~75 DEG C, concentration is 0.1g/mL~0.3g/mL
In, then in the case where temperature is 68 DEG C~71 DEG C and mixing speed is 1000r/min~1200r/min it is stirred to react 3min~5min,
It is cooled to room temperature, obtains reaction solution I;The pH value of reaction solution I is adjusted to using the sodium bicarbonate solution that concentration is 1mol/L
4.5~5.5, then be filtered by vacuum, collect filtrate;Weight is carried out by cooling hot saturated solution crystallisation to the filtrate being collected into
The solid matter obtained after recrystallization is dried in the vacuum oven that temperature is 55 DEG C~60 DEG C 8h~12h, obtained by crystallization
Na7PW11O39·12H2O is denoted as PW11;
The quality and concentration of sodium chloride described in step 1 are the body of the phosphotungstic acid aqueous solution of 0.1g/mL~0.3g/mL
Product is than being (0.4g~1.2g):100mL;
Two, (Me is prepared4N)3[PW11O40Si2C6H16N2]:
1., aminopropyl triethoxysilane is add to deionized water, arrive aminopropyl triethoxysilane solution;
Step 2 1. described in aminopropyl triethoxysilane and deionized water volume ratio be (2~5):(150~
300);
2., by PW11It is dissolved into distilled water, obtains the PW that concentration is 2g/L~5g/L11Solution;
3., low whipping speed be that aminopropyl triethoxysilane solution is added to PW under 700r/min~800r/min11
In solution, reaction solution II is obtained;It reuses the hydrochloric acid that concentration is 1mol/L and the pH value of reaction solution II is adjusted to 1, then stirring
Speed is to be stirred to react for 24 hours~48h under 1000r/min~1200r/min, reuses G4 specification glass sand core funnel and carries out vacuum
It filters, obtains subnatant;
Step 2 3. described in aminopropyl triethoxysilane solution and PW11The volume ratio of solution is (0.1~0.2):
(0.6~1.2);
4., tetramethyl ammonium chloride is added in subnatant, then react 3min~8min at room temperature, then carry out vacuum
It filters, obtains solid matter;Solid matter is cleaned 3 times~5 times using deionized water first, isopropanol is reused and cleans 3 times
It~5 times, is finally cleaned solid matter 3 times~5 times using ether, then dries 8h~12h at being 55 DEG C~60 DEG C in temperature, obtained
(Me4N)3[PW11O40Si2C6H16N2], it is denoted as PW11-APTES;
Step 2 4. described in tetramethyl ammonium chloride quality and subnatant volume ratio be (1g~3g):
1200mL;
Three, (Me is prepared4N)3[PW11O40(SiC3H6NH2)2PtCl2]:
1., by PW11- APTES is dissolved into dimethylformamide, and obtaining concentration is 0.05mmol/L~0.3mmol/L's
PW11- APTES solution;
2., potassium tetrachloroplatinate is dissolved into dimethylformamide, obtaining concentration is 0.05mmol/L~0.15mmol/
Potassium tetrachloroplatinate solution;
3., by concentration be 0.05mmol/L~0.3mmol/L PW11- APTES solution is heated to 70 DEG C~80 DEG C, then plus
Enter the potassium tetrachloroplatinate solution that concentration is 0.05mmol/L~0.15mmol/L, then is reacted at being 70 DEG C~80 DEG C in temperature
40min~50min, then cooled to room temperature reuse Rotary Evaporators and rotate under conditions of temperature is 70 DEG C~80 DEG C
Evaporation, obtains (Me4N)3[PW11O40(SiC3H6NH2)2PtCl2], it is denoted as PtII-PW11, can as inhibit the organic of A beta
Platinum replaces polyacid;
Step 3 3. described in concentration be 0.05mmol/L~0.3mmol/L PW11- APTES solution is with concentration
The volume ratio of the potassium tetrachloroplatinate solution of 0.05mmol/L~0.15mmol/ is (1~5):(0.2~1.5).
The advantages of present embodiment:
One, Keggin-type polyacid can effectively inhibit the fibrosis of amyloid beta, higher but there are toxic side effects,
And internal the disadvantages of stability is low, targeting is poor;Present embodiment considers itself and biologically active organic compound
It combines, forms hybrid inorganic-organic materials, can will have complementary advantages, form low toxicity, stable structure with Keggin polyacid, improve
The structural limitations of vacant structure with Keggin polyacid;
Two, organic or organometallic group is bonded with polyoxometallic acid anion, and polyacid and target biological molecules can be improved
The activity of interaction, so that the validity of drug and targeting is made to be significantly improved, and platinum complexes are to A beta
Inhibiting effect be also proven;In present embodiment organic platinum replace polyacid, the A beta inhibitor being prepared with
The inhibitor of single structure is compared, and functional and Molecular interaction ability is stronger;
Three, present embodiment simple synthetic method is easy, and the synthesized organic platinum that can inhibit A beta replaces polyacid
The bioactivity of inhibition A beta is shown in vivo and in vitro;What as a result, prepared by present embodiment can inhibit A beta
Organic platinum replaces polyacid to can be used as the drug candidate for the treatment of AD, is particularly advantageous in that rejection ability is strong, bio-toxicity is low, right
The dysfunction of AD model mouse has significant recovery effects.
Present embodiment can get a kind of organic platinum substitution polyacid that can inhibit A beta.
Specific embodiment two:The differences between this implementation mode and the specific implementation mode are that:Sodium chloride is added in step 1
Enter to temperature be 65 DEG C~70 DEG C, concentration is in the phosphotungstic acid aqueous solution of 0.1g/mL~0.2g/mL, then temperature be 68 DEG C~
70 DEG C are to be stirred to react 3min~4min under 1000r/min~1100r/min with mixing speed, are cooled to room temperature, obtain anti-
Answer liquid I;The pH value of reaction solution I is adjusted to 4.5~5 using the sodium bicarbonate solution that concentration is 1mol/L, then carries out vacuum pumping
Filtrate is collected in filter;The filtrate being collected into is recrystallized by cooling hot saturated solution crystallisation, by what is obtained after recrystallization
Solid matter dry 8h~10h in the vacuum oven that temperature is 55 DEG C~60 DEG C, obtains Na7PW11O39·12H2O is denoted as
PW11.Other steps are same as the specific embodiment one.
Specific embodiment three:One of present embodiment and specific embodiment one or two difference are:Institute in step 1
The volume ratio for the phosphotungstic acid aqueous solution that the quality and concentration for the sodium chloride stated are 0.1g/mL~0.2g/mL is (0.4g~0.8g):
100mL.Other steps are the same as one or two specific embodiments.
Specific embodiment four:One of present embodiment and specific embodiment one to three difference are:Step 2 1. in
The volume ratio of the aminopropyl triethoxysilane and deionized water is (2~3):(150~200).Other steps and specific
Embodiment one to three is identical.
Specific embodiment five:One of present embodiment and specific embodiment one to four difference are:Step 2 2. in
By PW11It is dissolved into distilled water, obtains the PW that concentration is 2g/L~3g/L11Solution.Other steps and specific embodiment one to
Four is identical.
Specific embodiment six:One of present embodiment and specific embodiment one to five difference are:Step 2 3. in
The aminopropyl triethoxysilane solution and PW11The volume ratio of solution is (0.1~0.2):(1.0~1.2).Other steps
It is identical as specific embodiment one to five.
Specific embodiment seven:One of present embodiment and specific embodiment one to six difference are:Step 2 4. in
The quality of the tetramethyl ammonium chloride and the volume ratio of subnatant are (1.54g~2g):1200mL.Other steps and specific
Embodiment one to six is identical.
Specific embodiment eight:One of present embodiment and specific embodiment one to seven difference are:Step 3 1. in
By PW11- APTES is dissolved into dimethylformamide, obtains the PW that concentration is 0.05mmol/L~0.1mmol/L11- APTES is molten
Liquid.Other steps are identical as specific embodiment one to seven.
Specific embodiment nine:One of present embodiment and specific embodiment one to eight difference are:Step 3 2. in
Potassium tetrachloroplatinate is dissolved into dimethylformamide, the tetrachloro that concentration is 0.05mmol/L~0.1mmol/ is obtained and closes platinic acid
Potassium solution.Other steps are identical as specific embodiment one to eight.
Specific embodiment ten:One of present embodiment and specific embodiment one to nine difference are:Step 3 3. in
The concentration is the PW of 0.05mmol/L~0.3mmol/L11- APTES solution and concentration are 0.05mmol/L~0.15mmol/
Potassium tetrachloroplatinate solution volume ratio be (1~2):(0.2~1.2).Other steps and one to nine phase of specific embodiment
Together.
Beneficial effects of the present invention are verified using following embodiment:
Embodiment one:A kind of organic platinum that can inhibit A beta replaces the preparation method of polyacid, is complete according to the following steps
At:
One, vacant structure with Keggin polyacid is prepared:
Sodium chloride is added to temperature is 70 DEG C, concentration is in the phosphotungstic acid aqueous solution of 0.2g/mL, then in temperature is 70 DEG C
It is to be stirred to react 5min under 1000r/min with mixing speed, is cooled to room temperature, obtains reaction solution I;It the use of concentration is 1mol/L
Sodium bicarbonate solution the pH value of reaction solution I is adjusted to 5, then be filtered by vacuum, collect filtrate;It is logical to the filtrate being collected into
The hot saturated solution crystallisation of supercooling is recrystallized, and the solid matter obtained after recrystallization is done in the vacuum that temperature is 60 DEG C
Dry 10h, obtains Na in dry case7PW11O39·12H2O is denoted as PW11;
The volume ratio for the phosphotungstic acid aqueous solution that the quality of sodium chloride described in step 1 is 0.2g/mL with concentration is
0.8g:100mL;
Two, (Me is prepared4N)3[PW11O40Si2C6H16N2]:
1., 3mL aminopropyl triethoxysilane is added in 200mL deionized water, arrive aminopropyl triethoxysilane
Solution;
2., by PW11It is dissolved into distilled water, obtains the PW that concentration is 3g/L11Solution;
3., low whipping speed be that 200mL aminopropyl triethoxysilane solution is added to 1200mL under 800r/min
PW11In solution, reaction solution II is obtained;It reuses the hydrochloric acid that concentration is 1mol/L and the pH value of reaction solution II is adjusted to 1, then stirring
Mixing speed is to be stirred to react for 24 hours under 1200r/min, reuses G4 specification glass sand core funnel and is filtered by vacuum, obtains lower layer
Clear liquid;
4., tetramethyl ammonium chloride is added in subnatant, then react 5min at room temperature, then be filtered by vacuum,
Obtain solid matter;Solid matter is cleaned 5 times using deionized water first, isopropanol is reused and cleans 5 times, finally use second
Ether cleans solid matter 5 times, then dries 10h at being 60 DEG C in temperature, obtains (Me4N)3[PW11O40Si2C6H16N2], it is denoted as
PW11-APTES;
Step 2 4. described in tetramethyl ammonium chloride quality and subnatant volume ratio be 1.54g:1200mL;
Three, (Me is prepared4N)3[PW11O40(SiC3H6NH2)2PtCl2]:
1., by PW11- APTES is dissolved into dimethylformamide, obtains the PW that concentration is 0.1mmol/L11- APTES is molten
Liquid;
2., potassium tetrachloroplatinate is dissolved into dimethylformamide, obtain the tetrachloro that concentration is 0.1mmol/ and close platinic acid
Potassium solution;
3., by concentration be 0.1mmol/L PW11- APTES solution is heated to 70 DEG C, and adding concentration is 0.1mmol/L's
Potassium tetrachloroplatinate solution, then 45min, then cooled to room temperature are reacted at being 70 DEG C in temperature, reuse Rotary Evaporators
Rotary evaporation under conditions of temperature is 80 DEG C, obtains (Me4N)3[PW11O40(SiC3H6NH2)2PtCl2], it is denoted as PtII-PW11,
The organic platinum of A beta can be as inhibited to replace polyacid;
Step 3 3. described in concentration be 0.1mmol/L PW11The tetrachloro that-APTES solution and concentration are 0.1mmol/L
The volume ratio for closing platinic acid potassium solution is 1:1.2.
Fig. 1 is PW prepared by embodiment one11、PW11- APTES and PtII-PW11Infrared spectrogram;
From fig. 1, it can be seen that PW11In spectrogram, wave number 1099cm-1And 1044cm-1Correspond to P-O vibration peak, 953cm-1Corresponding W
=O vibration peak, 807cm-1Corresponding W-O-W vibration peak, above several peak types represent typical Keggin-type structure.In addition, figure medium wave
Number 3403cm-1Locate the corresponding asymmetric stretching vibration of O-H, 1620cm-1Locate the bending vibration of corresponding H-O-H.Result explanation is logical
PH value of solution is overregulated, this paper is successfully prepared the PW of single omission11。
PW11In-APTES spectrogram, PW is represented11Characteristic peak ownership it is as follows:1080cm-1(P-O), 980cm-1And 894cm-1
(W=O), 810cm-1(W-O-W);In addition, 1483cm-1Locate the flexural vibrations peak of-CH2- in corresponding A PTES, 3041cm-1Place pair
Answer the stretching vibration peak of-CH2- in APTES, 3596cm-1Locate the stretching vibration peak of N-H in corresponding A PTES, and since hydrogen bond is made
Failed to show flexural vibrations peak in spectrogram with-NH2-.By upper, PW is showed in spectrogram simultaneously11With the chemistry in APTES
Key primarily determines the success of silane substituted.
PtII-PW11In spectrogram, PW is indicated11The peak ownership of functional group is as follows in-APTES:1483cm-1(- CH2-),
1080cm-1(P-O), 980cm-1(W=O), 810cm-1(W-O-W);In addition, wave number 3455cm-1Locate the stretching vibration of corresponding N-H
Peak, 3030cm-1The stretching vibration peak for locating corresponding-CH2-, relative to PW11Red shift occurs for the infrared results of-APTES, this two peak,
Side illustration PW11- APTES is coordinated with Pt;Meanwhile coordination destroys the hydrogen bond action of-NH2-, thus occurs
1654cm-1Locate the in-plane bending vibration peak of N-H.Infrared results tentative confirmation PW11- APTES and Pt is successfully coordinated.
To sum up, the successful preparation of each intermediate product of Fig. 1 infrared spectrum result tentative confirmation and final product PtII-PW11
Synthesis.
Fig. 2 is PW prepared by embodiment one11、PW11- APTES and PtII-PW11's31P H NMR spectroscopy;
As can be seen from Figure 2, PW11:31P NMR (400MHz, D2O, room temperature):δ=- 10.821ppm (s, 1P);Foundation document,
PW11Formant of the chemical shift shown in spectrogram at -10.821ppm belongs to Na7PW11O39·12H2Center P atom in O.
Since P spectrum test result is consistent with vacant polyacid, vacant PW is further demonstrated11Synthesis.
PW11-APTES:31P NMR (400MHz, DMSO, room temperature):δ=- 15.621ppm (s, 1P);APTES is added to cause
After silane substituted, the chemical environment around P atom is changed, so that its resonant field changes, is showed in phosphorus spectrum
To generate chemical shift.That is PW11Formant of the chemical shift at -15.602ppm belongs to PW in-APTES spectrogram11-
P in APTES, the result further determine that APTES and vacant polyacid form covalent bond.
PtII-PW11:31P NMR (400MHz, DMSO, room temperature):δ=- 15.60ppm (s, 1P);Compared to PW11-APTES
Test result, the chemical shift of P atom do not occur obviously to deviate, and illustrates that chemical environment locating for P atom does not change.It should
The result shows that:Pt2+With the coordination of silane last-in-chain(LIC) Amino End Group, the skeleton structure of polyacid will not be had an impact.
The above nuclear-magnetism result (Fig. 3-3) is analyzed in conjunction with document, further demonstrates PtII-PW11Successful system
It is standby.
Fig. 3 is Pt prepared by embodiment oneII-PW11Electrospray ionization mass spectrum;
As can be seen from Figure 3, occur apparent peak value at mass-to-charge ratio 955 and 1256, by molecule of the mass-to-charge ratio peak value at 955 from
Sub- peak is attributed to [PW11O40(SiC3H6NH2)2]3-, mass-to-charge ratio peak value is attributed to [PW in 1256 molecular ion peak11O40
(SiC3H6NH2)2PtCl2]3-·12H2O, the H in structure2O is from reactant phosphotungstic acid (H3PW12O40·nH2O the combination in)
Water.According to above-mentioned analysis, which confirms target compound PtII-PW11Structure be [PW11O40(SiC3H6NH2)2PtCl2]3-。
Fig. 4 is Pt prepared by embodiment oneII-PW11XPS result phenogram;
As can be seen from Figure 4, peak each in figure is belonged in conjunction with data as follows:35.8eV(W 4f7/2), 73.4eV (Pt 4f7/2),
100.2eV (Si 2p), 131.4eV (P 2p), 197.4eV (Cl 2p), 259.0eV (W 4d), 285.4eV (C 1s),
428.6eV (N 1s), 531.0eV (O 1s), 596.6eV (W 4s).From analyzing above:PtII-PW11In containing W, Pt,
The elements such as Si, P, Cl, C, N, O, element species and [PW11O40(SiC3H6NH2)2PtCl2]3-In contained element consistent (XPS cannot
Detect H).The result is further PtII-PW11Successful preparation provide strong proof.
Fig. 5 is Pt prepared by embodiment oneII-PW11Pt 4f XPS spectrum.
As can be seen from Figure 5, due to the 4f of Pt7/2Track and 4f5/2The combination of track can differ 1.7eV.Platinous 4f7/2Rail
Road, which is located at, to be combined at energy 72.77eV, tetravalence platinum 4f7/2Track, which is located at, to be combined at energy 76.22eV, is carried out using XPS Peak software
Fitting Analysis analyzes the valence distribution of Pt element in sample after peak-fit processing.This as the result is shown divalent platinum proportion compared with
Greatly, with PtII-PW11Synthesis be consistent.
Embodiment two:Replaced using the organic platinum that can inhibit A beta prepared by ThT fluorescence spectrum detection embodiment one
The ability of polyacid inhibition A beta:
1., in 0.27mg A β be added 0.5 μm of ol/L of 3mL embodiment one prepare PtII-PW11Solution, then in temperature
Degree is to incubate 48h at 37 DEG C, reuses ThT fluorescence spectrum fluorescence intensity, wherein control group is that 3mL 0.27mg A β is pure
Solution;
2., in 0.27mg A β be added 1 μm of ol/L of 3mL embodiment one prepare PtII-PW11Solution, then in temperature
It is to incubate 48h at 37 DEG C, reuses ThT fluorescence spectrum fluorescence intensity, wherein control group is that 3mL 0.27mg A β is pure molten
Liquid;
3., in 0.27mg A β be added 2 μm of ol/L of 3mL embodiment one prepare PtII-PW11Solution, then in temperature
It is to incubate 48h at 37 DEG C, reuses ThT fluorescence spectrum fluorescence intensity, wherein control group is that 3mL 0.27mg A β is pure molten
Liquid;
4., in 0.27mg A β be added 5 μm of ol/L of 3mL embodiment one prepare PtII-PW11Solution, then in temperature
It is to incubate 48h at 37 DEG C, reuses ThT fluorescence spectrum fluorescence intensity, wherein control group is that 3mL 0.27mg A β is pure molten
Liquid.
The result shows that embodiment two 1. in fluorescence intensity relative to the variation of control group be about 60%, embodiment two is 2.
In fluorescence intensity relative to the fluorescence intensity in the variation 4. of control group relative to control group variation close to 100%.Therefore,
The Pt of various concentrationII-PW11Inhibitory effect of the solution to fibrosis:5μM>2μM>1μM>0.5μM.This illustrates PtII-PW11Concentration
It is bigger, it is stronger to the inhibiting effect of fibrosis.Work as PtII-PW11Concentration be 5 μM when (PtII-PW11With A β42Molar ratio be 5:
2), to A β42Fibrosis achieve the effect that complete inhibition.
Embodiment three:The organic platinum that can inhibit A beta prepared by detection embodiment one is characterized using transmission and replaces polyacid
Inhibit the ability of A beta:
Characterizing the organic platinum that can inhibit A beta prepared by detection embodiment one using transmission replaces polyacid to inhibit A β fine
The ability of dimensionization is as shown in Fig. 6~9;
The A β that Fig. 6 is 0.5mL, concentration is 20 μm of ol/L42SEM schemes after solution incubates 48h at being 37 DEG C in temperature;
The A β that Fig. 7 is 0.5mL, concentration is 20 μm of ol/L42Solution and 0.5mL, the Pt that concentration is 10 μm of ol/LII-PW11It is molten
SEM schemes after liquid incubates 48h at 37 DEG C jointly;
The A β that Fig. 8 is 0.5mL, concentration is 20 μm of ol/L42Solution and 0.5mL, the Pt that concentration is 20 μm of ol/LII-PW11It is molten
SEM schemes after liquid incubates 48h at 37 DEG C jointly;
The A β that Fig. 9 is 0.5mL, concentration is 20 μm of ol/L42Solution and 0.5mL, the Pt that concentration is 50 μm of ol/LII-PW11It is molten
SEM schemes after liquid incubates 48h at 37 DEG C jointly;
As can be seen from Figure 6, the A β for being individually 20 μm of ol/L by concentration42After solution incubates 48h at being 37 DEG C in temperature, formation
Fiber is long and more;
From Fig. 7~Fig. 9 it is found that and working as A β42With PtII-PW11When common incubation, fiber, which tails off, to shorten.Wherein, when 0.5mL,
Concentration is the A β of 20 μm of ol/L42Solution and 0.5mL, the Pt that concentration is 10 μm of ol/LII-PW11Solution incubates at 37 DEG C jointly
48h, transmission photo show that fiber number significantly reduces;As 0.5mL, the A β that concentration is 20 μm of ol/L42Solution and 0.5mL, concentration
For the Pt of 20 μm of ol/LII-PW11Solution incubates 48h at 37 DEG C jointly, and fiber is reduced and shortened;When 0.5mL, concentration are 20 μ
The A β of mol/L42Solution and 0.5mL, the Pt that concentration is 50 μm of ol/LII-PW11Solution incubates 48h at 37 DEG C jointly, fiber
Growth is substantially achieved complete inhibition, i.e., with addition PtII-PW11The increase of concentration, A β42Gradually tail off at fibre weight, institute's shape
It is also shorter and shorter at the length of fiber.
Example IV:Replaced using the organic platinum that can inhibit A beta prepared by circular dichroism detector detection embodiment one more
Acid inhibits the ability of A beta:
By the A β of same concentrations42Respectively with the Pt of various concentrationII-PW11After incubating for 24 hours jointly, the circular dichroism of solution is measured
Spectrum.Wherein, the A β that concentration is 16 μm of ol/L is only added42When aqueous solution, the CD value of positive negative peak is respectively 6.1 and 7.2;It is added
PtII-PW11Afterwards, the relative altitude at the positive and negative peak CD is substantially reduced, and as the A β of 0.5mL, 16 μm of ol/L42Aqueous solution is added
0.5mL, the Pt that concentration is 8 μm of ol/LII-PW11The CD value of solution, positive negative peak is respectively 4.1 and 1.8;As 0.5mL, 16 μm of ol/L
A β42The Pt that 0.5mL is added in aqueous solution, concentration is 8 μm of ol/LII-PW11The CD value of solution, positive negative peak is respectively 2.8 and 1.6;
The Pt of 16 μm of ol/L is addedII-PW11Solution is relative to the Pt that 8 μm of ol/L are addedII-PW11The experimental group of solution, reduction amount will be more
Obviously.Should the result shows that:It is analyzed from secondary structure, PtII-PW11It is to inhibit A β by reducing the quantity of β-pleated sheet42Fibrosis
, and PtII-PW11Concentration it is higher, the inhibiting effect of β-pleated sheet is more obvious.
Embodiment five:It is taken using the organic platinum that can inhibit A beta prepared by immunofluorescence staining detection embodiment one
Inhibit the ability of A beta for polyacid:
After senile plaque on pathological section is identified by antibody, it is marked using green fluorescence.Wherein, in control group slice
There is no fluorescence spot, the fluorescence spot quantity in model group slice is more and area is big, illustrates that model group shows the bright of A β deposition
Aobvious pathological characters.Using PtII-PW11After treating to model mouse, the spot number and speck area in low dose group are all obvious
It reduces;Spot number is very few in high dose group, and reduction amount becomes apparent relative to low dose group, illustrates PtII-PW11It is logical
It crosses and reduces aβ protein deposition from pathogeny to treat AD.High dose group is more preferable to the effect for reducing A β deposition.
Claims (10)
1. the preparation method that a kind of organic platinum that can inhibit A beta replaces polyacid, it is characterised in that a kind of to inhibit A beta
The organic platinum of change replaces the preparation method of polyacid to be completed by the following steps:
One, vacant structure with Keggin polyacid is prepared:
Sodium chloride is added to temperature is 65 DEG C~75 DEG C, concentration is in the phosphotungstic acid aqueous solution of 0.1g/mL~0.3g/mL, then
It is stirred to react 3min~5min in the case where temperature is 68 DEG C~71 DEG C and mixing speed is 1000r/min~1200r/min, then is cooled down
To room temperature, reaction solution I is obtained;The pH value of reaction solution I is adjusted to 4.5 using the sodium bicarbonate solution that concentration is 1mol/L~
5.5, then be filtered by vacuum, collect filtrate;The filtrate being collected into is recrystallized by cooling hot saturated solution crystallisation,
The solid matter obtained after recrystallization is dried into 8h~12h in the vacuum oven that temperature is 55 DEG C~60 DEG C, is obtained
Na7PW11O39·12H2O is denoted as PW11;
The quality and concentration of sodium chloride described in step 1 are the volume ratio of the phosphotungstic acid aqueous solution of 0.1g/mL~0.3g/mL
For (0.4g~1.2g):100mL;
Two, (Me is prepared4N)3[PW11O40Si2C6H16N2]:
1., aminopropyl triethoxysilane is add to deionized water, arrive aminopropyl triethoxysilane solution;
Step 2 1. described in aminopropyl triethoxysilane and deionized water volume ratio be (2~5):(150~300);
2., by PW11It is dissolved into distilled water, obtains the PW that concentration is 2g/L~5g/L11Solution;
3., low whipping speed be that aminopropyl triethoxysilane solution is added to PW under 700r/min~800r/min11Solution
In, obtain reaction solution II;It reuses the hydrochloric acid that concentration is 1mol/L and the pH value of reaction solution II is adjusted to 1, then low whipping speed
To be stirred to react for 24 hours~48h under 1000r/min~1200r/min, reuses G4 specification glass sand core funnel and carry out vacuum pumping
Filter, obtains subnatant;
Step 2 3. described in aminopropyl triethoxysilane solution and PW11The volume ratio of solution is (0.1~0.2):(0.6
~1.2);
4., tetramethyl ammonium chloride is added in subnatant, then react 3min~8min at room temperature, then carry out vacuum pumping
Filter, obtains solid matter;Solid matter is cleaned 3 times~5 times using deionized water first, reuses isopropanol cleaning 3 times~5
It is secondary, it is finally cleaned solid matter 3 times~5 times, then dry 8h~12h at being 55 DEG C~60 DEG C in temperature, is obtained using ether
(Me4N)3[PW11O40Si2C6H16N2], it is denoted as PW11-APTES;
Step 2 4. described in tetramethyl ammonium chloride quality and subnatant volume ratio be (1g~3g):1200mL;
Three, (Me is prepared4N)3[PW11O40(SiC3H6NH2)2PtCl2]:
1., by PW11- APTES is dissolved into dimethylformamide, obtains the PW that concentration is 0.05mmol/L~0.3mmol/L11-
APTES solution;
2., potassium tetrachloroplatinate is dissolved into dimethylformamide, obtain four that concentration is 0.05mmol/L~0.15mmol/
Chlorine closes platinic acid potassium solution;
3., by concentration be 0.05mmol/L~0.3mmol/L PW11- APTES solution is heated to 70 DEG C~80 DEG C, adds dense
Degree is the potassium tetrachloroplatinate solution of 0.05mmol/L~0.15mmol/L, then reacts 40min at being 70 DEG C~80 DEG C in temperature
~50min, then cooled to room temperature reuse Rotary Evaporators rotary evaporation under conditions of temperature is 70 DEG C~80 DEG C,
Obtain (Me4N)3[PW11O40(SiC3H6NH2)2PtCl2], it is denoted as PtII-PW11, the organic platinum of A beta can as be inhibited to replace
Polyacid;
Step 3 3. described in concentration be 0.05mmol/L~0.3mmol/L PW11- APTES solution is with concentration
The volume ratio of the potassium tetrachloroplatinate solution of 0.05mmol/L~0.15mmol/ is (1~5):(0.2~1.5).
2. a kind of organic platinum that can inhibit A beta according to claim 1 replaces the preparation method of polyacid, feature
It is in step 1 sodium chloride being added to the phosphotungstic acid that temperature is 65 DEG C~70 DEG C, concentration is 0.1g/mL~0.2g/mL water-soluble
In liquid, then be stirred to react in the case where temperature is 68 DEG C~70 DEG C and mixing speed is 1000r/min~1100r/min 3min~
4min is cooled to room temperature, obtains reaction solution I;Using the sodium bicarbonate solution that concentration is 1mol/L by the pH value tune of reaction solution I
Section is to 4.5~5, then is filtered by vacuum, and filtrate is collected;The filtrate being collected into is carried out by cooling hot saturated solution crystallisation
The solid matter obtained after recrystallization is dried in the vacuum oven that temperature is 55 DEG C~60 DEG C 8h~10h, obtained by recrystallization
To Na7PW11O39·12H2O is denoted as PW11。
3. a kind of organic platinum that can inhibit A beta according to claim 1 replaces the preparation method of polyacid, feature
It is quality and the concentration of sodium chloride described in step 1 for the volume ratio of the phosphotungstic acid aqueous solution of 0.1g/mL~0.2g/mL
For (0.4g~0.8g):100mL.
4. a kind of organic platinum that can inhibit A beta according to claim 1 replaces the preparation method of polyacid, feature
The volume ratio of aminopropyl triethoxysilane and deionized water described in being step 2 1. is (2~3):(150~200).
5. a kind of organic platinum that can inhibit A beta according to claim 1 replaces the preparation method of polyacid, feature
By PW in being step 2 2.11It is dissolved into distilled water, obtains the PW that concentration is 2g/L~3g/L11Solution.
6. a kind of organic platinum that can inhibit A beta according to claim 1 replaces the preparation method of polyacid, feature
Aminopropyl triethoxysilane solution and PW described in being step 2 3.11The volume ratio of solution is (0.1~0.2):(1.0
~1.2).
7. a kind of organic platinum that can inhibit A beta according to claim 1 replaces the preparation method of polyacid, feature
The quality of tetramethyl ammonium chloride described in being step 2 4. and the volume ratio of subnatant are (1.54g~2g):1200mL.
8. a kind of organic platinum that can inhibit A beta according to claim 1 replaces the preparation method of polyacid, feature
By PW in being step 3 1.11- APTES is dissolved into dimethylformamide, and obtaining concentration is 0.05mmol/L~0.1mmol/L
PW11- APTES solution.
9. a kind of organic platinum that can inhibit A beta according to claim 1 replaces the preparation method of polyacid, feature
Potassium tetrachloroplatinate is dissolved into dimethylformamide in being step 3 2., obtain concentration be 0.05mmol/L~
The potassium tetrachloroplatinate solution of 0.1mmol/.
10. a kind of organic platinum that can inhibit A beta according to claim 1 replaces the preparation method of polyacid, feature
The PW that concentration described in being step 3 3. is 0.05mmol/L~0.3mmol/L11- APTES solution is with concentration
The volume ratio of the potassium tetrachloroplatinate solution of 0.05mmol/L~0.15mmol/ is (1~2):(0.2~1.2).
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