CN109836579A - A kind of spiro polymer and its preparation method and application - Google Patents
A kind of spiro polymer and its preparation method and application Download PDFInfo
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- 229920000642 polymer Polymers 0.000 title claims abstract description 120
- 125000003003 spiro group Chemical group 0.000 title claims abstract description 107
- 238000002360 preparation method Methods 0.000 title claims abstract description 53
- 239000000178 monomer Substances 0.000 claims abstract description 65
- 238000006243 chemical reaction Methods 0.000 claims abstract description 33
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 32
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 23
- 201000011510 cancer Diseases 0.000 claims abstract description 23
- 125000001931 aliphatic group Chemical group 0.000 claims abstract description 17
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000001257 hydrogen Substances 0.000 claims abstract description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 16
- 239000013067 intermediate product Substances 0.000 claims abstract description 13
- 230000001376 precipitating effect Effects 0.000 claims abstract description 9
- 125000003118 aryl group Chemical group 0.000 claims abstract description 5
- 125000000524 functional group Chemical group 0.000 claims abstract description 5
- 238000001914 filtration Methods 0.000 claims abstract description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 33
- 239000002904 solvent Substances 0.000 claims description 19
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 10
- 239000002246 antineoplastic agent Substances 0.000 claims description 5
- 229940041181 antineoplastic drug Drugs 0.000 claims description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 abstract description 25
- 239000005864 Sulphur Substances 0.000 abstract description 25
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 abstract description 10
- 229910052757 nitrogen Inorganic materials 0.000 abstract description 5
- 239000000126 substance Substances 0.000 abstract description 5
- 239000000523 sample Substances 0.000 abstract description 4
- 230000008685 targeting Effects 0.000 abstract description 2
- 238000009826 distribution Methods 0.000 description 21
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 19
- 239000001301 oxygen Substances 0.000 description 19
- 229910052760 oxygen Inorganic materials 0.000 description 19
- 239000000243 solution Substances 0.000 description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 238000012360 testing method Methods 0.000 description 12
- 239000002861 polymer material Substances 0.000 description 10
- 238000004458 analytical method Methods 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 8
- 229910052799 carbon Inorganic materials 0.000 description 8
- 230000005311 nuclear magnetism Effects 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 238000001228 spectrum Methods 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 230000004580 weight loss Effects 0.000 description 6
- 238000006116 polymerization reaction Methods 0.000 description 5
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- 238000002474 experimental method Methods 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 238000001291 vacuum drying Methods 0.000 description 4
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 3
- 238000004140 cleaning Methods 0.000 description 3
- 238000003501 co-culture Methods 0.000 description 3
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
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- 230000000242 pagocytic effect Effects 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
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- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- PFRUBEOIWWEFOL-UHFFFAOYSA-N [N].[S] Chemical compound [N].[S] PFRUBEOIWWEFOL-UHFFFAOYSA-N 0.000 description 1
- 239000003560 cancer drug Substances 0.000 description 1
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Abstract
The present invention relates to spiro polymer technical fields, more particularly, to a kind of spiro polymer and its preparation method and application.The structural formula of the spiro polymer is as follows:Wherein, R1Selected from aliphatic or aromatic functional groups, R2Selected from aliphatic functionality, R3Selected from any one of hydrogen or aliphatic functionality, n is positive integer.The preparation method of the spiro polymer includes the following steps: monomer A, monomer B and monomer C hybrid reaction, obtains intermediate product；Intermediate product is added in precipitating reagent and is precipitated, it is the spiro polymer that precipitating, which is collected by filtration,.The New-type spiro polymer that the present invention synthesizes contains aerobic, sulphur, nitrogen in structure, can be used as fluorescence probe substance, to the selective targeting of cancer cell, can be directly used for cancer cell lights label.
Description
Technical field
The present invention relates to spiro polymer technical fields, more particularly, to a kind of spiro polymer and preparation method thereof and answer
With.
Background technique
The polymerization of multiple groups part is to receive significant attention a kind of novel polymeric reaction in recent years, because it is controllable with product structure
Property, yield it is higher, reaction it is moderate the advantages that.2018, Tang Benzhong and Hu Rongrong etc. using sulphur simple substance, diamine, double isonitrile as raw material,
Using DMF and toluene as solvent, be not necessarily to catalyst, polythiourea can be synthesized by carrying out a step at room temperature, the polymer have to mercury from
Son has good cleaning effect.Spiro polymer (Spiro-polymers) is that one kind contains loop coil, two rings in structural unit
Shape structure shares a bond object material.Traditional spiro polymer generally first passes through small molecule list of the preparation containing loop coil
Body, then polymerize, reaction step is relatively complicated, and metallic catalyst is needed to be catalyzed.
The heteroatomic loop coil small molecule containing aerobic, nitrogen, sulphur etc. has been widely reported at present and can apply to biological field, but
It is also seldom reported at present containing heteroatomic spiro polymers such as aerobic sulphur nitrogen.And the research of spiro polymer is concentrated mainly on chemistry
The fields such as modification, photovoltaic applications, it is relatively fewer for its research in biological field.But loop coil itself is a kind of medicines structure
Molecule, if spiro-compound can be applied to biological level, can greatly speed up the development of spiro polymer class material into
Journey.
Currently, the early diagnosis means of cancer mainly have ultrasonic examination, multi-layer spiral CT and magnetic resonance imaging.As non-
Although the ultrasonic method of invasive inspection is smaller and easy to operate, low-cost to tissue injury, it is easy to be operated
The interference of personnel's experience, careful degree；And multi-layer spiral CT technology resolution ratio is much higher than ultrasonic examination, can objectively respond cancer comprehensively
The characteristic of disease is the important conventional means of current diagnosing cancer of liver, but in checking process intravenous administration diodone to people
Body has larger toxic side effect, reduces side effect even across improvement, but expensive, more suspected patient is made to be difficult to bear；
Magnetic resonance imaging belongs to efficient, non-invasive cancer detection means, but similarly there is high-cost problem.Therefore, it operates
Simply, at low cost, have no toxic side effect, the development and application of the apparent cancer early detection means of clarity high effect have become it is existing
The popular research of stage clinical research worker.
In view of this, the present invention is specifically proposed.
Summary of the invention
The first object of the present invention is to provide a kind of spiro polymer, containing aerobic, sulphur, nitrogen member in the spiro polymer
Element can be used as fluorescence probe substance, be directly used in label cancer cell.
The second object of the present invention is to provide a kind of preparation method of spiro polymer, and the preparation method is complete by a step
At without pre-synthesis spiromonomer, and reaction process meets the requirement of Green Chemistry without adding catalyst.
The third object of the present invention is to provide a kind of application of spiro polymer, which can be used as fluorescence spy
Needle is for detecting label cancer cell.
In order to realize above-mentioned purpose of the invention, the following technical scheme is adopted:
A kind of spiro polymer, structural formula are as follows:
Wherein, R1Selected from aliphatic or aromatic functional groups, R2Selected from aliphatic functionality, R3Selected from hydrogen or aliphatic official
Any one of can roll into a ball, n is positive integer.
Spiro polymer of the invention contains aerobic, sulphur, nitrogen in structure, can be used as fluorescence probe substance, directly use
In label cancer cell.Also, spiro polymer dissolubility of the invention is good, in chloromethanes, chloroform, tetrahydrofuran, N, N-
Dimethylformamide etc. improves the dissolubility of polymer, has widened polymer there are commonly can all dissolve in solvent
Application range.
Preferably, the R1Structure include following any:
Preferably, the R2Structure include following any :-CmH2m+1；Wherein m is selected from the integer between 1-6.
Preferably, the weight average molecular weight of the spiro polymer is 1000-80000.It is furthermore preferred that the spiro polymer
Weight average molecular weight be 2000-40000.
Preferably, the R2Structure be-C2H5.Using the spiro polymer of this structure, can further increase to cancer
The specific recognition of cell.
The present invention also provides a kind of preparation methods of spiro polymer, include the following steps:
Monomer A, monomer B and monomer C hybrid reaction, obtain intermediate product；
Intermediate product is added in precipitating reagent and is precipitated, it is the spiro polymer that precipitating, which is collected by filtration,；
Wherein, the structural formula of the monomer A isThe R1Selected from aliphatic or aromatic functional groups；It is described
The structural formula of monomer B isThe R2Selected from aliphatic functionality；The structural formula of the monomer C isThe R3Selected from any one of hydrogen or aliphatic functionality.
The preparation method of spiro polymer of the invention is not necessarily to catalyst, and reacts without removing water deoxygenation, in air atmosphere
Under can carry out, mild condition, and prepare products collection efficiency it is higher.
Preferably, the molar ratio of the monomer A, monomer B and monomer C are 1 ﹕ (0.8-1) ﹕ (0.8-1).It is furthermore preferred that institute
The molar ratio for stating monomer A, monomer B and monomer C is 1 ﹕, 1 ﹕ 1.
Preferably, monomer A, monomer B and monomer C are mixed with solvent, reaction obtains intermediate product.It is furthermore preferred that described
Solvent includes one of methylene chloride, chloroform and toluene or a variety of, preferably methylene chloride.
Preferably, the concentration of the monomer A in a solvent is 0.05-0.2mol/L.
Preferably, the precipitating reagent includes one or both of n-hexane and petroleum ether, preferably n-hexane.More preferably
, intermediate product is slowly added in the precipitating reagent under stirring.
Preferably, the R1Structure include following any:
Preferably, the R2Structure be CmH2m+1；Wherein m is selected from the integer between 1-6.It is furthermore preferred that m=2.
Preferably, the R3Selected from any one of hydrogen or aliphatic functionality.It is furthermore preferred that the R3For hydrogen.
Preferably, the temperature of the reaction is 0-50 DEG C, and the time of the reaction is 3-24h.It is furthermore preferred that the reaction
Temperature be 25-50 DEG C, time of the reaction is 12-18h.
Preferably, dry to get the spiro polymer after precipitating being collected by filtration.
The present invention also provides a kind of application of spiro polymer, the spiro polymer is used for fluorescent marker cancer cell.
Preferably, the spiro polymer is dissolved in good solvent, is co-cultured with cancer cell, it is glimmering to be carried out to cancer cell
Signal.
Wherein, it co-cultures condition and suitable condition of culture is selected according to the practical type of cell.Such as can at 37 DEG C,
The CO that volume fraction is 5%2It is cultivated in incubator.
Preferably, the cancer cell includes any in HeLa cell, HepG2 cell, A549 cell and MCF-7 cell
Kind.Preferably HeLa cell and HepG2 cell.
The good solvent preferably includes DMSO, has preferable biocompatibility.
Preferably, spiro polymer dissolved concentration in good solvent is 10-6-10-4Mol/L, more preferably 10- 5mol/L。
Preferably, the time of co-cultivation is 2-5h, preferably 3-4h, more preferably 3h.
The present invention also provides a kind of spiro polymers to prepare the application in anticancer drug.Such as anti-cervix cancer drug
And/or medicines resistant to liver cancer etc..Spiro polymer of the invention can be directly used for the label of cancer cell, can be used for anticancer drug
In containing, quickly and easily to detect target-oriented drug.
Compared with prior art, the invention has the benefit that
(1) present invention synthesizes a kind of New-type spiro polymer, contains aerobic, sulphur, nitrogen in structure, can be used as fluorescence probe
Substance is directly used in label cancer cell；And it is with good dissolubility, methylene chloride, chloroform, tetrahydrofuran,
There are commonly can Quan Rong in solvent for N,N-dimethylformamide etc.；
(2) preparation method of spiro polymer of the invention is not necessarily to pre-synthesis spiromonomer, and reaction process is not necessarily to
Catalyst is added, the requirement of Green Chemistry is met；
(3) spiro polymer of the invention is prepared into fluorescent reagent, to the selective targeting of cancer cell, can directly use
Label is lighted in cancer cell；
(4) spiro polymer of the invention can be used for preparing anticancer drug, contain etc. to anticancer drug, with quickly side
Just detection target-oriented drug.
Detailed description of the invention
It, below will be to specific in order to illustrate more clearly of the specific embodiment of the invention or technical solution in the prior art
Embodiment or attached drawing needed to be used in the description of the prior art be briefly described, it should be apparent that, it is described below
Attached drawing is some embodiments of the present invention, for those of ordinary skill in the art, before not making the creative labor
It puts, is also possible to obtain other drawings based on these drawings.
Fig. 1 is the infrared spectrogram for the spiro polymer that 1-6 of the embodiment of the present invention is prepared；Wherein, Figure 1A -1F distinguishes
For the infrared spectrogram of embodiment 1-6 spiro polymer P1, P2, P3, P4, P5 and P6 being prepared；
Fig. 2 is the nucleus magnetic hydrogen spectrum figure for the spiro polymer that 1-6 of the embodiment of the present invention is prepared；Wherein, Fig. 2A -2F distinguishes
For the nucleus magnetic hydrogen spectrum figure of embodiment 1-6 spiro polymer P1, P2, P3, P4, P5 and P6 being prepared；
Fig. 3 is the nuclear-magnetism carbon spectrogram for the spiro polymer that 1-6 of the embodiment of the present invention is prepared；Wherein, Fig. 3 A-3F distinguishes
For the nuclear-magnetism carbon spectrogram of embodiment 1-6 spiro polymer P1, P2, P3, P4, P5 and P6 being prepared；
Fig. 4 is the TGA curve graph for the spiro polymer that 1-6 of the embodiment of the present invention is prepared；
Fig. 5 is the imaging that the spiro polymer that the embodiment of the present invention 2 is prepared is used for HeLa cell and NIH 3T3 cell
Figure；Wherein, left side is light field, and right side is fluorescence field-blue；
Fig. 6 is the image that the spiro polymer that the embodiment of the present invention 2 is prepared is used for HepG2 cell and LO2 cell；
Wherein, left side is light field, and right side is fluorescence field-blue；
Fig. 7 is that the spiro polymer that the embodiment of the present invention 2 is prepared is thin in HeLa cell, NIH 3T3 cell, HepG2
Phagocytic rate in born of the same parents and LO2 cell；Wherein, Control represents control group；
Fig. 8 is that the spiro polymer that the embodiment of the present invention 2 is prepared is thin in HeLa cell, NIH 3T3 cell, HepG2
Fluorescence enhancement ratio I/I after 15min and 3h is co-cultured in born of the same parents and LO2 cell0；
Fig. 9 is that the spiro polymer that the embodiment of the present invention 2 is prepared is thin in HeLa cell, NIH 3T3 cell, HepG2
Apoptosis rate in born of the same parents and LO2 cell.
Specific embodiment
Technical solution of the present invention is clearly and completely described below in conjunction with the drawings and specific embodiments, but
Be it will be understood to those of skill in the art that it is following described embodiments are some of the embodiments of the present invention, rather than it is whole
Embodiment is merely to illustrate the present invention, and is not construed as limiting the scope of the invention.Based on the embodiments of the present invention, ability
Domain those of ordinary skill every other embodiment obtained without making creative work, belongs to guarantor of the present invention
The range of shield.The person that is not specified actual conditions in embodiment, carries out according to conventional conditions or manufacturer's recommended conditions.Agents useful for same
Or production firm person is not specified in instrument, is the conventional products that can be obtained by commercially available purchase.
The part device information that the present invention uses is as follows:
Gel permeation chromatograph (GPC): measurement weight average molecular weight and molecular weight distribution, WATERS company, the U.S., model
Waters 1515isocratic HPLC pump；Wherein, using THF as mobile phase, using Narrow distribution polystyrene as standard specimen, test
Temperature is 25 DEG C；
Nuclear Magnetic Resonance: Bruker company, model AV 400；
Infrared spectrometer: Brooker (ALPHA) spectrometer；
Fluorescence spectrophotometer spectrometer: Hitachi, model F-7000；
Ultraviolet-visible spectrometer: Beijing Pu Xi general instrument Corp., model TU-1901；
Confocal microscope: Nikon Instrument Ltd., model A1R One；
Flow cytometer: Beckman (Beckman) Kurt commerce and trade company, model FC500MCL.
Embodiment 1
The preparation method of spiro polymer is present embodiments provided, specific reaction equation is as follows:
The preparation method of the spiro polymer of the present embodiment includes the following steps:
(1) by the two of 67mg (0.5mmol) monomer A, 71mg (0.5mmol) monomer B, 82mg (0.5mmol) monomer C, 5mL
Chloromethanes is added in polymerization pipe, in air atmosphere, stops reaction after 18h is reacted at 50 DEG C, is cooled to room temperature, obtains centre
Product；
(2) intermediate product is added dropwise in n-hexane while stirring, there are a large amount of solids to be precipitated, after stirring 10min, taken out
Filter, obtained solid are put into vacuum drying oven dry 6h, obtain a kind of oxygen-containing sulphur nitrogen-spiro polymer P1, yield 79.3%.
Phenetic analysis, results of IR such as Fig. 1 (A) are carried out to the spiro polymer P1 that above-mentioned steps are prepared
Shown, shown in nucleus magnetic hydrogen spectrum result such as Fig. 2 (A), shown in nuclear-magnetism carbon spectrogram such as Fig. 3 (A), thermal weight loss result is as shown in Figure 4.
The weight average molecular weight M of GPC test P1w=8000, molecular weight distribution MWD=2.00.
Embodiment 2
The preparation method of spiro polymer is present embodiments provided, specific reaction equation is as follows:
The preparation method of the spiro polymer of the present embodiment includes the following steps:
(1) by the two of 67mg (0.5mmol) monomer A, 85mg (0.5mmol) monomer B, 82mg (0.5mmol) monomer C, 5mL
Chloromethanes is added in polymerization pipe, in air atmosphere, stops reaction after 18h is reacted at 50 DEG C, is cooled to room temperature, obtains centre
Product；
(2) intermediate product is added dropwise in n-hexane while stirring, there are a large amount of solids to be precipitated, after stirring 10min, taken out
Filter, obtained solid are put into vacuum drying oven dry 6h, obtain a kind of oxygen-containing sulphur nitrogen-spiro polymer P2, yield 76.0%.
Phenetic analysis, results of IR such as Fig. 1 (B) are carried out to the spiro polymer P2 that above-mentioned steps are prepared
Shown, shown in nucleus magnetic hydrogen spectrum result such as Fig. 2 (B), shown in nuclear-magnetism carbon spectrogram such as Fig. 3 (B), thermal weight loss result is as shown in Figure 4.
The weight average molecular weight M of GPC test P2w=13000, molecular weight distribution MWD=1.98.
Embodiment 3
The preparation method of spiro polymer is present embodiments provided, specific reaction equation is as follows:
The preparation method of the spiro polymer of the present embodiment includes the following steps:
(1) by 115mg (0.5mmol) monomer A, 71mg (0.5mmol) monomer B, 82mg (0.5mmol) monomer C, 5mL's
Methylene chloride is added in polymerization pipe, in air atmosphere, stops reaction after 18h is reacted at 50 DEG C, is cooled to room temperature, obtains
Between product；
(2) intermediate product is added dropwise in n-hexane while stirring, there are a large amount of solids to be precipitated, after stirring 10min, taken out
Filter, obtained solid are put into vacuum drying oven dry 6h, obtain a kind of oxygen-containing sulphur nitrogen-spiro polymer P3, yield 73.5%.
Phenetic analysis, results of IR such as Fig. 1 (C) are carried out to the spiro polymer P3 that above-mentioned steps are prepared
Shown, shown in nucleus magnetic hydrogen spectrum result such as Fig. 2 (C), shown in nuclear-magnetism carbon spectrogram such as Fig. 3 (C), thermal weight loss result is as shown in Figure 4.
The weight average molecular weight M of GPC test P3w=13600, molecular weight distribution MWD=1.91.
Embodiment 4
The preparation method of spiro polymer is present embodiments provided, specific reaction equation is as follows:
The preparation method of the spiro polymer of the present embodiment includes the following steps:
(1) by 115mg (0.5mmol) monomer A, 85mg (0.5mmol) monomer B, 82mg (0.5mmol) monomer C, 5mL's
Methylene chloride is added in polymerization pipe, in air atmosphere, stops reaction after 18h is reacted at 50 DEG C, is cooled to room temperature, obtains
Between product；
(2) intermediate product is added dropwise in n-hexane while stirring, there are a large amount of solids to be precipitated, after stirring 10min, taken out
Filter, obtained solid are put into vacuum drying oven dry 6h, obtain a kind of oxygen-containing sulphur nitrogen-spiro polymer P4, yield 68.4%.
Phenetic analysis, results of IR such as Fig. 1 (D) are carried out to the spiro polymer P4 that above-mentioned steps are prepared
Shown, shown in nucleus magnetic hydrogen spectrum result such as Fig. 2 (D), shown in nuclear-magnetism carbon spectrogram such as Fig. 3 (D), thermal weight loss result is as shown in Figure 4.
The weight average molecular weight M of GPC test P3w=12500, molecular weight distribution MWD=1.84.
Embodiment 5
The preparation method of spiro polymer is present embodiments provided, specific reaction equation is as follows:
The preparation method of the preparation method reference implementation example 1 of the spiro polymer of the present embodiment, difference is only that, to monomer
The type of A is replaced, and the structure of monomer A isAnd the additional amount of monomer A is 165mg
(0.5mmol)。
The oxygen-containing sulphur nitrogen-spiro polymer P5 being prepared, yield 89.1%.
Phenetic analysis, results of IR such as Fig. 1 (E) are carried out to the spiro polymer P5 that above-mentioned steps are prepared
Shown, shown in nucleus magnetic hydrogen spectrum result such as Fig. 2 (E), shown in nuclear-magnetism carbon spectrogram such as Fig. 3 (E), thermal weight loss result is as shown in Figure 4.
The weight average molecular weight M of GPC test P5w=23800, molecular weight distribution MWD=2.97.
Embodiment 6
The preparation method of spiro polymer is present embodiments provided, specific reaction equation is as follows:
The preparation method of the preparation method reference implementation example 2 of the spiro polymer of the present embodiment, difference is only that, to monomer
The type of A is replaced, and the structure of monomer A isAnd the additional amount of monomer A is 165mg
(0.5mmol)。
The oxygen-containing sulphur nitrogen-spiro polymer P6 being prepared, yield 85.2%.
Phenetic analysis, results of IR such as Fig. 1 (F) are carried out to the spiro polymer P6 that above-mentioned steps are prepared
Shown, shown in nucleus magnetic hydrogen spectrum result such as Fig. 2 (F), shown in nuclear-magnetism carbon spectrogram such as Fig. 3 (F), thermal weight loss result is as shown in Figure 4.
The weight average molecular weight M of GPC test P6w=34400, molecular weight distribution MWD=2.82.
Embodiment 7
The preparation method of spiro polymer is present embodiments provided, specific reaction equation is as follows:
The preparation method of the preparation method reference implementation example 2 of the spiro polymer of the present embodiment, difference is only that, to monomer
The type of A is replaced, and the structure of monomer A isAnd the additional amount of monomer A is 153mg
(0.5mmol)。
The oxygen-containing sulphur nitrogen-spiro polymer P7 being prepared, yield 84.6%.
Phenetic analysis is carried out to the spiro polymer P7 that above-mentioned steps are prepared, GPC tests the weight average molecular weight M of P7w
=29500, molecular weight distribution MWD=2.65.
Embodiment 8
The preparation method of spiro polymer is present embodiments provided, specific reaction equation is as follows:
The preparation method of the preparation method reference implementation example 2 of the spiro polymer of the present embodiment, difference is only that, to monomer
The type of A is replaced, and the structure of monomer A isAnd the additional amount of monomer A is 78mg (0.5mmol).
The oxygen-containing sulphur nitrogen-spiro polymer P8 being prepared, yield 88.0%.
Phenetic analysis is carried out to the spiro polymer P8 that above-mentioned steps are prepared, GPC tests the weight average molecular weight M of P8w
=16400, molecular weight distribution MWD=2.82.
Embodiment 9
The preparation method of spiro polymer is present embodiments provided, specific reaction equation is as follows:
The preparation method of the preparation method reference implementation example 2 of the spiro polymer of the present embodiment, difference is only that, to monomer
The type of A is replaced, and the structure of monomer A isAnd the additional amount of monomer A is 134mg
(0.5mmol)。
The oxygen-containing sulphur nitrogen-spiro polymer P9 being prepared, yield 84.2%.
Phenetic analysis is carried out to the spiro polymer P9 that above-mentioned steps are prepared, GPC tests the weight average molecular weight M of P9w
=7900, molecular weight distribution MWD=3.01.
Embodiment 10
The preparation method of the present embodiment reference implementation example 2, difference are only that addition 10mL methylene chloride is single as solvent
The molar concentration of body A is 0.05mol/L.The oxygen-containing sulphur nitrogen-spiro polymer material P10 being prepared, yield 45.2%.
GPC measures its weight average molecular weight MW=8800, molecular weight distribution MWD=1.87.
Embodiment 11
The preparation method of the present embodiment reference implementation example 2, difference are only that addition 2.5mL methylene chloride is single as solvent
The molar concentration of body A is 0.2mol/L.The oxygen-containing sulphur nitrogen-spiro polymer material P11 being prepared, yield 67.3%.GPC
Measure its weight average molecular weight MW=15300, molecular weight distribution MWD=2.42.
Embodiment 12
The preparation method of the present embodiment reference implementation example 2, difference are only that the molar ratio of monomer A, monomer B and monomer C are
The dosage of 1 ﹕ 1 ﹕ 0.8, monomer C are 0.4mmol.The oxygen-containing sulphur nitrogen-spiro polymer material P12 being prepared, yield are
60.5%.GPC measures its weight average molecular weight MW=4400, molecular weight distribution MWD=1.52.
Embodiment 13
The preparation method of the present embodiment reference implementation example 2, difference are only that, replace methylene chloride conduct using chloroform
Solvent.The oxygen-containing sulphur nitrogen-spiro polymer material P13 being prepared, yield 72.7%.GPC measures its weight average molecular weight MW
=9900, molecular weight distribution MWD=2.11.
Embodiment 14
The preparation method of the present embodiment reference implementation example 2, difference are only that, using toluene replacement methylene chloride as molten
Agent.The oxygen-containing sulphur nitrogen-spiro polymer material P14 being prepared, yield 47.6%.GPC measures its weight average molecular weight MW=
16700, molecular weight distribution MWD=3.48.
Embodiment 15
The preparation method of the present embodiment reference implementation example 2, difference are only that reaction temperature is 0 DEG C, and oxygen-containing sulphur is prepared
Nitrogen-spiro polymer material P15, yield 34.5%.GPC measures its weight average molecular weight MW=2000, molecular weight distribution MWD
=1.33.
Embodiment 16
The preparation method of the present embodiment reference implementation example 2, difference are only that reaction temperature is 25 DEG C, are prepared oxygen-containing
Sulphur nitrogen-spiro polymer material P16, yield 60.2%.GPC measures its weight average molecular weight MW=7600, molecular weight distribution is
MWD=2.37.
Embodiment 17
The preparation method of the present embodiment reference implementation example 2, difference are only that oxygen-containing sulphur is prepared in reaction time 3h
Nitrogen-spiro polymer material P17, yield 20.8%.GPC measures its weight average molecular weight MW=4900, molecular weight distribution MWD
=1.58.
Embodiment 18
The preparation method of the present embodiment reference implementation example 2, difference are only that oxygen-containing sulphur is prepared in reaction time 6h
Nitrogen-spiro polymer material P18, yield 31.5%.GPC measures its weight average molecular weight MW=5500, molecular weight distribution MWD
=1.47.
Embodiment 19
The preparation method of the present embodiment reference implementation example 2, difference are only that the reaction time is for 24 hours, oxygen-containing sulphur to be prepared
Nitrogen-spiro polymer material P19, yield 77.9%.GPC measures its weight average molecular weight MW=13900, molecular weight distribution is
MWD=1.95.
Embodiment 20
HeLa cell and NIH 3T3 cell-specific identification test
Prepare fluorescent reagent: the spiro polymer P2 that Example 2 is prepared is dissolved in DMSO, and preparation obtains concentration
For 10-4The DMSO solution of the spiro polymer P2 of mol/L, as fluorescent reagent；
Before experiment, HeLa cell and NIH 3T3 are planted respectively on the cell dish of dedicated cell culture for 24 hours in advance, then
The aforementioned prepared fluorescent reagent of 0.1mL is taken, every dish is added and fills in the cell dish of the sugared culture solution of 1mL high, is co-cultured with cell
It after 15min and 3h, is cleaned 1 time with PBS buffer solution, then rejoins high sugared culture solution and be placed in the cell after co-cultivation glimmering
It is observed under light Laser Scanning Confocal Microscope.
As shown in figure 5, it is used for after being configured to fluorescent reagent for the spiro polymer P2 that the embodiment of the present invention 2 is prepared
The image of HeLa cell and NIH 3T3 cell.As can be known from Fig. 5, under identical condition of culture and concentration, in 15min,
HeLa cell and NIH 3T3 cell cannot see that obvious fluorescence, but can see obvious blue fluorescence after 3h in HeLa cell,
I.e. the specific recognition to HeLa cell may be implemented in fluorescent reagent.
Embodiment 21
HepG2 cell and LO2 cell-specific identification test
Prepare fluorescent reagent: the spiro polymer P2 that Example 2 is prepared is dissolved in DMSO, and preparation obtains concentration
For 10-4The DMSO solution of the spiro polymer P2 of mol/L, as fluorescent reagent；
Before experiment, HepG2 cell and LO2 cell are planted respectively on the cell dish of dedicated cell culture for 24 hours in advance, then
The aforementioned prepared fluorescent reagent of 0.1mL is taken, every dish is added and fills in the cell dish of 1mL culture solution, co-cultures 15min with cell
It after 3h, is cleaned 1 time with PBS buffer solution, then rejoins high sugared culture solution and the cell after co-cultivation is placed in fluorescence and be total to
It is observed under focusing microscope.
As shown in fig. 6, it is used for after being configured to fluorescent reagent for the spiro polymer P2 that the embodiment of the present invention 2 is prepared
The image of HepG2 cell and LO2 cell.As can be known from Fig. 6, under identical condition of culture and concentration, in 15min, HepG2
Cell and LO2 cell cannot see that obvious fluorescence, but can see obvious blue fluorescence, i.e. fluorescence after 3h in HepG2 cell
The specific recognition to HepG2 cell may be implemented in reagent.
Embodiment 22
The phagocytic rate of HeLa cell, NIH 3T3 cell, HepG2 cell and LO2 cell to fluorescent reagent
Prepare fluorescent reagent: the spiro polymer P2 that Example 2 is prepared is dissolved in DMSO, and preparation obtains concentration
For 10-4The DMSO solution of the spiro polymer P2 of mol/L, as fluorescent reagent；
Before experiment, HeLa cell, NIH 3T3 cell, HepG2 cell and LO2 cell are planted respectively dedicated thin for 24 hours in advance
In the cell bottle of born of the same parents' culture, the aforementioned prepared fluorescent reagent of 1mL is then taken, every bottle of cell bottle for filling 10mL culture solution is added
In, 15min is co-cultured with cell, culture solution is taken out and measures ultraviolet absorptivity, being free of to 10mL is added with 1mL fluorescent reagent
The ingredient that the culture solution of cell obtains as a control group, as shown in fig. 7, cell can have the spiro polymer in fluorescent reagent
Effect phagocytosis.
Embodiment 23
After fluorescent reagent dyes, the luminous intensity survey of HeLa cell, NIH 3T3 cell, HepG2 cell and LO2 cell
It is fixed
Prepare fluorescent reagent: the spiro polymer P2 that Example 2 is prepared is dissolved in DMSO, and preparation obtains concentration
For 10-4The DMSO solution of the spiro polymer P2 of mol/L, as fluorescent reagent；
Co-culture method in reference implementation example 20 and 21, by fluorescent reagent and HeLa cell, NIH 3T3 cell, HepG2
After cell and LO2 cell cultivate 15min and 3h respectively, with 0.05% pancreatin by cell dissociation, cell is made to suspend, it is clear with PBS
After washing-being centrifuged 3 times, after the PBS of 3mL is added, its fluorescence intensity, I are tested with Fluorescence Spectrometer0For cell and fluorescent reagent culture
Digested the obtained fluorescence intensity of cleaning treatment after 15min, I is cell and loop coil reagent 1 is cultivated after 3h through digesting cleaning treatment
Obtained fluorescence intensity.
Calculate the fluorescence enhancement ratio I/I after fluorescent reagent is co-cultured with four kinds of cells respectively0, as shown in Figure 8.It can from figure
Know, fluorescence intensity of two kinds of cancer cells after cultivating 3h improves 4 times or more.
Embodiment 24
Prepare fluorescent reagent: the spiro polymer P2 that Example 2 is prepared is dissolved in DMSO, and preparation obtains concentration
For 10-4The DMSO solution of the spiro polymer P2 of mol/L, as fluorescent reagent；
Before experiment, HeLa cell, NIH 3T3 cell, HepG2 cell and LO2 cell are planted respectively dedicated thin for 24 hours in advance
In the cell bottle of born of the same parents' culture, the aforementioned prepared fluorescent reagent of 1mL is then taken, every bottle of cell bottle for filling 10mL culture solution is added
In, it is co-cultured respectively with cell for 24 hours, after 48h, 72h, dyed through FITC/PI kit, tests its apoptosis with flow cytometer
Rate, test results are shown in figure 9.
Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention., rather than its limitations；To the greatest extent
Pipe present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that: its according to
So be possible to modify the technical solutions described in the foregoing embodiments, or to some or all of the technical features into
Row equivalent replacement；And these are modified or replaceed, various embodiments of the present invention technology that it does not separate the essence of the corresponding technical solution
The range of scheme.
Claims (10)
1. a kind of spiro polymer, which is characterized in that its structural formula is as follows:
Wherein, R1Selected from aliphatic or aromatic functional groups, R2Selected from aliphatic functionality, R3Selected from hydrogen or aliphatic functionality
Any one of, n is positive integer.
2. spiro polymer according to claim 1, which is characterized in that the R1Structure include following any:
3. spiro polymer according to claim 1, which is characterized in that the R2Structure include following any :-
CmH2m+1；Wherein m is selected from the integer between 1-6；
Preferably, the R2For-C2H5。
4. spiro polymer according to claim 1-3 again, which is characterized in that the spiro polymer is divided equally
Son amount is 1000-80000；
Preferably, the weight average molecular weight of the spiro polymer is 2000-40000.
5. a kind of preparation method of spiro polymer, which comprises the steps of:
Monomer A, monomer B and monomer C hybrid reaction, obtain intermediate product；
Intermediate product is added in precipitating reagent and is precipitated, it is the spiro polymer that precipitating, which is collected by filtration,；
Wherein, the structural formula of the monomer A isThe R1Selected from aliphatic or aromatic functional groups；The monomer
The structural formula of B isThe R2Selected from aliphatic functionality；The structural formula of the monomer C isThe R3Selected from any one of hydrogen or aliphatic functionality.
6. the preparation method of spiro polymer according to claim 5, which is characterized in that the monomer A, monomer B and list
The molar ratio of body C is 1 ﹕ (0.8-1) ﹕ (0.8-1)；
Preferably, the molar ratio of the monomer A, monomer B and monomer C are 1 ﹕, 1 ﹕ 1.
7. the preparation method of spiro polymer according to claim 5, which is characterized in that by monomer A, monomer B and monomer C
It is mixed with solvent, reaction obtains intermediate product；
Preferably, the concentration of the monomer A in a solvent is 0.05-0.2mol/L；
Preferably, the solvent includes one of methylene chloride, chloroform and toluene or a variety of；
It is furthermore preferred that the solvent is methylene chloride.
8. the preparation method of spiro polymer according to claim 5, which is characterized in that the R1Structure include following
It is any:
Preferably, the R2Structure be CmH2m+1；Wherein m is selected from the integer between 1-6；
Preferably, the R3Selected from any one of hydrogen or aliphatic functionality；
Preferably, the temperature of the reaction is 0-50 DEG C, and the time of the reaction is 3-24h；
It is furthermore preferred that the temperature of the reaction is 25-50 DEG C, the time of the reaction is 12-18h.
9. the application of the described in any item spiro polymers of claim 1-4, which is characterized in that the spiro polymer is for glimmering
Signal cancer cell；
Preferably, the spiro polymer is dissolved in good solvent, is co-cultured with cancer cell, to carry out fluorescence mark to cancer cell
Note；
Preferably, the cancer cell includes any one of HeLa cell, HepG2 cell, A549 cell and MCF-7 cell；
It is furthermore preferred that the good solvent preferably includes DMSO；
Preferably, the spiro polymer dissolved concentration in good solvent is 10-6-10-4mol/L；
Preferably, the time of the co-cultivation is 2-5h.
10. the described in any item spiro polymers of claim 1-4 are preparing the application in anticancer drug.
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| CN108948349A (en) * | 2018-08-01 | 2018-12-07 | 北京理工大学 | A kind of spiro polymer material and preparation method thereof |
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