CN112574227A - A class of pH probes with spirolactone-linked morpholine structure and their synthesis methods and applications - Google Patents
A class of pH probes with spirolactone-linked morpholine structure and their synthesis methods and applications Download PDFInfo
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- CN112574227A CN112574227A CN202011473620.9A CN202011473620A CN112574227A CN 112574227 A CN112574227 A CN 112574227A CN 202011473620 A CN202011473620 A CN 202011473620A CN 112574227 A CN112574227 A CN 112574227A
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- spirolactam
- rhodamine
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- 239000000523 sample Substances 0.000 title claims abstract description 57
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 title claims abstract description 10
- 238000001308 synthesis method Methods 0.000 title abstract description 4
- LXMSZDCAJNLERA-ZHYRCANASA-N spironolactone Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)SC(=O)C)C[C@@]21CCC(=O)O1 LXMSZDCAJNLERA-ZHYRCANASA-N 0.000 title abstract 2
- 229960002256 spironolactone Drugs 0.000 title abstract 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 14
- 239000000543 intermediate Substances 0.000 claims description 14
- -1 hydrogen Chemical class 0.000 claims description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
- 239000003208 petroleum Substances 0.000 claims description 8
- 238000010898 silica gel chromatography Methods 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 7
- PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 150000002431 hydrogen Chemical class 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- RWIVICVCHVMHMU-UHFFFAOYSA-N n-aminoethylmorpholine Chemical compound NCCN1CCOCC1 RWIVICVCHVMHMU-UHFFFAOYSA-N 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- 239000003638 chemical reducing agent Substances 0.000 claims description 4
- 239000003480 eluent Substances 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 238000001704 evaporation Methods 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- VYXSBFYARXAAKO-WTKGSRSZSA-N chembl402140 Chemical compound Cl.C1=2C=C(C)C(NCC)=CC=2OC2=C\C(=N/CC)C(C)=CC2=C1C1=CC=CC=C1C(=O)OCC VYXSBFYARXAAKO-WTKGSRSZSA-N 0.000 claims description 3
- 238000003384 imaging method Methods 0.000 claims description 3
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 3
- MUSLHCJRTRQOSP-UHFFFAOYSA-N rhodamine 101 Chemical compound [O-]C(=O)C1=CC=CC=C1C(C1=CC=2CCCN3CCCC(C=23)=C1O1)=C2C1=C(CCC1)C3=[N+]1CCCC3=C2 MUSLHCJRTRQOSP-UHFFFAOYSA-N 0.000 claims description 3
- 229940043267 rhodamine b Drugs 0.000 claims description 3
- 239000012279 sodium borohydride Substances 0.000 claims description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 3
- JNGRENQDBKMCCR-UHFFFAOYSA-N 2-(3-amino-6-iminoxanthen-9-yl)benzoic acid;hydrochloride Chemical compound [Cl-].C=12C=CC(=[NH2+])C=C2OC2=CC(N)=CC=C2C=1C1=CC=CC=C1C(O)=O JNGRENQDBKMCCR-UHFFFAOYSA-N 0.000 claims description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 2
- 230000029918 bioluminescence Effects 0.000 claims description 2
- 238000005415 bioluminescence Methods 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- 229910000085 borane Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 238000013375 chromatographic separation Methods 0.000 claims description 2
- 230000006837 decompression Effects 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 239000000741 silica gel Substances 0.000 claims description 2
- 229910002027 silica gel Inorganic materials 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- WGTODYJZXSJIAG-UHFFFAOYSA-N tetramethylrhodamine chloride Chemical compound [Cl-].C=12C=CC(N(C)C)=CC2=[O+]C2=CC(N(C)C)=CC=C2C=1C1=CC=CC=C1C(O)=O WGTODYJZXSJIAG-UHFFFAOYSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims 2
- 238000012863 analytical testing Methods 0.000 claims 1
- 125000000753 cycloalkyl group Chemical group 0.000 claims 1
- 125000004417 unsaturated alkyl group Chemical group 0.000 claims 1
- 238000001514 detection method Methods 0.000 abstract description 10
- 238000004458 analytical method Methods 0.000 abstract description 4
- 238000000799 fluorescence microscopy Methods 0.000 abstract description 3
- 238000001228 spectrum Methods 0.000 description 18
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 239000011550 stock solution Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 239000000243 solution Substances 0.000 description 5
- 238000001035 drying Methods 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 239000007853 buffer solution Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 description 3
- 239000011707 mineral Substances 0.000 description 3
- 239000001022 rhodamine dye Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 230000002159 abnormal effect Effects 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 210000003712 lysosome Anatomy 0.000 description 2
- 230000001868 lysosomic effect Effects 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 210000003463 organelle Anatomy 0.000 description 2
- 238000009987 spinning Methods 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000012472 biological sample Substances 0.000 description 1
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 description 1
- 238000003759 clinical diagnosis Methods 0.000 description 1
- 238000001218 confocal laser scanning microscopy Methods 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 230000002900 effect on cell Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000001139 pH measurement Methods 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 230000002123 temporal effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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- C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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Abstract
本发明属于分析检测领域，具体涉及一类具有螺内胺连接吗啉结构的pH探针及其合成方法和应用。本发明基于螺内胺连接吗啉基团构建pH探针，通过替换荧光团实现对pH检测范围的控制，其合成方法具有总产率高、反应条件简单、操作方便、能够大量制备、底物选择范围广等优点。可应用于分析检测、生物荧光成像等领域。
The invention belongs to the field of analysis and detection, and in particular relates to a pH probe having a spirolactam-linked morpholine structure, a synthesis method and application thereof. The invention constructs a pH probe based on spirolactone connecting a morpholine group, and realizes the control of the pH detection range by replacing the fluorophore. A wide range of options and other advantages. It can be used in the fields of analysis and detection, biological fluorescence imaging, etc.
Description
Technical Field
The invention belongs to the field of analysis and detection, and particularly relates to a pH probe with a spirolactam-connected morpholine structure, and a synthesis method and application thereof.
Background
The stable pH in vivo is an important factor in maintaining normal physiological activities, and is typically within the range of 4.5-8.0 in mammalian cells, while the pH in different organelles varies, e.g., the pH in the cytoplasmic matrix is typically 6.8-7.4, and the pH in lysosomes is about 4.0-6.0. When the pH of the cell or organelle deviates from the above range, abnormal growth states and metabolic processes are implied. Establishing a link between these abnormal phs and related diseases has become a leading hotspot in the biomedical field today. Therefore, accurate measurement and visualization of intracellular pH is of great importance for biological research and clinical diagnosis. Because the cell and subcellular system is different from the macroscopic solution system, it also means that the traditional pH test paper or pH meter can not be used in the pH test in the cell environment.
In recent years, the fluorescence probe method has been widely used in the pH detection of biological samples due to its advantages of simple operation, strong visibility, small amount of sample required, good selectivity, high spatial and temporal resolution, and small toxic and side effects on cells. However, existing pH probes can only detect within a few immobilized pH ranges and the wavelength selection is limited. The pH probe is constructed based on spiro-lactam connected morpholine groups, and the control of the pH detection range is realized by replacing fluorophores.
Disclosure of Invention
The invention aims to construct a probe capable of realizing pH detection by connecting a morpholine group with spirolactam, and the probe plays a role in the fields of analysis and detection, biological fluorescence imaging and the like.
In order to achieve the aim, the invention provides a pH probe with a spirolactam-linked morpholine structure, and the pH probe has the structure
Wherein:
R1、R2each independently hydrogen, C1-C5 linear or branchedA saturated or unsaturated hydrocarbon group selected from: methyl, ethyl, n-propyl, isopropyl, allyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl;
R3、R4respectively hydrogen, fluorine, chlorine and methyl;
R1or R2And R3Or R4Connected by carbon chains to form a five-membered or six-membered ring structure with a parent benzene ring.
Preferably, said R is1、R2Hydrogen, methyl, ethyl are preferred.
Preferably, the preparation method of the probe comprises the following steps:
(1) synthesis of key spirolactam intermediates
Dissolving 1.0 mol of rhodamine, 3.0 mol of N- (2-aminoethyl) morpholine and 1.1 mol of onium salt catalyst in dichloromethane, stirring and reacting at room temperature for 48 hours, evaporating the solvent under vacuum reduced pressure, and then separating by silica gel column chromatography, wherein the eluent is a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of ethyl acetate: and (3) obtaining a key spirolactam intermediate by using petroleum ether at a ratio of 1: 1-10, wherein the reaction process is as follows:
(2) reduction of key spirolactam intermediate to generate pH probe with spirolactam structure
Dissolving key spirolactam intermediate in 1.0 molar amount and reductant in 5.0 molar amount in tetrahydrofuran, reacting at 70 deg.c for 8 hr, evaporating to eliminate solvent under vacuum and decompression condition, and chromatographic separation with silica gel column to obtain mixed solvent of petroleum ether and ethyl acetate as eluent, ethyl acetate: obtaining the pH probe with a spirolactam structure by using petroleum ether at a ratio of 1: 1-10, wherein the reaction process comprises the following steps:
preferably, the rhodamine in the step (1) is one of rhodamine B, rhodamine 6G, rhodamine 110, rhodamine 101 and tetramethyl rhodamine.
Preferably, the onium salt catalyst in step (1) is one of 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate, benzotriazole-N, N, N ', N' -tetramethyluronium hexafluorophosphate or 1H-benzotriazole-1-yloxytripyrrolidinylphosphonium hexafluorophosphate.
Preferably, the reducing agent in step (2) is one of hydrogen, borane, sodium borohydride or lithium aluminum hydride.
Preferably, the pH probe is preferably used in analytical detection or bioluminescence imaging.
Compared with the prior art, the invention has the beneficial effects that: the spirolactam-linked morpholine structure is introduced into the rhodamine dye by a simple and efficient method to obtain the probe capable of detecting the pH of the environment where the molecule is located, the pH range which can be detected by the probe can be adjusted by changing the structure of the linked rhodamine dye, and the spirolactam-linked rhodamine dye can be applied to the fields of solution pH detection, biological pH fluorescence imaging and the like.
Drawings
FIG. 1 is a schematic diagram of the structure of the pH probe according to the present invention;
FIG. 2 is a nuclear magnetic spectrum hydrogen spectrum of the probe prepared in example 1 of the present invention;
FIG. 3 is a nuclear magnetic spectrum carbon spectrum of the probe prepared in example 1 of the present invention;
FIG. 4 is a nuclear magnetic spectrum hydrogen spectrum of the probe prepared in example 2 of the present invention;
FIG. 5 is a nuclear magnetic spectrum carbon spectrum of a probe prepared in example 2 of the present invention;
FIG. 6 is a nuclear magnetic spectrum hydrogen spectrum of the probe prepared in example 3 of the present invention;
FIG. 7 is a nuclear magnetic spectrum carbon spectrum of a probe prepared in example 3 of the present invention;
FIG. 8 is a graph showing the change of fluorescence intensity with pH of a probe prepared in example 3 of the present invention;
FIG. 9 is a standard curve of the probe prepared in example 1 of the present invention for pH measurement of a solution;
FIG. 10 is a graph showing the change of fluorescence intensity with pH of a probe prepared in example 2 of the present invention;
FIG. 11 is a graph showing the effect of the probe prepared in example 2 on Hela cell staining confocal fluorescence imaging.
Detailed Description
The present invention will be further described with reference to examples.
Example 1
442mg of rhodamine B, 390mg of N- (2-aminoethyl) morpholine and 572mg of Pybop are mixed, dissolved in 30mL of dichloromethane, stirred at room temperature for 48 hours, and then the solvent is dried by spin-drying, and purified by silica gel column chromatography to obtain 500mg of a spirolactam intermediate. Dissolving 200mg of spirolactam intermediate in 20mL of tetrahydrofuran, adding 75mg of lithium aluminum hydride, reacting at 70 ℃ for 8 hours, cooling to room temperature, and purifying by spin-drying solvent silica gel column chromatography to obtain 120mg of target pH probe, wherein the reaction process comprises the following steps:
the nuclear magnetic hydrogen spectrum and nuclear magnetic carbon spectrum of the synthesized pH probe are shown in figure 1 and figure 2 respectively, and the specific data are as follows:
1H NMR(400MHz,CDCl3)δ7.39–7.21(m,4H),6.61(dd,J＝18.9,8.6Hz,2H),6.42(t,J＝2.6Hz,2H),6.29(ddd,J＝9.7,8.6,2.7Hz,2H),3.95(qd,J＝14.0,6.2Hz,2H),3.49(td,J＝7.5,6.8,3.5Hz,4H),3.45–3.23(m,8H),2.78(td,J＝10.0,5.5Hz,1H),2.53–2.18(m,4H),2.17–1.96(m,3H),1.17(dt,J＝8.5,7.0Hz,12H).13C NMR(101MHz,CDCl3)δ151.86,151.69,147.95,147.89,146.11,133.19,131.87,130.55,129.82,129.55,128.79,126.80,110.79,110.51,107.53,107.29,98.99,66.66,56.25,54.11,53.23,49.13,44.44,44.38,12.65,12.60.
example 2
414mg of rhodamine 6G analogue, 390mg of N- (2-aminoethyl) morpholine and 420mg of HATU are mixed, dissolved in 30mL of dichloromethane, stirred at room temperature for 48 hours, and then the solvent is dried by spinning, and the mixture is purified by silica gel column chromatography to obtain 450mg of spirolactam intermediate. Dissolving 200mg of spirolactam intermediate by using 20mL of tetrahydrofuran, adding 70mg of sodium borohydride, reacting at 70 ℃ for 8 hours, cooling to room temperature, and purifying by spin-drying solvent silica gel column chromatography to obtain 100mg of target pH probe, wherein the reaction process comprises the following steps:
the nuclear magnetic hydrogen spectrum and nuclear magnetic carbon spectrum of the synthesized pH probe are respectively shown in FIG. 3 and FIG. 4, and the specific data are as follows:
1H NMR(400MHz,CDCl3)δ7.28(d,J＝3.9Hz,4H),6.52–6.30(m,4H),3.88(qd,J＝16.4,15.3,6.9Hz,2H),3.50–3.40(m,4H),3.19(p,J＝6.9Hz,4H),2.77–2.01(m,8H),1.94(d,J＝3.4Hz,6H),1.30(q,J＝6.9Hz,6H).13C NMR(101MHz,CDCl3)δ150.08,149.91,146.32,146.30,146.11,133.29,131.87,130.56,130.07,129.88,128.68,126.88,117.09,116.82,111.13,110.81,97.60,97.58,66.67,56.04,54.14,53.12,49.19,38.47,16.82,16.73,14.86,14.82.。
example 3
500mg of rhodamine 101, 390mg of N- (2-aminoethyl) morpholine and 420mg of HBTU are mixed, dissolved in 30mL of dichloromethane, stirred at room temperature for 48 hours, and then the solvent is dried by spinning, and purified by silica gel column chromatography to obtain 350mg of spirolactam intermediate. Taking 200mg spirolactam intermediate, dissolving with 20mL tetrahydrofuran, adding 1.8mL 1M borane tetrahydrofuran solution, reacting at 70 ℃ for 8 hours, cooling to room temperature, and purifying by spin-drying solvent silica gel column chromatography to obtain 85mg target pH probe, wherein the reaction process is as follows:
the nuclear magnetic hydrogen spectrum and nuclear magnetic carbon spectrum of the synthesized pH probe are shown in FIG. 5 and FIG. 6 respectively, and the specific data are as follows:
1H NMR(400MHz,CDCl3)δ7.44–7.13(m,3.5H),6.24–6.03(m,1.7H),5.24(d,J＝21.0Hz,0.8H),3.95–3.71(m,2H),3.69–3.35(m,4H),3.08(qdt,J＝10.7,7.0,4.1Hz,8H),2.97–2.82(m,4H),2.72–2.13(m,10H),2.11–1.84(m,10H).13C NMR(101MHz,CDCl3)δ146.86,146.64,146.28,142.76,142.71,133.30,131.80,131.04,128.59,126.77,126.21,126.14,125.88,116.50,116.43,116.38,111.17,110.88,109.15,109.03,108.65,66.85,66.74,56.24,54.35,53.65,53.45,53.22,50.09,50.04,49.63,49.59,48.90,41.37,27.22,27.19,27.16,22.36,22.32,22.29,21.77,21.74,21.71,21.33,21.28,21.23.
example 4
EXAMPLE 3 fluorescent intensity of synthesized Probe as a function of pH
The pH probe synthesized in example 3 was precisely weighed and dissolved in DMSO to prepare 2mM of test stock solution, and the test stock solution was diluted to a concentration of 10. mu.M with buffer solutions of different pH, respectively, and the fluorescence emission intensity was measured under the same conditions. As shown in FIG. 7, the pH probe synthesized in example 1 was substantially non-fluorescent in the solution at pH greater than 10, and gradually increased in fluorescence with further decrease in pH and stabilized at pH less than 7. Illustrating that the pH probe synthesized in example 3 is suitable for measurement in the pH range of 7-10.
Example 5
EXAMPLE 1 Probe synthesized for measuring pH of commercially available mineral Water
The pH probe synthesized in example 1 was precisely weighed and dissolved in DMSO to prepare 2mM assay stock solutions, the assay stock solutions were diluted to 10. mu.M concentrations with buffer solutions of different pH, the fluorescence emission intensity was measured under the same conditions, and a standard curve of the fluorescence intensity I/Imax as a function of pH was plotted as shown in FIG. 8. The pH probe synthesized in example 1 was diluted to a concentration of 10. mu.M with a certain brand of commercially available mineral water to be measured, the ratio of the fluorescence emission intensity to the maximum fluorescence intensity was measured to be 0.53, and the pH of the brand of mineral water was calculated to be 7.13 by the standard curve
Example 6
Example 2 synthetic probes for imaging of cell staining
The pH probe synthesized in example 2 was precisely weighed and dissolved in DMSO to prepare 2mM of test stock solution, and the test stock solution was diluted to a concentration of 10. mu.M with buffer solutions of different pH, respectively, and the fluorescence emission intensity was measured under the same conditions. As shown in fig. 9, the pH probe synthesized in example 2 exhibits strong fluorescence at pH less than 6 and is substantially non-fluorescent at pH greater than 7.5, and thus can be used to indicate an acidic pH in a cell.
Hela cells were seeded in a confocal dish at a concentration of 2 ten thousand cells/dish and cultured at 37 ℃ for 48 hours in a medium of 5% CO2, 10% fetal bovine serum 1640. The dye prepared in example 2 was added to the medium to a final concentration of 0.5. mu.M, incubated for 10min and observed under a confocal microscope. As shown in fig. 10, the site where strong fluorescence occurs is lysosome having an acidic pH.
Claims (7)
1. A pH probe with a spirolactam connected morpholine structure is characterized in that: the pH probe has a structure of
Wherein:
R1、R2hydrogen, a C1-C5 linear or branched, saturated or unsaturated alkyl or cycloalkyl group, respectively, said alkyl group being selected from: methyl, ethyl, n-propyl, isopropyl, allyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl;
R3、R4respectively hydrogen, fluorine, chlorine and methyl;
R1or R2And R3Or R4Connected by carbon chains to form a five-membered or six-membered ring structure with a parent benzene ring.
2. The pH probe structure of claim 1, wherein: the R is1、R2Hydrogen, methyl, ethyl are preferred.
3. The pH probe structure of claim 1, wherein: the preparation method of the probe comprises the following steps:
(1) synthesis of key spirolactam intermediates
Dissolving 1.0 mol of rhodamine, 3.0 mol of N- (2-aminoethyl) morpholine and 1.1 mol of onium salt catalyst in dichloromethane, stirring and reacting at room temperature for 48 hours, evaporating the solvent under vacuum reduced pressure, and then separating by silica gel column chromatography, wherein the eluent is a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of ethyl acetate: and (3) obtaining a key spirolactam intermediate by using petroleum ether at a ratio of 1: 1-10, wherein the reaction process is as follows:
(2) reduction of key spirolactam intermediate to generate pH probe with spirolactam structure
Dissolving key spirolactam intermediate in 1.0 molar amount and reductant in 5.0 molar amount in tetrahydrofuran, reacting at 70 deg.c for 8 hr, evaporating to eliminate solvent under vacuum and decompression condition, and chromatographic separation with silica gel column to obtain mixed solvent of petroleum ether and ethyl acetate as eluent, ethyl acetate: obtaining the pH probe with a spirolactam structure by using petroleum ether at a ratio of 1: 1-10, wherein the reaction process comprises the following steps:
4. the method for preparing the probe according to claim 3, wherein: in the step (1), the rhodamine is one of rhodamine B, rhodamine 6G, rhodamine 110, rhodamine 101 and tetramethyl rhodamine.
5. The method for preparing the probe according to claim 3, wherein: the onium salt catalyst in the step (1) is one of 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate, benzotriazole-N, N, N ', N' -tetramethylurea hexafluorophosphate or 1H-benzotriazole-1-oxytriazolyl alkyl phosphonium hexafluorophosphate.
6. The method for preparing the probe according to claim 3, wherein: the reducing agent in the step (2) is one of hydrogen, borane, sodium borohydride or lithium aluminum hydride.
7. Use of a pH probe according to any one of claims 1 to 6 in analytical testing or bioluminescence imaging.
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