CN105037692B - Polythiophene and preparation method and application - Google Patents
Polythiophene and preparation method and application Download PDFInfo
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- 229920000123 polythiophene Polymers 0.000 title abstract description 6
- 238000002360 preparation method Methods 0.000 title abstract description 5
- 229920000642 polymer Polymers 0.000 claims abstract description 33
- 238000003384 imaging method Methods 0.000 claims abstract description 15
- 239000003642 reactive oxygen metabolite Substances 0.000 claims abstract description 12
- 206010070834 Sensitisation Diseases 0.000 claims abstract description 7
- 230000008313 sensitization Effects 0.000 claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 235000010378 sodium ascorbate Nutrition 0.000 claims description 6
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 claims description 6
- 229960005055 sodium ascorbate Drugs 0.000 claims description 6
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 claims description 6
- 229940126214 compound 3 Drugs 0.000 claims description 5
- 238000006392 deoxygenation reaction Methods 0.000 claims description 5
- 238000000502 dialysis Methods 0.000 claims description 5
- 230000001939 inductive effect Effects 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 230000001629 suppression Effects 0.000 claims description 4
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 3
- 229910000366 copper(II) sulfate Inorganic materials 0.000 claims description 3
- 238000006352 cycloaddition reaction Methods 0.000 claims description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims 2
- 239000002253 acid Substances 0.000 claims 2
- 239000010949 copper Substances 0.000 claims 2
- 229910052802 copper Inorganic materials 0.000 claims 2
- 210000004027 cell Anatomy 0.000 abstract description 37
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract description 23
- 239000001301 oxygen Substances 0.000 abstract description 23
- 229910052760 oxygen Inorganic materials 0.000 abstract description 23
- 230000000694 effects Effects 0.000 abstract description 12
- 239000003814 drug Substances 0.000 abstract description 11
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 abstract description 9
- 210000000170 cell membrane Anatomy 0.000 abstract description 8
- 231100000419 toxicity Toxicity 0.000 abstract description 4
- 230000001988 toxicity Effects 0.000 abstract description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 abstract description 3
- 231100000135 cytotoxicity Toxicity 0.000 abstract description 3
- 230000003013 cytotoxicity Effects 0.000 abstract description 3
- 230000006698 induction Effects 0.000 abstract description 3
- 230000001105 regulatory effect Effects 0.000 abstract description 2
- 102000001838 Angiotensin II receptor type 1 Human genes 0.000 abstract 1
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- 238000006735 epoxidation reaction Methods 0.000 abstract 1
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- 239000000975 dye Substances 0.000 description 10
- 238000002474 experimental method Methods 0.000 description 10
- 230000003834 intracellular effect Effects 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000010521 absorption reaction Methods 0.000 description 9
- 238000003752 polymerase chain reaction Methods 0.000 description 9
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 238000005516 engineering process Methods 0.000 description 8
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 5
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 238000004113 cell culture Methods 0.000 description 4
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- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 3
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 102000004722 NADPH Oxidases Human genes 0.000 description 3
- 108010002998 NADPH Oxidases Proteins 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000001464 adherent effect Effects 0.000 description 3
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- 125000003963 dichloro group Chemical group Cl* 0.000 description 3
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- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 102100025386 Oxidized low-density lipoprotein receptor 1 Human genes 0.000 description 2
- 101710199789 Oxidized low-density lipoprotein receptor 1 Proteins 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 108010000134 Vascular Cell Adhesion Molecule-1 Proteins 0.000 description 2
- 102100023543 Vascular cell adhesion protein 1 Human genes 0.000 description 2
- XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 description 2
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- 229910021641 deionized water Inorganic materials 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 125000004925 dihydropyridyl group Chemical group N1(CC=CC=C1)* 0.000 description 2
- 230000005284 excitation Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
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- 238000000926 separation method Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
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- 239000006228 supernatant Substances 0.000 description 2
- GRVDJDISBSALJP-FIBGUPNXSA-N trideuterio($l^{1}-oxidanyl)methane Chemical compound [2H]C([2H])([2H])[O] GRVDJDISBSALJP-FIBGUPNXSA-N 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 1
- 102000005862 Angiotensin II Human genes 0.000 description 1
- 101800000733 Angiotensin-2 Proteins 0.000 description 1
- 108010064733 Angiotensins Proteins 0.000 description 1
- 102000015427 Angiotensins Human genes 0.000 description 1
- 108090000312 Calcium Channels Proteins 0.000 description 1
- 102000003922 Calcium Channels Human genes 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 239000004593 Epoxy Substances 0.000 description 1
- ZFDIRQKJPRINOQ-HWKANZROSA-N Ethyl crotonate Chemical compound CCOC(=O)\C=C\C ZFDIRQKJPRINOQ-HWKANZROSA-N 0.000 description 1
- 208000035126 Facies Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 206010054949 Metaplasia Diseases 0.000 description 1
- LFZAGIJXANFPFN-UHFFFAOYSA-N N-[3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-thiophen-2-ylpropyl]acetamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CCC(C=1SC=CC=1)NC(C)=O)C LFZAGIJXANFPFN-UHFFFAOYSA-N 0.000 description 1
- BOPGDPNILDQYTO-NNYOXOHSSA-L NADH(2-) Chemical compound C1=CCC(C(=O)N)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP([O-])(=O)OP([O-])(=O)OC[C@@H]2[C@H]([C@@H](O)[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)O1 BOPGDPNILDQYTO-NNYOXOHSSA-L 0.000 description 1
- 102000016610 Oxidized LDL Receptors Human genes 0.000 description 1
- 108010028191 Oxidized LDL Receptors Proteins 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229950006323 angiotensin ii Drugs 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 238000010804 cDNA synthesis Methods 0.000 description 1
- 229960004424 carbon dioxide Drugs 0.000 description 1
- 229910002090 carbon oxide Inorganic materials 0.000 description 1
- 230000021164 cell adhesion Effects 0.000 description 1
- 238000010609 cell counting kit-8 assay Methods 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000001218 confocal laser scanning microscopy Methods 0.000 description 1
- 238000004624 confocal microscopy Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- JZCCFEFSEZPSOG-UHFFFAOYSA-L copper(II) sulfate pentahydrate Chemical compound O.O.O.O.O.[Cu+2].[O-]S([O-])(=O)=O JZCCFEFSEZPSOG-UHFFFAOYSA-L 0.000 description 1
- 238000002242 deionisation method Methods 0.000 description 1
- 239000005547 deoxyribonucleotide Substances 0.000 description 1
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
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- 238000004108 freeze drying Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000012160 loading buffer Substances 0.000 description 1
- 238000000816 matrix-assisted laser desorption--ionisation Methods 0.000 description 1
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- 239000002244 precipitate Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- UORVCLMRJXCDCP-UHFFFAOYSA-N propynoic acid Chemical compound OC(=O)C#C UORVCLMRJXCDCP-UHFFFAOYSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 1
- 238000012113 quantitative test Methods 0.000 description 1
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- ZFDIRQKJPRINOQ-UHFFFAOYSA-N transbutenic acid ethyl ester Natural products CCOC(=O)C=CC ZFDIRQKJPRINOQ-UHFFFAOYSA-N 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of polythiophene and preparation method and application.Shown in the structural formula of polymer provided by the present invention such as formula (III), wherein m：N=3：7, m and n are 10 200, and are not all 10 and 200.This polymer is applied to following two aspects：1) on the one hand pyridine ring can be generated by dihydropyridine epoxidation and effectively consume active oxygen, reduce the cytotoxicity being caused by the active oxygen that dye sensitization produces during imaging；2) on the other hand pass through the increase that dihydropyridine medicine reduces the reactive oxygen species because of Ang II induction, thus effectively reducing the concentration of reactive oxygen species, in addition, because polymer can hinder the combination of Ang II and angiotensin Ⅱ receptor type 1 so that PTDHP possesses the effect of active oxygen in more preferable regulating cell with the effect of cell membrane.Result shows that this polymer has reduction imaging cells toxicity.
Description
Technical field
The invention belongs to chemical field, it is related to a kind of polythiophene and preparation method and application.
Background technology
Intracellular high concentration active oxygen often causes damage to cell, for example, destroy structure, the infringement intracellular of cell membrane
Energy albumen and deoxyribonucleotide structure etc., and then lead to apoptosis or even the canceration of cell.Angiotensin II (Ang II)
By improving the oxidasic activity of intracellular NADPH (NADPH), live in inducing cell
The increase of property oxygen, is an Important cause of disease of cardiovascular and cerebrovascular disease.In addition, during cell imaging, dye molecule also can be in light source
In the presence of sensitization around oxygen produce active oxygen, cell is caused damage.
Dihydropyridines drugs are a kind of calcium-ion channel antagonists as clinical medicine, but find this medicine energy in recent years
The enough concentration passing through to suppress the activity of intracellular nadph oxidase effectively to reduce reactive oxygen species, protects cell.
Content of the invention
It is an object of the invention to provide a kind of polythiophene and preparation method and application.
The invention provides compound shown in formula III (abbreviation PTDHP) or its pharmaceutically acceptable salt,
In described formula III, m：N=3：7；
M and n is 10-200, and is not all 10 and 200.
Present invention also offers a kind of method preparing polymer shown in described formula III, comprise the steps：
Compound 3, anhydrous cupric sulfate and sodium ascorbate shown in polymer P T, Formula II are carried out click ring in solvent
Change additive reaction, obtain polymer shown in described formula III after completion of the reaction；
The structural formula of described polymer P T is as follows：
Wherein, the definition of m and n is as hereinbefore；
In said method, described click cycloaddition reaction is carried out under the conditions of lucifuge；
The temperature of reaction is room temperature；
The time of reaction is 24-72 hour, specially 48 hours.
Described polymer P T, the mass ratio of compound, anhydrous cupric sulfate and sodium ascorbate shown in Formula II are 1：0.1-1：
0.5-5：0.5-20, specially 1：0.4：1：2；
Described solvent is the solvent after deoxygenation is processed, and is chosen in particular from the dimethyl sulfoxide after deoxygenation is processed, water
With at least one in oxolane；
The amount ratio of described polymer P T and described solvent is 1mg：0.01-2ml, specially 1mg：0.1mL.
Methods described also comprises the steps：Described after completion of the reaction, in gained reaction system add water after putting
Dialyse in molecular cut off is for the bag filter of 3500Da, be dried.
In described dialysis step, the time of dialysis is 3 days.
The formula III polymer that the invention described above provides or its pharmaceutically acceptable salt are preparing following 1) or 2) or 3) in
Product in application, fall within protection scope of the present invention：
1) reactive oxygen species that when reducing imaging, dye molecule sensitization produces；
2) reactive oxygen species being produced by Ang II inducing cell are reduced；
3) combination of suppression Ang II and its receptor.
The new polythiophene of dihydropyridine modified by the side chain that the present invention provides：1) dihydropyridine epoxy can on the one hand be passed through
Metaplasia becomes pyridine ring effectively to consume active oxygen, reduces the cytotoxicity being caused during imaging by the active oxygen that dye sensitization produces；
2) on the other hand pass through the increase that dihydropyridine medicine reduces the reactive oxygen species because of Ang II induction, thus effectively reducing thin
The concentration of intracellular reactive oxygen species generation, in addition, because polymer can hinder Ang II and angiotensin with the effect of cell membrane
The combination of receptor 1 is so that PTDHP possesses the effect of active oxygen in more preferable regulating cell, and passes through polymerase chain reaction
(PCR) demonstrate this conclusion.
The invention described above reduces cell imaging experiment phototoxicity experiments, and its principle is：Dihydropyridines drugs dihydropyridine
On ring, two hydrogen are more active, can react generation pyridine ring with active oxygen, can be had using this process dihydropyridine
The active oxygen that when consuming cell imaging, dye molecule sensitization produces of effect, thus improve the bio-compatible of cell dye molecular imaging
Property.The present invention reduces reactive oxygen species concentration experiment, and its principle is：As a kind of in vivo important signaling molecule of biology, Ang
II can be combined with the Ang II receptor 1 of surface of cell membrane, activation oxidized ldl receptor 1 (LOX-1), vascular cell
Adhesion factor 1 (VCAM-1) etc. generates closely related albumen with active oxygen and then improves the activity of nadph oxidase.It is modified with
The PTDHP of dihydropyridine can effectively suppress the expression of LOX-1 and VCAM-1, and then suppresses the activity of nadph oxidase
To reduce intracellular reactive oxygen concentration.In addition, in view of PTDHP, mainly in combination with cell membrane, can effectively disturb Ang II
Combination with Ang II receptor 1 is so that PTDHP has the effect that more preferable inhibitory activity oxygen generates.
The present invention can not only improve bio-compatibility during system cell imaging moreover it is possible to effective suppression is induced by Ang II
Reactive oxygen species increase, because the synergism PTDHP of polymer possess more preferable than dihydropyridine medicine under same concentrations
Inhibition.
Brief description
Fig. 1 is that PTDHP cell common location is imaged picture.
Fig. 2 is compared with the dark toxicity of PT and phototoxicity for PTDHP.
Fig. 3 suppresses CLSM figure and the statistics block diagram being increased by active oxygen in Ang II inducing cell for PTDHP.
Fig. 4 is PCR experiment interpretation of result and statistics.
Fig. 5 is the synthetic route of polymer P TDHP.
Specific embodiment
Below by specific embodiment, the present invention will be described, but the invention is not limited in this.
Experimental technique in following embodiments, if no special instructions, is conventional method.Examination used in following embodiments
Test material, if no special instructions, be and be commercially available from routine biochemistry reagent shop.X% in following embodiments, such as no special
Different explanation, is weight/mass percentage composition.Quantitative test in following examples, is respectively provided with three times and repeats to test, result is averaged
Value.
In following embodiments 1, it is to be prepared as follows as compound shown in the Formula II of initial reactant and obtains：
Reaction process is as shown in Figure 5：
1) synthesis of compound 2
1.89g compound 1 and 0.83mL pyridinium dissolution, in 6mL toluene, after stirring 10 minutes, add in above-mentioned system
50 DEG C of 1.26mL2- trifluoromethylated benzaldehyde reacts 1 hour, finally adds 0.33mL acetic acid to continue reaction 12 in the mixture little
When.Mixture is cooled to after room temperature, washes 2 with the deionization that 1mL saturated sodium bicarbonate aqueous solution washes 1 time and 2mL respectively
Secondary, add 10mL dichloro extraction product, organic faciess are dried with anhydrous magnesium sulfate, after solvent is evaporated off, adopt silica gel post separation (eluting
Agent：Petroleum ether：Ethyl acetate：Dichloromethane=10:2:1) obtain 1.81g white solid after.Characterization of The Products：1H NMR
(400MHz,CDCl3)δ8.05(s,1H),7.942(d,1H),7.74(m,3H),4.25(t,2H),3.85(t,2H),2.49
(s,3H).13C NMR(400MHz,CDCl3)δ198.70,165.13,148.52,131.94,130.07,128.21,120.87,
122.01,65.99,61.33,20.95.HR-MS(MALDI,[M+Na+]):Calcd.For C14H13F3O4:325.06636；
Found:325.06553. characterize data shows, product is compound 2.
2) synthesis of compound shown in Formula II (namely compound 3)
This reaction is carried out in apparatus,Soxhlet'ses.3- amino -2- the Ethyl crotonate of 0.785g compound 2 and 0.194g is molten
Solution adds in 50mL round-bottomed flask in 30mL isopropanol, is warming up to 100 DEG C and reacts 10 hours, adds and divide in apparatus,Soxhlet'ses
Son sieves the water generating for absorbing reaction.Mixture is cooled to room temperature, and after steaming solvent, crude product continues next step reaction.
In 200mg crude product, 5mgDMAP and 66mg acetylenecarboxylic acid dissolving 15mL dichloro, the dichloro being slowly added dropwise DCC under the conditions of ice salt bath is molten
After liquid, room temperature continues reaction 8h.It is centrifuged off white precipitate, solvent after silica gel post separation (eluant is evaporated off：Petroleum ether：Acetic acid
Ethyl ester=3:1) obtain 59mg clear yellow viscous solid after.Product characterizes：1H NMR(400MHz,CDCl3)δ7.51(d,1H),7.50
(d,1H),7.40(t,1H),5.64(s,1H),5.57(s,1H),4.38(m,2H),4.16(m,2H),4.00(m,1H),2.88
(s,1H),2.31(s,1H),1.70(t,1H).13C NMR(400MHz,CDCl3)δ167.51,167.04,152.40,
146.63,144.77,143.11,131.90,131.12,126.47,105.31,103.93,105.31,103.93,63.79,
60.71,59.81,35.54,19.57,19.21,13.94.ESI-MS:464.13081(M+-H).Characterize data shows, product
For compound 3.
In addition, the polymer P T as initial reactant is to be prepared as follows and obtains：
Reaction process is as shown in Figure 5：
29.9mg compound 4 and 71.6mg compound 5 are dissolved in 10mL anhydrous chloroform, add under nitrogen atmosphere
216.4mg ferric chloride, room temperature lucifuge reacts 36h.After adding 1mL methanol that reaction is quenched, remove supernatant, black solid dissolves
In mixed solution (dimethyl sulfoxide：Chloroform：Methanol=1:5:5), in, stirring is lower to add 1mL hydrazine hydrate to be centrifuged off after removing precipitating.
After chloroform and methanol are evaporated off, add 10mL deionized water.Above-mentioned aqueous solution is added to dialysis in the bag filter that molecular weight is 3500
Remove dimethyl sulfoxide and ion, finally obtain 26mg red solid.Characterization of The Products：1H NMR(400MHz,D2O+CD3O)δ7.27-
7.09(b,1H),3.869(s,2H),3.87-3.61(d,15H),3.11(s,10H).Characterize data shows, product is tied for target
The polymer P T of structure.
Embodiment 1, the synthesis of PTDHP (namely polymer shown in formula III)
The structural formula of polymer P T is as follows：
Wherein, m：N=3：7；M and n is 10-200, and is not all 10 and 200)
Compound 3 shown in 10mg polymer P T, 4mg Formula II, 10mg copper sulphate pentahydrate and 20mg sodium ascorbate are dissolved
In 1mL deoxygenation dimethyl sulfoxide, room temperature lucifuge carries out click cycloaddition reaction 48 hours.After adding 10mL deionized water
After dialysing 3 days in molecular weight is for the bag filter of 3500Da (purchased from middle life magnificent (Beijing) Science and Technology Ltd.), lyophilization
Obtain 11mg red solid.Characterization of The Products：1H NMR(400MHz,D2O+CD3O)δ7.42-7.16(b,1H),3.92(s,1H),
3.67(b,10H),3.19(b,10H),2.42(b,1H),1.332(b,0.5H),1.05-1.03(b,0.7H).Characterize data table
Bright, product is polymer P TDHP, wherein, m：N=3：7；M and n is 10-200, and is not all 10 and 200.
According to Characterization of The Products result, the load factor being calculated PTDHP is 25%.
Embodiment 2, PTDHP common location imaging experiment
Rat aortic endothelial cells are seeded in culture dish puts into overnight adherent in 37 DEG C of cell culture incubators, addition enforcement
After (20 μM) cultures of example 1 gained PTDHP 9 hours, remove culture medium and washed after three times with PBS, cell is in serum-free medium
With cell membrane dyestuff (DiD, 5 μM) (Invitrogen Corporation, C34554), cytoplasmic dye (LysoTracker,
0.5 μM) (Life technologies, L12492) lucifuge is cultivated 0.5 hour and 1 hour respectively, washes away the dyestuff not acted on
Afterwards, imaging results are carried out macroscopical common location analysis and local linear analysis by laser confocal microscope imaging with imaging software,
See Fig. 1.During imaging, the excitation wavelength that PTDHP selects is 488nm, and DiD is 635nm, and LysoTracker is 559nm.
As seen from the figure, PTDHP and cell membrane dyestuff have good common location effect, with cytoplasmic dye common location effect
Then poor, it is mainly distributed on cell surface after PTDHP and cytosiies are described, Ang can be partly disturbed in this distribution of PTDHP
II and the Ang II receptor binding of surface of cell membrane.
Embodiment 3, the cytotoxicity experiment of PTDHP and PT
First, rat aortic endothelial cells culture
Rat aortic endothelial cells are containing the special hyclone of 10% primary cell, 1% dual anti-and 1% primary cell
The primitive cell culture base (purchased from Wuhan Protozoic biological medicine Science and Technology Ltd.) of special additive is put into 37 DEG C and is contained 5% 2
The constant incubator culture of carbonoxide.
2nd, PTDHP and PT tests to the dark toxicity of rat aortic endothelial cells
Rat aortic endothelial cells are seeded in 96 orifice plates, and density is 8 × 103Individual/hole, puts into 37 DEG C of cell culture incubators
In overnight adherent, add (0-64 μM) of variable concentrations PTDHP to cultivate 24 hours.Every hole adds 10 μ Lcck-8 (cell
Counting kit-8 is purchased from green skies Bioisystech Co., Ltd) after 37 DEG C of cultures 4 hours, direct detection in microplate reader
Uv absorption at 490nm.
PT is detected to cell dark toxicity, in addition to adding the polymer P T (0-64 μM) of variable concentrations, other operations one
Cause.
All uv absorption absorbing all deduction cck-8 and polymer itself.
The ultraviolet absorption value of blank control group cell is designated as A0, add the cell uv absorption of PTDHP or PT culture to be designated as
A, cell survival rate (VR) calculates according to below equation, and draws cell survival rate curve, sees Fig. 2.
3rd, the phototoxicity experiments to rat aortic endothelial cells for PTDHP and PT
Rat aortic endothelial cells are seeded in 96 orifice plates, and density is 8 × 103Individual/hole, puts into 37 DEG C of cell culture incubators
In overnight adherent, after adding (0-64 μM) of variable concentrations PTDHP culture 6 hours, suck supernatant, add fresh culture.Light
Dosage is 1mW/cm2White light 15 minutes, 37 DEG C culture 24 hours after add cck-8, continue culture 4 hours, in microplate reader
Uv absorption at upper direct detection 490nm.
PT is detected to cell phototoxicity, in addition to adding variable concentrations PT (0-64 μM), other operations are consistent.
All uv absorption absorbing all deduction cck-8 and polymer itself.
The ultraviolet absorption value of blank control group cell is designated as A0, add the cell purple of white light after PTDHP or PT culture
Outer absorption is designated as A, and cell survival rate (VR) calculates according to below equation, and draws cell survival rate curve, sees Fig. 2.
As seen from the figure, under the conditions of same light is shone, with respect to PT, PTDHP is demonstrated by relatively low phototoxicity, illustrates to connect
The active oxygen being generated by illumination sensitization can effectively be consumed, thus improve the bio-compatibility of system after drug molecule.
Embodiment 4, the intracellular active oxygen because of Ang II induction of PTDHP suppression increase experiment
First, packet administration
Rat aortic endothelial cells with, after (20 μM) of PTDHP culture rat aortic endothelial cells 1 hour, removing training
Foster base, adds the fresh culture being mixed with Ang II (0.1 μM) to continue culture 8 hours, is set to PTDHP+Ang II group.Use respectively
It is further continued for being set to PT+Ang II, DHP+Ang II group with Ang II culture after PT (20 μM), (5 μM) cultures of DHP, only use
The cell of Ang II culture is set to Ang II group, and this three groups as a control group, does not carry out the cell of any process as blank group
(blank).
2nd, reactive oxygen species level determination
Each group cell uses the PBS solution lucifuge of active oxygen probe dihydro second ingot DHE (5 μM) to cultivate respectively 0.5 hour, washes away
Carry out Laser scanning confocal microscopy, the excitation wavelength of selection is 559nm, finally with imaging software to each after the DHE not acted on
Group cell carries out quantitative analyses to fluorescence probe, as shown in Figure 3.
As seen from the figure, by the quantitative study to active oxygen probe, it can be found that PTDHP can effectively suppress intracellular work
Property oxygen level, and compared with drug alone molecule, there is more preferable rejection ability.
Embodiment 5, using PCR to inhibitory activity oxygen generate verify
First, packet administration
After PTDHP culture rat aortic endothelial cells 1 hour, remove culture medium, add and be mixed with the fresh of Ang II
Culture medium continues culture 8 hours, is set to PTDHP+Ang II group.Respectively with being further continued for after PT, DHP culture with Ang II culture point
It is not set to PT+Ang II, DHP+Ang II group, be only set to Ang II group with the cell of Ang II culture, this three groups as comparison
Group.The cell not carrying out any process is as blank group (blank).
2nd, Total RNAs extraction and the first chain cDNA synthesis
Illustrated according to test kit, extract each group with TRIZOL reagent (Tiangeng biochemical technology company limited, DP405) intracellular
Total serum IgE, according to RNA at 260nm uv absorption Lai quantitative RNA concentration, according to the explanation of FastQuant RT test kit (sky with
Biochemical technology company limited, KR106) synthesis the first chain cDNA.
3rd, PCR
As shown in table 1, primer concentration is 10 μM, using thermal starting polymerase HotmasterTaq for primer and PCR condition
(1.25U) (Tiangeng biochemical technology company limited, ET106), other materials addition is carried out according to description
Table 1, PCR primer sequence and PCR experiment condition list
4th, agarose gel electrophoresiies and quantitative analyses
Prepare 1% agarose gel, by 5 μ L PCR primer and 1 μ L sample-loading buffer (Tiangeng biochemical technology company limited,
RT202 add in sample cell after) mixing, deposition condition is：100 volts, 0.5 hour.Electrophoresis is become with gel imaging instrument after terminating
Picture, and quantitative analyses are carried out to picture.Intracellular GADPH (the nicotinamide adenine dinucleotide reduced itself existing herein
Phosphoric acid) as internal reference, acquired results all compared with GADPH after make block diagram, as shown in Figure 4.
As seen from the figure, PTDHP can effectively suppress to generate the expression of the messenger RNA of closely related albumen with active oxygen really,
And this compound has more preferable inhibition compared with drug alone molecule.
Claims (9)
1. formula III polymer or its pharmaceutically acceptable salt,
In described formula III, m：N=3：7；
M and n is 10-200, and is not all 10 and 200.
2. a kind of method preparing polymer shown in formula III described in claim 1, comprises the steps：
Compound 3, anhydrous cupric sulfate and sodium ascorbate shown in polymer P T, Formula II are carried out click cyclisation in solvent add
Become reaction, obtain polymer shown in described formula III after completion of the reaction；
The structural formula of described polymer P T is as follows：
Wherein, the definition of m with n is identical with claim 1；
3. method according to claim 2 it is characterised in that：Described click cycloaddition reaction is entered under the conditions of lucifuge
OK；
The temperature of reaction is room temperature；
The time of reaction is 24-72 hour.
4. method according to claim 3 it is characterised in that：The time of reaction is 48 hours.
5. method according to claim 2 it is characterised in that：Described polymer P T, compound, anhydrous slufuric acid shown in Formula II
The mass ratio of copper and sodium ascorbate is 1：0.1-1：0.5-5：0.5-20；
Described solvent is the solvent after deoxygenation is processed；
The amount ratio of described polymer P T and described solvent is 1mg：0.01-2ml.
6. method according to claim 5 it is characterised in that：Described polymer P T, compound, anhydrous slufuric acid shown in Formula II
The mass ratio of copper and sodium ascorbate is 1：0.4：1：2；
Described solvent is selected from least one in the dimethyl sulfoxide after deoxygenation is processed, water and oxolane；
The amount ratio of described polymer P T and described solvent is 1mg：0.1mL.
7. according to the arbitrary described method of claim 2-6 it is characterised in that：Methods described also comprises the steps：Described
After completion of the reaction, dialyse in being placed in the bag filter that molecular cut off is 3500Da after adding water in gained reaction system, do
Dry.
8. method according to claim 7 it is characterised in that：In described dialysis step, the time of dialysis is 3 days.
9. formula III polymer described in claim 1 or its pharmaceutically acceptable salt are preparing following 1) or 2) or 3) product
In application：
1) reactive oxygen species that when reducing imaging, dye molecule sensitization produces；
2) reactive oxygen species being produced by Ang II inducing cell are reduced；
3) combination of suppression Ang II and its receptor.
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