CN104928227B - The application of conjugated polymer PFP-G2 - Google Patents
The application of conjugated polymer PFP-G2 Download PDFInfo
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- CN104928227B CN104928227B CN201510263116.9A CN201510263116A CN104928227B CN 104928227 B CN104928227 B CN 104928227B CN 201510263116 A CN201510263116 A CN 201510263116A CN 104928227 B CN104928227 B CN 104928227B
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- signaling molecule
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- 229920000547 conjugated polymer Polymers 0.000 title abstract description 18
- 230000011664 signaling Effects 0.000 claims abstract description 48
- 206010059866 Drug resistance Diseases 0.000 claims abstract description 36
- 244000005700 microbiome Species 0.000 claims abstract description 23
- 230000002906 microbiologic effect Effects 0.000 claims abstract description 21
- 229920000642 polymer Polymers 0.000 claims abstract description 17
- 238000001514 detection method Methods 0.000 claims abstract description 8
- 230000008859 change Effects 0.000 claims abstract description 7
- 241000660147 Escherichia coli str. K-12 substr. MG1655 Species 0.000 claims description 24
- 241000588724 Escherichia coli Species 0.000 claims description 10
- 229960000723 ampicillin Drugs 0.000 claims description 9
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 claims description 9
- 230000003115 biocidal effect Effects 0.000 claims description 6
- 229930182555 Penicillin Natural products 0.000 claims description 5
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 229940049954 penicillin Drugs 0.000 claims description 5
- 241000305071 Enterobacterales Species 0.000 claims 1
- 241000894006 Bacteria Species 0.000 abstract description 34
- 241000607618 Vibrio harveyi Species 0.000 abstract description 15
- 150000001875 compounds Chemical class 0.000 abstract description 10
- 238000000034 method Methods 0.000 abstract description 4
- 230000009881 electrostatic interaction Effects 0.000 abstract description 2
- 230000002209 hydrophobic effect Effects 0.000 abstract description 2
- 238000004020 luminiscence type Methods 0.000 abstract description 2
- 238000004088 simulation Methods 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 28
- 238000006243 chemical reaction Methods 0.000 description 28
- 239000000243 solution Substances 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 239000007787 solid Substances 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 10
- 239000012530 fluid Substances 0.000 description 10
- 235000015097 nutrients Nutrition 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- FRXSZNDVFUDTIR-UHFFFAOYSA-N 6-methoxy-1,2,3,4-tetrahydroquinoline Chemical compound N1CCCC2=CC(OC)=CC=C21 FRXSZNDVFUDTIR-UHFFFAOYSA-N 0.000 description 9
- 239000012043 crude product Substances 0.000 description 9
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- 239000012153 distilled water Substances 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 7
- 238000010898 silica gel chromatography Methods 0.000 description 7
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical class C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
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- 239000002609 medium Substances 0.000 description 5
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- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 238000009630 liquid culture Methods 0.000 description 4
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000003708 ampul Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
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- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229920000742 Cotton Polymers 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 235000019445 benzyl alcohol Nutrition 0.000 description 2
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
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- 230000003993 interaction Effects 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 2
- 239000000178 monomer Substances 0.000 description 2
- 230000010355 oscillation Effects 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 238000003408 phase transfer catalysis Methods 0.000 description 2
- 239000003444 phase transfer catalyst Substances 0.000 description 2
- 239000013612 plasmid Substances 0.000 description 2
- 230000018612 quorum sensing Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000008223 sterile water Substances 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000012549 training Methods 0.000 description 2
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- 239000003643 water by type Substances 0.000 description 2
- QSLPNSWXUQHVLP-UHFFFAOYSA-N $l^{1}-sulfanylmethane Chemical compound [S]C QSLPNSWXUQHVLP-UHFFFAOYSA-N 0.000 description 1
- 0 *CCCCCOc1cc(OCCC*)cc(*)c1 Chemical compound *CCCCCOc1cc(OCCC*)cc(*)c1 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- QAJQGIKKGDHNMI-UHFFFAOYSA-N CC1(C)C(C(O)=O)OBOC1 Chemical compound CC1(C)C(C(O)=O)OBOC1 QAJQGIKKGDHNMI-UHFFFAOYSA-N 0.000 description 1
- UDIGROVRERQTRH-UHFFFAOYSA-O COc1cc([NH2+]CN)cc(OC)c1 Chemical compound COc1cc([NH2+]CN)cc(OC)c1 UDIGROVRERQTRH-UHFFFAOYSA-O 0.000 description 1
- 238000007445 Chromatographic isolation Methods 0.000 description 1
- 206010010254 Concussion Diseases 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 239000012491 analyte Substances 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000002924 anti-infective effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 238000005415 bioluminescence Methods 0.000 description 1
- 230000029918 bioluminescence Effects 0.000 description 1
- 229940041514 candida albicans extract Drugs 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
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- 238000007872 degassing Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 239000002027 dichloromethane extract Substances 0.000 description 1
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- 230000036457 multidrug resistance Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
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- 125000006633 tert-butoxycarbonylamino group Chemical group 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of applications of conjugated polymer PFP G2.Polymer shown in the Formulas I is in following applications in any one：1) application in the product of variation for the signaling molecule concentration that can cause Microbiological release is prepared；2) application in the product of time that can extend Microbiological release signaling molecule is prepared；3) application in the product that microorganism drug resistance can be caused to change is prepared；4) application in the product for preparing the concentration of signaling molecule of detection Microbiological release；The microorganism can generate signaling molecule and the signaling molecule is responded.The present invention builds novel conjugated polymer-bacterium compound population using the electrostatic interaction and hydrophobic effect between conjugated polymer and bacterium by self-assembling method simulation.The phenomenon that exogenous signals molecule itself luminescence enhancement being responded using vibrio harveyi, the concentration variation of detection signaling molecule, thus the variation of reacting bacteria concentration, and then the variation of reacting bacteria drug resistance.
Description
Technical field
The invention belongs to chemical fields, are related to a kind of application of conjugated polymer PFP-G2.
Background technology
Quorum sensing is the letter that microorganism is referred to as self derivant (Autoinducer, AI) by secreting, discharging one kind
Number molecule, and the variation of its concentration is perceived, to detect population density, regulation and control flora physiological function, so as to adapt to the one of ambient enviroment
Kind signal communication mechanism.The burst size of signaling molecule and the stand density of thalline are closely related, and bacterium can utilize signaling molecule
The population density of itself or other bacteriums in ambient enviroment is perceived to change.When the concentration of signaling molecule reaches certain threshold value, letter
Number molecule will enter inside bacterium, regulate and control the expression of certain specific genes, such as antibiotics production, symbiosis, bioluminescence, solid
Nitrogen gene regulation, sporogenesis, the expression of virulent gene, the engagement transfer of Ti-plasmids, pigment generate, the formation of biomembrane and thin
Flora body mobility etc., among these several factors will all cause bacterium generate drug resistance.
In recent years, the cross discipline of the conjugated polymer with luminous current-conducting characteristic and life science has attracted numerous scientific researches
The interest of worker.Fluorescent conjugated polymer can be used as chemistry and the highly reactive optic delivery body of bio-target molecule, have
Double optic response, can be used to amplify fluorescence sense signal.Work of the domestic and international researchers about conjugated polymer at present
The design of Optical Properties of Novel Conjugated material and synthesis and the foundation of newborn analyte detection, imaging system are concentrated mainly on, but will
Fluorescent conjugated polymer senses applied to bacterial community, explores the phase based on the quorum sensing of conjugated polymer with bacterial drug resistance
Interaction relationship, has not been reported.
Invention content
The object of the present invention is to provide a kind of applications of conjugated polymer PFP-G2.
The present invention provides polymer (namely conjugated polymer PFP-G2) shown in a kind of Formulas I or its is pharmaceutically acceptable
Salt is in following applications in any one：
1) application in the variation for the signaling molecule concentration for causing Microbiological release；
2) application in the time for extending Microbiological release signaling molecule；
3) application in microorganism drug resistance is caused to change；
4) application in the concentration of the signaling molecule of detection Microbiological release；
In the Formulas I, n 3-5, X F, Cl, Br or I；
The microorganism meets following condition：Signaling molecule can be generated and the signaling molecule is responded.
In addition, polymer shown in the Formulas I that the invention described above provides or its pharmaceutically acceptable salt are following arbitrary in preparation
A kind of application in product, also belongs to protection scope of the present invention：
1) application in the variation for the signaling molecule concentration for causing Microbiological release；
2) application in the time for extending Microbiological release signaling molecule；
3) application in microorganism drug resistance is caused to change；
4) application in the concentration of the signaling molecule of detection Microbiological release；
In the Formulas I, n 3-5, X F, Cl, Br or I；
The microorganism meets following condition：Signaling molecule can be generated and the signaling molecule is responded.
Wherein, the structural formula of the signaling molecule is concretely shown in Formula II：
Above application more specifically can be to co-culture compound shown in Formulas I and the microorganism；The item of the culture
Part is conventional microculture condition；Such as Escherichia coli, the temperature of culture is 37 DEG C, and the time of culture can be 1
- 10 hours hours；
The microorganism is bacterium, specially Escherichia coli, more specifically Escherichia coli MG1655 or e. coli k12.
The variation of the signaling molecule concentration for causing Microbiological release concretely makes the signal of the Microbiological release
Molecular concentration is raised and lowered.
It is described that the variation of microorganism drug resistance is caused concretely to increase the drug resistance of the microorganism.
The drug resistance concretely antibiotic-resistant, specially penicillin resistant, more specifically resistance to ampicillin.
The main component of bacterium surface is polysaccharide, protein, lipoid etc., and with negative electrical charge, and polymer carries shown in Formulas I
So bacterium is combined closely by electrostatic interaction and hydrophobic effect with compound, it is multiple to form conjugated polymer-bacterium for positive charge
Gregarious body, the distance between bacterium of furthering, makes bacterium experience the variation of concentration around, releases more signaling molecules.By band
The supernatant for having signaling molecule is added in vibrio harveyi, and vibrio harveyi response exogenous signals molecule, itself luminescence enhancement is shown as
Signal increases at 490nm.By comparing the variation of vibrio harveyi luminous value at 490nm, the large intestine of culture different time can be obtained
The variation of signaling molecule concentration in bacillus supernatant, so as to the variation of reacting bacteria concentration.
The present invention combines the multi-crossed disciplines advantages such as chemistry, material, biology and Medical Microbiology, mutual by electrostatic
Self assembly structure conjugated polymer-micropopulation induction system is acted on, new approaches and Xin Fang are provided to solve bacterial drug resistance
Method can develop for the relevant novel identification of bacterial drug resistance and detection architecture.The mould that microorganism prepares as self-assembled material
Plate, have be easy to get, inexpensively, structured size, the advantages such as environmental-friendly.Fluorescent conjugated polymer shown in Formulas I and bacterial interactions,
The novel intervention school-based built by self assembly has important novelty；Help to understand Plasmid and thin
Bacterium evolution laws, Bacterial multi-drug resistance is formed in order to control, anti-infective therapy and studying for antibiotic provide new thinking and plan
Slightly, new pattern is also provided in the application of biomedicine field for conjugated polymer self-assembled material.
Description of the drawings
Fig. 1 is the growth curve of vibrio harveyi BB170.
Fig. 2 is the luminosity curve of vibrio harveyi BB170.
Fig. 3 is the fluorescence microscope figure of PFP-G2- Escherichia coli MG1655 complexs.
After Fig. 4 responds PFP-G2- Escherichia coli MG1655 complex culture different time supernatants for vibrio harveyi BB170
The luminous intensity figure of 3.5 hours, abscissa are Escherichia coli MG1655 and the incubation time after the effect of polymer shown in Formulas I.
Fig. 5 is survival rate of the PFP-G2- Escherichia coli MG1655 complexs to ampicillin.
Specific embodiment
With reference to specific embodiment, the present invention is further elaborated, but the present invention is not limited to following embodiments.Institute
It is conventional method unless otherwise instructed to state method.Test material used in following embodiments is certainly unless otherwise specified
What routine biochemistry reagent shop was commercially available.Quantitative test in following embodiment is respectively provided with three repeated experiments, as a result makes even
Mean value.
In following embodiments, polymer P FP-G2 shown in Formulas I (n 4, X Cl) can be prepared (X in accordance with the following steps
The method of Formulas I during for F, Br or I is similar, and it is F only to replace corresponding anion in raw material-、Br-Or I-)：
3-N- tertbutyloxycarbonyls-amido -1- propyl alcohol：3- amido -1- propyl alcohol (30g, 0.4mol) and carbonic acid-two-tert-butyl ester
[(Boc) 2O, 87.4g, 0.4mol] is dissolved in 200ml tetrahydrofurans, reacts 6h at room temperature.After reaction stops, it is removed under reduced pressure
Solvent.Crude product silica gel column chromatography separating purification, solvent are methylene chloride/methanol (25/1), obtain the thick liquid of water white transparency
Body 65.2g, yield 93%.1H-NMR:(300MHz,CDCl3,ppm)δ:1.44(s,9H),1.65(m,2H),3.26(b,2H),
3.66(t,2H,11.5),5.01(b,1H,NH).
3-N- tertbutyloxycarbonyls-amido -1- propoxyl group -4 '-methylphenyl sulfoxide：3-N- tertbutyloxycarbonyls-amido -1-
Propyl alcohol (35g, 0.2mol) is dissolved in the in the mixed solvent (v/v, 3/1) of 150ml tetrahydrofurans and water, and reaction solution is cooled to 0 DEG C,
Sodium hydroxide (16g, 0.4mol) is added in, stirs to sodium hydroxide and is completely dissolved, be slowly added dropwise dissolved with paratoluensulfonyl chloride
The tetrahydrofuran solution 80ml (more than 1h) of (57.2g, 0.3mol) after being added dropwise, is reacted and is gradually got warm again after a cold spell to room temperature, continues anti-
Answer 12h.After reaction stops, solvent is removed under reduced pressure.Crude product silica gel column chromatography separating purification, solvent are petroleum ether/acetic acid second
Ester (5/1) obtains colorless transparent viscous liquid 55.2g, yield 84%.1H-NMR:(400MHz,CDCl3,ppm)δ:1.44(s,
9H), 1.83 (m, 2H), 2.45 (s, 3H), 3.16 (b, 2H), 4.08 (t, 2H, J=11.1), 4.65 (b, 1H, NH), 7.70 (d,
2H, J=7.1), 7.79 (d, 2H, J=7.0)
9,9 2-(4 '-hydroxyl)-phenyl-2,7- dibromo fluorenes：Phenol (7.52g, 80mmol) is added in 50ml reaction bulbs
55 DEG C are warming up to, makes its thawing, under nitrogen protection, is rapidly added 9- carbonyl -2,7- dibromos fluorenes (3.38g, 10mmol) and methylsulphur
Sour (0.67ml, 67mmol) is warming up to 135 DEG C, reacts 4h.After reaction stops, excessive phenol is removed under reduced pressure.Crude product silica gel
Column chromatographic isolation and purification, solvent are petrol ether/ethyl acetate (4/1), obtain white solid 4.4g, yield 87%.1H-NMR:
(400MHz,d6-DMSO,ppm)δ:6.66 (d, 4H, J=8.7), 6.89 (d, 4H, J=8.7), 7.52 (s, 2H), 7.58 (d,
2H, J=5.7), 7.89 (d, 2H, J=10.3), 9.50 (s, 2H, OH) .ESI-MS (m/z):508,M+.
3,5- bis--[3- (tert-butoxycarbonylamino) propoxyl group]-benzyl alcohol：3,5- dihydroxybenzyl alcohols (8.4g60mmol)
With K2CO3(41.46g300mmol) is dissolved in 200ml acetone, sequentially adds 3-N- tertbutyloxycarbonyls-the third oxygen of amido -1-
Base -4 '-methylphenyl sulfoxide (41.46g, 126mmol) and a small amount of 18- crown-s 6 are used as phase transfer catalyst.It is anti-under nitrogen atmosphere
Liquid is answered to be warming up to 70 DEG C, reacts 3d.After reaction stops and is cooled to room temperature, reaction solution is poured into 150ml water, and uses dichloromethane
It extracts (80ml × 3), merges organic phase, be washed with distilled water (50ml × 3), anhydrous magnesium sulfate drying is filtered, concentration.Thick production
Object silica gel column chromatography separating purification, solvent are petrol ether/ethyl acetate (5/2), obtain colorless transparent viscous liquid product
19.9g, yield 73%.1H-NMR(400MHz,CDCl3):δ(ppm)1.44(m,18H),1.95(m,4H),3.31(m,4H),
3.98 (t, 4H, J=13.2), 4.61 (s, 2H), 4.76 (br, 2H, NH), 6.36 (s, 1H), 6.51 (s, 2H) .13C-NMR
(100MHz,CDCl3):δ(ppm)28.3,29.5,38.7,66.1,68.3,79.8,100.7,107.3,139.7,155.6,
159.6.MALDI-TOF:477.8[M+Na].Anal.Calcd for C23H37O6N2Br:C,60.77；H,8.43；N,
6.16.Found:C,61.23；H,8.51；N,5.83.
3,5- bis--[3- (tert-butoxycarbonylamino) propoxyl group]-benzyl bromine：3,5- bis--[the third oxygen of 3- (tert-butoxycarbonylamino)
Base]-benzyl alcohol (19.5g, 43mmol), triethylamine (TEA, 5.98g, 60mmol) is dissolved in 150ml anhydrous tetrahydro furans, instead
Liquid is answered to be cooled to 0 DEG C, methylsulphur isoxazolecarboxylic acid (7.42g, 64.6mmol) is slowly added dropwise.After being added dropwise, 30min is reacted at 0 DEG C, so
After get warm again after a cold spell to room temperature the reaction was continued 2h, obtain methanesulfonates.Reaction system does not detach, be directly added into lithium bromide (22.5g,
215mmol) the reaction was continued 16h.After reaction stops, reaction solution is poured into 100ml water, and extracts (50ml × 3) with dichloromethane,
Merge organic phase, be washed with distilled water (50ml × 3), anhydrous magnesium sulfate drying is filtered, concentration.Crude product silica gel column chromatography point
From purifying, solvent is petrol ether/ethyl acetate (3/1), obtains white solid product 20.45g, yield 92%.1H-NMR
(400MHz,CDCl3):δ (ppm) 1.44 (m, 18H), 1.98 (m, 4H), 3.32 (m, 4H), 3.99 (t, 4H, J=12.7),
4.49(s,2H),4.72(br,2H,NH),6.36(s,1H),6.52(s,2H).13C-NMR(100MHz,CDCl3):δ(ppm)
28.4,29.5,33.4,37.9,65.8,79.2,101.5,107.6,139.3,155.9,160.0.MALDI-TOF:540.2[M
+Na].Anal.Calcd for C23H38O7N2:C,53.39；H,7.21；N,5.41.Found:C,53.83；H,7.16；N,
5.32.
Second generation benzyl alcohol：3,5- dihydroxybenzyl alcohols (1.7g, 12.2mmol) and K2CO3(8.44g, 61mmol) dissolves
In 200ml acetone, sequentially add 3,5- bis--[3- (tert-butoxycarbonylamino) propoxyl group]-benzyl bromine (12.92g,
12.5mmol) and a small amount of 18- crown-s 6 are used as phase transfer catalyst.Reaction solution is warming up to 70 DEG C under nitrogen atmosphere, reacts 2d.Reaction
After stopping and being cooled to room temperature, reaction solution is poured into 100ml water, and is extracted (50ml × 3) with dichloromethane, merges organic phase,
It is washed with distilled water (50ml × 3), anhydrous magnesium sulfate drying is filtered, concentration.Crude product silica gel column chromatography separating purification, expansion
Agent is petrol ether/ethyl acetate (1/1), obtains colorless transparent viscous liquid product 7.65g, yield 62%.1H-NMR
(400MHz,CDCl3):δ (ppm) 1.44 (m, 36H), 1.94 (m, 8H), 3.30 (m, 8H), 4.01 (t, 8H, J=13.7),
4.63(s,2H),4.77(br,2H,NH),4.96(m,4H),6.39(s,2H),6.51(s,1H),6.55(m,4H),6.61(m,
2H).13C-NMR(100MHz,CDCl3):δ(ppm)28.3,29.4,38.7,65.7,68.4,69.9,79.2,100.8,
101.9,105.8,107.6,138.9,139.7,156.1,159.8,160.1.MALDI-TOF:1035.8[M+Na]
.Anal.Calcd for C53H80O15N4:C,62.81；H,7.96；N,5.53.Found:C,63.26；H,7.87；N,5.45.
Second generation benzyl bromine：Second generation benzyl alcohol (7.2g, 7.12mmol), triethylamine (TEA, 0.99g, 10mmol) are dissolved in
In 80ml anhydrous tetrahydro furans, reaction solution is cooled to 0 DEG C, and methylsulphur isoxazolecarboxylic acid (1.24g, 10.8mmol) is slowly added dropwise.It drips
Bi Hou reacts 30min at 0 DEG C, then gets warm again after a cold spell to room temperature the reaction was continued 2h, obtain methanesulfonates.Reaction system does not detach, directly
Add in lithium bromide (3.74g, 35.2mmol) the reaction was continued 16h.After reaction stops, reaction solution is poured into 100ml water, and uses dichloro
Methane extracts (50ml × 3), merges organic phase, is washed with distilled water (50ml × 3), and anhydrous magnesium sulfate drying is filtered, concentration.
Crude product silica gel column chromatography separating purification, solvent are petrol ether/ethyl acetate (1/1), obtain colorless transparent viscous liquid production
Object 5.92g, yield 77%.1H-NMR(400MHz,CDCl3):δ(ppm)1.44(m,36H),1.95(m,8H),3.31(m,
8H), 3.99 (t, 8H, J=11.8), 4.41 (s, 2H), 4.51 (br, 2H, NH), 4.95 (m, 4H), 6.41 (s, 2H), 6.48
(s,1H),6.56(m,4H),6.62(m,2H).13C-NMR(100MHz,CDCl3):δ(ppm)28.4,29.4,33.5,38.7,
65.8,69.9,79.1,100.9,102.0,105.9,108.1,138.9,139.8,156.0,159.9,160.1.MALDI-
TOF:1115.8[M+K].Anal.Calcd for C53H79O14N4Br:C,59.12；H,7.40；N,5.21.Found:C,
59.56；H,7.56；N,5.34.
Monomer：9,9 2-(4 '-hydroxyl)-phenyl-2,7- dibromos fluorenes (0.508g, 1mmol) and K2CO3(0.694g5mmol)
It is dissolved in 50ml acetone, sequentially adds second generation benzyl bromine (2.15g, 2mmol) and a small amount of 18- crown-s 6 are used as phase transfer catalysis (PTC)
Agent.Reaction solution is warming up to 70 DEG C under nitrogen atmosphere, reacts 2d.After reaction stops and is cooled to room temperature, reaction solution pours into 100ml water
In, and extracted (50ml × 3) with dichloromethane, merge organic phase, be washed with distilled water (50ml × 3), anhydrous magnesium sulfate drying,
Filtering, concentration.Crude product utilizes silica gel column chromatography separating purification, and solvent is petrol ether/ethyl acetate (2/3), is obtained colourless
Bright viscous liquid product 1.29g, yield 52%.1H-NMR(400MHz,CDCl3):δ(ppm)1.44(m,72H),1.96(t,
16H), 3.31 (m, 16H), 4.00 (t, 16H, J=11.6), 4.78 (br, 8H, NH), 4.95 (s, 12H), 6.40 (s, 4H),
6.56 (s, 10H), 6.66 (s, 4H), 6.84 (d, 4H, J=8.3), 7.04 (d, 4H, J=8.9), 7.47 (d, 4H, J=8.7),
7.64 (d, 2H, J=7.3) .13C-NMR (100MHz, CDCl3):δ(ppm)28.4,29.4,37.9,54.9,65.8,69.9,
79.2,100.9,101.6,105.9,106.4,114.8,121.6,121.8,128.4,129.0,129.2,130.8,132.0,
137.9,139.1,139.3,153.6,156.0,157.9,159.8,160.1,160.2.MALDI-TOF:2535[M+K]
.Anal.Calcd for C131H172O30N8Br2:C,62.97；H,6.94；N,4.48.Found:C,63.39；H,6.82；N,
4.32.
Polymer B oc-PFP-G2：Monomer (0.4992g 0.2mmol) and 5,5- dimethyl -2- (4- (5,5- dimethyl -
1,3,2- dioxaborinate -2- phenyl) -1,3,2- dioxaborinates (0.0603g 0.2mmol) are dissolved in 5ml toluene, add
Enter 3ml 2M K2CO3Solution, degassing, nitrogen protection is lower to add in 10mg catalyst Pd (PPh3)4.In a nitrogen atmosphere, it is warming up to
100 DEG C, react 48h.After stopping reacting and being cooled to room temperature, reaction solution is poured into 50ml distilled water, chloroform extraction (30ml ×
3), merge organic phase, anhydrous magnesium sulfate drying is filtered, concentration.Residue is dissolved with minimal amount of chloroform, and in 100ml acetone
It is precipitated out, centrifuges in solution.Crude product repeats to settle in acetone twice, vacuum drying.Obtain brownish black solid
0.187g, yield 39%.1H-NMR(400MHz,CDCl3):δ(ppm)1.42(br,72H),1.92(br,16H),3.27(br,
16H),3.95(br,16H),4.82(br,8H,NH),4.91(br,12H),6.36(br,4H),6.52(br,12H),6.61
(br,4H),6.82(br,6H),7.64(br,8H),7.70(br,2H).13C-NMR(100MHz,CDCl3):δ(ppm)28.4,
29.3,37.8,54.9,65.9,69.9,79.2,100.8,101.7,105.9,106.4,114.8,121.7,121.9,
128.3,129.0,129.2,129.6,130.8,132.0,132.7,137.9,139.2,139.3,153.5,156.1,
157.8,159.7,160.1,160.2.
Compound PFP-G2 shown in Formulas I：Polymer B oc-PFP-G2 (0.150g, 0.062mmol), is dissolved in 5ml 1,4-
In dioxane, be protected from light and nitrogen atmosphere under add in 6MHCl (2ml, 12mmol), reaction for 24 hours.After reaction stops, decompression
It goes out solvent, crude product settles in acetone, centrifuges, vacuum drying.Obtain brownish black solid 0.118g, structure verification data
It is compound PFP-G2 shown in target compound Formulas I to prove the compound.1H-NMR(400MHz,DMSO-d6):δ(ppm)1.98
(br,16H)2.94(br,16H),4.01(br,8H),4.94(br,12H),6.46(br,4H),6.59(br,8H),6.95
(br,4H),7.21(br,4H),7.59-7.62(br,10H),7.96(br,24H,NH3+)。
Embodiment 1, the growth of vibrio harveyi and luminosity curve
(1), the recovery culture of vibrio harveyi
Using vibrio harveyi BB170 as template, Kazakhstan arc is housed to purchasing with 75% alcohol absorbent cotton in superclean bench
After the ampere bottle outer surface of bacterium BB170 carries out disinfection, its top, drop 300-400 μ L sterile waters to the peace heated are heated with flame
Small jar bottle top is allowed to rupture.The suitable fluid nutrient mediums (can be replaced with sterile water) of 300-500 μ L are drawn, are instilled in ampoule bottle,
Gently oscillation piping and druming makes the dissolving of freeze-drying thalline draw whole bacteria suspensions in suspension, transplant consolidate in the two 2216 raw bacterium in sea respectively
In body culture medium, 30 DEG C are cultivated 24 hours.Appropriate thalline picture Z-type, which is scraped, with oese is inoculated into the raw bacterium solids training in 2216 new seas
It supports in base, 30 DEG C are continued to cultivate, and the so continuous 3-4 that passes is commissioned to train foster, obtains stable bacterial strain, and putting 4 DEG C, to make strain spare.
The raw bacteria liquid culture medium in 2216 sea and the 2216 raw bacterium solid medium bacterium in sea win biology purchased from Qingdao GaoKeYuan sea
Technology Co., Ltd.；Vibrio harveyi BB170 is purchased from ATCC, and number is：BAA-1117.
(2), the growth curve of vibrio harveyi measures
Appropriate thalline is in the raw bacteria liquid culture medium in 2216 seas or AB fluid nutrient mediums in picking solid medium, at 30 DEG C
Rotating speed 180rpm shake cultures are to OD600It is worth for 0.7-1.2.After a small amount of bacterium solution AB culture mediums is taken to dilute 1000 times, at 30 DEG C
Rotating speed 180rpm shake cultures surveyed its OD every 30 minutes600It is worth (Fig. 1).
The AB fluid nutrient mediums can according to document (E.P.Greenberg, J.W.Hastings, S.Ulitzur,
Arch.Microbiol.1979,120,87. it) prepares.
(3), the luminosity curve of vibrio harveyi measures
Appropriate thalline is in the raw bacteria liquid culture medium in 2216 seas or AB fluid nutrient mediums in picking solid medium, at 30 DEG C
Rotating speed 180rpm shake cultures are to OD600It is worth for 0.7-1.2.After a small amount of bacterium solution AB culture mediums is taken to dilute 1000 times, at 30 DEG C
Rotating speed 180rpm shake cultures surveyed luminous value at its 490nm every 30 minutes.Vibrio harveyi BB170 itself shines minimum institute
The corresponding time is 3.5 hours (Fig. 2).
Embodiment 2, Escherichia coli MG1655 and conjugated polymer PFP-G2 imaging experiments
(1), the recovery culture of Escherichia coli
By taking Escherichia coli MG1655 as an example, Escherichia coli are housed to purchasing with 75% alcohol absorbent cotton in superclean bench
After the ampere bottle outer surface of MG1655 carries out disinfection, its top, drop 300-400 μ L sterile waters to the ampoule heated are heated with flame
Bottle top is allowed to rupture.The suitable fluid nutrient mediums (can be replaced with sterile water) of 300-500 μ L are drawn, are instilled in ampoule, gently
Oscillation piping and druming, making the dissolving of freeze-drying thalline, the whole bacteria suspensions of absorption are transplanted respectively in two LB solid mediums in suspension,
Rotating speed 180rpm is cultivated 12 hours at 37 DEG C.Appropriate thalline picture Z-type is scraped with oese to be inoculated into new LB solid mediums,
Rotating speed 180rpm continues to cultivate at 37 DEG C, and the so continuous 3-4 that passes is commissioned to train foster, obtains stable bacterial strain, and putting 4 DEG C, to make strain spare.
The LB fluid nutrient mediums constituent is by weight percentage：1.0% tryptone, 0.5% yeast extract,
1%NaCl, 97.5% distilled water；LB solid culture based formulas is：The fine jade of 1.2%-1.5% is added in into LB fluid nutrient mediums
Fat；
Escherichia coli MG1655 is purchased from Chinese agriculture Culture Collection ACCC, and number is：ACCC
No.11202。
(2), the fluorescence microscope of PFP-G2- bacteriums compound population
Appropriate MG1655 thalline are in LB fluid nutrient mediums in picking solid medium, rotating speed 180rpm concussions training at 37 DEG C
5-10h is supported, with LB culture keynotes OD600Be worth is 1.0.After a small amount of bacterium solution LB culture mediums is taken to dilute 1000 times, final concentration is added in
For PFP-G2 polymer shown in 100 μM of Formulas I, rotating speed 180rpm shake culture 6h at 37 DEG C take 10 μ L to mix liquid in fluorescence microscopy
Microscopic observation.
It can be seen that the Escherichia coli MG1655 of light field is formed very with PFP-G2 polymer shown in Formulas I under fluorescence microscope
Good complex, the wherein fluorescent places of PFP-G2 are completely superposed (Fig. 3) with complex.
Influence of the PFP-G2 polymer shown in embodiment 3, Formulas I to signaling molecule shown in Formula II in Escherichia coli MG1655
(1), the recovery culture of Escherichia coli MG1655
With (one) the step of embodiment 2.
(2), the synthesis of PFP-G2 polymer shown in Formulas I
With (two) the step of embodiment 2.
(3), the polymer of compound PFP-G2 shown in Formulas I is introduced into Escherichia coli MG1655
Appropriate Escherichia coli MG1655 is in LB fluid nutrient mediums in picking LB solid mediums, rotating speed 180rpm at 37 DEG C
Shake culture 5-10h, with LB culture keynotes OD600Be worth is 1.0.After a small amount of bacterium solution LB culture mediums is taken to dilute 1000 times, add in
PFP-G2 polymer, control group are not added with PFP-G2 shown in final concentration of 100 μM of Formulas I.Rotating speed 180rpm shake cultures at 37 DEG C
Bacterium solution is centrifuged 5min by 1-8h with the centrifugal force room temperature of 11000g, recycles supernatant, and as main component is signal shown in Formula II
The solution of molecule.
(4), the recovery culture of vibrio harveyi BB170
With (one) the step of embodiment 1.
(5), conjugated polymer PFP-G2 shown in Formulas I is to signaling molecule concentration shown in Formula II in Escherichia coli MG1655
It influences
Appropriate BB170 thalline are in the raw bacteria liquid culture medium in 2216 seas in the 2216 raw bacterium solid medium in sea of picking, 30 DEG C
Lower rotating speed 180rpm shake cultures are to OD600It is worth for 0.7-1.2.A small amount of bacterium solution AB culture mediums is taken to dilute 1000 times, to 180 μ L
Supernatant obtained by 20 μ L step (3) are added in dilution cultivates 3.5h in 30 DEG C of shaking tables, is surveyed at its 490nm with microplate reader
Luminous value, conjugated polymer PFP-G2 shown in reaction equation I and Escherichia coli MG1655 are formed shown in the Formula II discharged after complex
The variation (Fig. 4) of signaling molecule concentration.
In control group, the concentration of signaling molecule shown in Formula II reaches peak in 5h, is reduced rapidly at 6h-8h.
In experimental group, the concentration of signaling molecule shown in Formula II maintains a higher concentration, formula I institutes in 4h-8h
Show the concentration raising of signaling molecule shown in the Formula II that PFP-G2 polymer can discharge Escherichia coli MG1655, and can extend
The time of signaling molecule shown in the Formula II of Escherichia coli MG1655 releases.
Influences of the conjugated polymer PFP-G2 to Escherichia coli MG1655 drug resistances shown in embodiment 4, Formulas I
(1), the recovery culture of Escherichia coli MG1655
With (one) the step of embodiment 2.
(2), Escherichia coli MG1655 adds in the viability study of ampicillin
Appropriate Escherichia coli MG1655 is in LB fluid nutrient mediums in picking LB solid mediums, rotating speed 180rpm at 37 DEG C
Shake culture 5-10h, with LB culture keynotes OD600Be worth is 1.0.After a small amount of bacterium solution LB culture mediums is taken to dilute 1000 times, add in
Final concentration of 100 μM of PFP-G2, control group are not added with PFP-G2, rotating speed 180rpm shake cultures 6h at 37 DEG C.It is trained with LB liquid
It supports base and above-mentioned culture is diluted 10 times, and the ampicillin of final concentration of 0.5mg/mL is added in it, rotating speed at 37 DEG C
180rpm shake cultures surveyed its OD every 30 minutes600The ratio of value, experimental group and control group is the survival rate of Escherichia coli
(Fig. 5).
After adding in ampicillin, with the increase of incubation time, Escherichia coli MG1655's deposits in experimental group and control group
Motility rate reduces, however same incubation time adds in control group survival rate of the experimental group survival rate than being not added with PFP-G2 of PFP-G2
Height, PFP-G2 compounds shown in formula I can extend the time of signaling molecule shown in the Formula II of Escherichia coli MG1655 releases,
And then increase the drug resistance of Escherichia coli, than control group more drug resistance.
Claims (21)
1. polymer shown in Formulas I is in following applications in any one：
1) application in the variation for the signaling molecule concentration for causing Microbiological release；
2) application in the time for extending Microbiological release signaling molecule；
3) application in microorganism drug resistance is caused to change；
4) application in the concentration of the signaling molecule of detection Microbiological release；
In the Formulas I, n 3-5, X F, Cl, Br or I；
The microorganism meets following condition：Signaling molecule can be generated and the signaling molecule is responded；
The structural formula of the signaling molecule is as shown in Formula II：
The microorganism is Escherichia coli.
2. application of the polymer shown in Formulas I in any one following product is prepared：
1) application in the product of variation for the signaling molecule concentration that can cause Microbiological release is prepared；
2) application in the product of time that can extend Microbiological release signaling molecule is prepared；
3) application in the product that microorganism drug resistance can be caused to change is prepared；
4) application in the product for preparing the concentration of signaling molecule of detection Microbiological release；
In the Formulas I, n 3-5, X F, Cl, Br or I；
The microorganism meets following condition：Signaling molecule can be generated and the signaling molecule is responded；
The structural formula of the signaling molecule is as shown in Formula II：
The microorganism is Escherichia coli.
3. application according to claim 1 or 2, it is characterised in that：The Escherichia coli are Escherichia coli MG1655 or big
Enterobacteria K12.
4. according to claims 1 or 2 application, it is characterised in that：The variation of the signaling molecule concentration for causing Microbiological release
Signaling molecule concentration to make the Microbiological release is raised and lowered.
5. application according to claim 3, it is characterised in that：The change of the signaling molecule concentration for causing Microbiological release
Turning to is raised and lowered the signaling molecule concentration of the Microbiological release.
6. application according to claim 1 or 2, it is characterised in that：It is described to cause the variation of microorganism drug resistance described to make
The drug resistance of microorganism increases.
7. application according to claim 3, it is characterised in that：It is described to cause the variation of microorganism drug resistance to make micro- life
The drug resistance of object increases.
8. application according to claim 4, it is characterised in that：It is described to cause the variation of microorganism drug resistance to make micro- life
The drug resistance of object increases.
9. application according to claim 5, it is characterised in that：It is described to cause the variation of microorganism drug resistance to make micro- life
The drug resistance of object increases.
10. application according to claim 1 or 2, it is characterised in that：The drug resistance is antibiotic-resistant.
11. application according to claim 10, it is characterised in that：The drug resistance is penicillin resistant.
12. application according to claim 11, it is characterised in that：The drug resistance is resistance to ampicillin.
13. application according to claim 3, it is characterised in that：The drug resistance is antibiotic-resistant.
14. application according to claim 13, it is characterised in that：The drug resistance is penicillin resistant.
15. application according to claim 14, it is characterised in that：The drug resistance is resistance to ampicillin.
16. application according to claim 4, it is characterised in that：The drug resistance is antibiotic-resistant.
17. application according to claim 16, it is characterised in that：The drug resistance is penicillin resistant.
18. application according to claim 17, it is characterised in that：The drug resistance is resistance to ampicillin.
19. application according to claim 6, it is characterised in that：The drug resistance is antibiotic-resistant.
20. application according to claim 19, it is characterised in that：The drug resistance is penicillin resistant.
21. application according to claim 20, it is characterised in that：The drug resistance is resistance to ampicillin.
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