CN105884734A - Double-photon fluorescent probe capable of fast detecting nitroreductase - Google Patents
Double-photon fluorescent probe capable of fast detecting nitroreductase Download PDFInfo
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Abstract
The invention discloses double-photon fluorescent probe capable of fast detecting nitroreductase. The double-photon fluorescent probe is named as 3-nitro-7-diethylin coumarin. The double-photon fluorescent probe has the advantages that the double-photon fluorescent probe can respond to the nitroreductase in cells, the fluorescence intensity is enhanced correspondingly along with the increasing of the concentration of the nitroreductase, and the probe can detect the nitroreductase of the hypoxia area in a tumor through fluorescent imaging.
Description
Technical field
The present invention relates to one quickly respond nitroreductase (NTR) there is the fluorescence probe of two-photon effect, belong to organic molecule fluorescence probe field.
Background technology
Weary oxygen refers to the physiological status of a kind of tissue hypoxia, is generally observed in entity tumor, is tumor microenvironment medium vessels disappearance or the performance of exception.Clinic study finds, the observation to the weary oxygen region of entity tumor has close ties with metastases potential quality with to the pernicious sign of treatment-resistant.Therefore, development of clinical studies carries out the novel method of weary oxygen detection and is significant.The degree of oxygen deficiency of assessment intra-tumor anoxic zones plays key player in the effect and correlative study of prediction treatment of cancer.
Accelerate bioreduction it is known that weary oxygen can be induced and cause the expression of intracellular reductase, such as quinone reductase, azo reductase and nitroreductase (NTR).Wherein, nitroreductase is the most representational.In the presence of the state and electron donor niacinamide of anoxic, intracellular nitroaromatic is obvious as the substrate feature of nitroreductase.The reaction of this enzymatic one-electron reduction is proved to be a kind of effective location and the design in imaging Fa Yang district.
Recently, there has been a lot according to nitroaromatic enzyme the most intrinsic nitroreductase probe, some has been employed for the imaging of Fa Yang district tumour cell.The defects such as the interference but these common fluorescence probes are had powerful connections more, scattering interference, sensitivity is the highest, and the response time is longer, detects limit for height, the most likely affects the application to nitroreductase detection in complex physiologic environment.Two-photon fluorescence probe has that near-infrared excites, ambient interferences is little, scattering disturbs little, sensitivity and selectivity higher, photobleaching and light intoxicating phenomenon is avoided to produce, and organism is injured the advantages such as little, in biological living analysis detects, demonstrate the biggest superiority.
Summary of the invention
For the deficiency of existing detection technique, the present invention proposes the two-photon probe (CNO of a kind of quick detection nitroreductase2-HY), and this probe is carried out bio-imaging.Utilize the present invention to detect the nitroreductase of anoxic zone, the weary oxygen level of tumor area is estimated.
The two-photon fluorescence probe of quick detection nitroreductase of the present invention is named: 3-nitro-7-diethylaminocoumarin.
Chemical structural formula is:
。
(I)
The synthetic method of above-mentioned two-photon fluorescence probe is as follows: in 100 milliliters of round-bottomed flasks, add 10 mMs of 4-diethylin salicylides and 30 milliliters of n-butanols, addition lower 11 mM ethyl nitroacetates, then dropping 0.15 milliliter piperidines and 0.3 milliliter glacial acetic acid are stirred at room temperature.Reaction system is cooled to room temperature, filtration under diminished pressure, filter cake ethyl alcohol recrystallization after being heated to reflux 12 hours, obtain product, productivity 77%.
Above-mentioned probe to prepare reaction equation as follows:
Mechanism:
It is demonstrated experimentally that the two-photon fluorescence probe solution of detection nitroreductase of the present invention, sending intense fluorescence in the presence of nitroreductase, this phenomenon explanation probe has response to nitroreductase, and reliable theoretical foundation has been established in the application for bio-imaging.Expect that the present invention can play a significant role in the detection of nitroreductase level in tumor hypoxia district.
Accompanying drawing explanation
The nuclear-magnetism of Fig. 1: probe characterizes:1H H NMR spectroscopy and13C H NMR spectroscopy；
Fig. 2: probe abosrption spectrogram in phosphate buffer.Concentration and probe concentration: 5 M；
Fig. 3: the dynamic experiment of probe in detecting nitroreductase: wherein excitation wavelength is 385
nm；The concentration of probe: 5 M；Nitroreductase concentration is respectively 0,0.1,0.25,0.5,0.75,1.5 g/mL, the testing time: 45 min, test interval: 5 min；
The titration experiments of Fig. 4: probe detected nitroreductase concentration；Wherein excitation wavelength is 385
nm；The concentration of probe: 5 M；
The selectivity in phosphate buffer of Fig. 5: the probe.Wherein excitation wavelength is 385
nm；The concentration of probe: 5 M, the concentration of selective ion is 2.5
mM；
The single photon cell imaging application of Fig. 6: probe.Excitation wavelength: 405
Nm and 488 nm, emission band: 425-
475 nm and 500-550 nm；
The two-photon cell imaging application of Fig. 7: probe.Excitation wavelength: 760
Nm, emission band: 425-475 nm and 500-550 nm.
The two-photon imaging of tissue application of Fig. 8: probe.Excitation wavelength: 760
Nm, emission band: 500-550 nm.
Detailed description of the invention
Below by embodiment and accompanying drawing, the present invention will be described.
Embodiment 1
Compound CNO2The synthesis of-HY
In 100 mL round-bottomed flasks, add 10
Mmol 4-diethylin salicylide and 30 mL n-butanols, be stirred at room temperature lower addition 11
Mmol ethyl nitroacetate, then drips 0.15 mL piperidines and 0.3
ML glacial acetic acid.Reaction system is cooled to room temperature, filtration under diminished pressure, filtrate ethyl alcohol recrystallization after being heated to reflux 12 hours, obtain product, named: 3-nitro-7-diethylaminocoumarin, is called for short CNO2-HY, productivity 77%.1H H NMR spectroscopy and13C NMR spectra such as Fig. 1.
1H NMR
(400 MHz, DMSO-d 6 ): 9.02 (s, 1H), 7.72 (d,J = 9.2 Hz,
1H), 6.91 (dd,J 1 = 9.2 Hz,J 2 / = 2.4 Hz,
1H), 6.63 (d,J = 2.4 Hz, 1H), 3.53 (q,J = 7.2 Hz, 4H), 1.15 (t,
J= 7.2 Hz, 6H)； 13C NMR
(400 MHz, DMSO-d 6 ): 158.86,154.97,153.39,144.52,133.83,126.31,111.85,106.62,96.51,45.24,12.82.
Embodiment 2
Compound CNO2The absorption spectrum test of-HY two-photon weary oxygen fluorescence probe
The two-photon fluorescence probe CNO of the 1 mM detection of the present invention nitroreductase of 1 part of 5 mL of preparation2Dimethyl sulfoxide (DMSO) (DMSO) solution of-HY.Take 25 μ L probe mother liquors respectively and add in 25 identical mL volumetric flasks, add DMSO solution 225 μ L, all add NADH (NADH) 500 μMs.One of them adds the phosphate buffer solution (10 μ g/mL, 500 μ L) of nitroreductase, and another is not added with.Two volumetric flasks all use phosphate buffer (PBS, pH=
7.4) constant volume is to 5 mL, 37 DEG C of effect 45 min, then carries out absorption spectrum test.Result is shown in Fig. 2 probe CNO2-HY is at phosphate buffer solution
(PBS) absorption curve in.Concentration and probe concentration is 5 μMs.(a): the absorption curve of probe itself；(b): probe and the absorption curve of 0.75 μ g/mL nitroreductase effect 45 min.
Embodiment 3
Compound CNO2-HY two-photon weary oxygen fluorescence probe and the kinetic test of nitroreductase effect
Prepare the two-photon fluorescence probe mother liquor of the aqueous solution that 5 mL concentration are 10 μ g/mL nitroreductases and the detection anoxic zones nitroreductase of the present invention that concentration is 1 mM as standby.Preparation probe and the solution of nitroreductase, its concentration is respectively as follows: probe 5 μMs；Nitroreductase: 0,0.1,0.25,0.5,0.75,1.5 μ g/mL.Carry out fluoroscopic examination (λex= 450 nm, λem=511 nm), test once every 5 min, test 45 min, record time dependent fluorescence intensity in each system, set up the time dependent calibration curve of fluorescence intensity.As it is shown on figure 3, reaction 20 min, reaction system fluorescence intensity reaches saturation state.So, 20 can be taked
Min is as the reaction time.In Fig. 3, concentration and probe concentration is 5 μMs, and nitroreductase concentration is: 0-1.5 μ g/mL, and excitation wavelength is 385 nm, a length of 511 nm of transmitted wave, the testing time: 45 min, test interval: 5 min.
Embodiment 4
The nitroreductase of variable concentrations is to compound CNO2The titration detection of-HY two-photon weary oxygen fluorescence probe
Prepare the two-photon fluorescence probe mother liquor of the aqueous solution that 5 mL concentration are 10 μ g/mL nitroreductases and the detection anoxic zones nitroreductase of the present invention that concentration is 1 mM as standby.
Final concentration of 5 μMs of probe of preparation, containing the PBS solution of 5 % DMSO solution, the nitroreductase (0-1.5 μ g/mL) with variable concentrations the most fully acts on respectively, carries out fluoroscopic examination (λex= 385 nm, λem=511 nm), the reaction time is 20
min.Obtain fluorescence intensity in each system, set up fluorescence intensity and nitroreductase concentration standard curve.As shown in Figure 4, along with the increase of nitroreductase concentration, reaction system fluorescence intensity is gradually increased, and when nitroreductase concentration reaches 0.75 μ g/mL, reaction system fluorescence intensity reaches saturation state.In Fig. 4, concentration and probe concentration is 5 μMs, and nitroreductase concentration is 0-1.5 μ g/mL, and excitation wavelength is 385 nm, a length of 511 nm of transmitted wave.Testing time is 20 min.
Embodiment 5
Compound CNO2-HY two-photon weary oxygen fluorescence probe is to different ions and active small molecular, amino acid whose selectivity
The two-photon fluorescence probe CNO of the 1 mM detection of the present invention nitroreductase of 1 part of 5 mL of preparation2Dimethyl sulfoxide (DMSO) (DMSO) solution of-HY.Dose volume is 5 mL, and concentration is the various different ions of 40 mM, and amino acid and active oxygen, active nitrogen solution is as standby.
In the volumetric flask of 5 mL, add 25 μ L probe mother liquors, 225 μ L DMSO and each solion of 500 equivalents or each Freamine Ⅲ of 1000 equivalents, use phosphate buffer constant volume, after shaking up, carry out fluoroscopic examination (λex= 385
nm, λem=511 nm), set up the block diagram (result is shown in Fig. 5) of fluorescence intensity and each ion, the concentration of test ion is 2.5 mM, and amino acid whose concentration is 5 mM, and activity of reactive oxygen species nitrogen concentration is 100 μMs.The fluorescence emission spectrum change of solution is detected, by Fig. 5 it is found that other ions (or amino acid) are to compound CNO after 20 min2The fluorescence of-HY has little to no effect.In Fig. 5, excitation wavelength is 385nm；Probe CNO2The concentration of-HY: 5 μMs, the concentration of test ion is 2.5 mM, and amino acid whose concentration is 5 mM, and activity of reactive oxygen species nitrogen concentration is 100 μMs.1-No. 26 add ion respectively: probe CNO2-HY, NADH, NaClO, H2O2, tert-butyl peroxide, tert-butyl peroxide alcohol, NO (sodium nitroprusside), CaCl2, MgCl2, Na2SO3, NaNO2, NaHSO3, NaHS, GSH, Cys, Hcy, NaNO3, KBr, ZnCl2, LiCl, KI, citric acid, sodium acetate, tert-butyl group epoxide, OH(hydroxyl radical free radical), NTR (containing NADH).
Embodiment 6
Compound CNO2The single photon cell imaging test of-HY two-photon weary oxygen fluorescence probe
It is 3 × 10 by density5The HeLa cell of individual/mL is inoculated in the 35 mm culture dishes being covered with cover glass (22 mm × 22 mm) of sterilizing, at CO2(temperature is 37 DEG C to incubator, 5 % CO2Being divided into two groups of cultivations in), after cell attachment, one group in normal oxygen condition, (temperature is 37 DEG C, 5 %
CO2Cultivate in)；One group in weary oxygen condition, (temperature is 37 DEG C, 5 %
CO2, 1 % O2Cultivate in), all cultivate 12 h.The two-photon fluorescence probe of detection anoxic zones nitroreductase of the present invention is added so that it is final concentration is 5 μMs in two groups of culture dishes.Continue to cultivate 0.5 h the most under two conditions, then cell culture fluid is siphoned away, rinse cell 3 times with PBS, two groups of cells are shot under the conditions of single photon respectively fluoroscopic image, find that the fluorescence that the cancer cell of growth sends under the conditions of weary oxygen is significantly stronger.(result is shown in Fig. 6).
In Fig. 6, excitation wavelength: 405
Nm and 488 nm, emission band: 425-
475 nm and 500-550 nm；The light field imaging of (a) often Hela cell that oxygen condition is cultivated;B () Hela cell that often oxygen condition is cultivated is at the fluorescence imaging of 425-475 nm passages; (c)
The Hela cell that often oxygen condition is cultivated is at the fluorescence imaging of 500-550 nm passage;(d) anoxia state (1 %
O2) the light field imaging of Hela cell cultivated;(e) anoxia state (1 %
O2) the Hela cell cultivated is at the fluorescence imaging of 425-475 nm passage; (f)
Anoxia state (1 % O2)
The Hela cell cultivated is at 500-550
The fluorescence imaging of nm passage;G () Hela cell that often oxygen condition is cultivated adds the light field imaging of probe (5 μMs);H () Hela cell that often oxygen condition is cultivated adds the probe (5 μMs) fluorescence imaging at 425-475 nm passages;I () Hela cell that often oxygen condition is cultivated adds the probe (5 μMs) fluorescence imaging at 500-550 nm passages;(j) anoxia state (1 %
O2) the Hela cell cultivated adds the light field imaging of probe (5 μMs);(k) anoxia state (1 %
O2) the Hela cell cultivated adds the probe (5 μMs) fluorescence imaging at 425-475 nm passages; (l)
Anoxia state (1 % O2)
The Hela cell cultivated adds the probe (5 μMs) fluorescence imaging at 500-550 nm passages.
Embodiment 7
Compound CNO2The two-photon cell imaging test of-HY two-photon weary oxygen fluorescence probe
The cell cultivated by example 6 shoots the fluorescence photo of two groups of cells under the conditions of two-photon respectively, finds that the fluorescence that the cancer cell of growth sends under the conditions of weary oxygen is remarkably reinforced (result is shown in Fig. 7).
In Fig. 7, excitation wavelength: 760nm, emission band: 425-475 nm and 500-
550 nm;The light field imaging of (a) often Hela cell that oxygen condition is cultivated;B () Hela cell that often oxygen condition is cultivated is at the fluorescence imaging of 425-475 nm passages; (c)
The Hela cell that often oxygen condition is cultivated is at the fluorescence imaging of 500-550 nm passages;(d) anoxia state (1 %
O2) the light field imaging of Hela cell cultivated;(e) anoxia state (1 %
O2) the Hela cell cultivated is at the fluorescence imaging of 425-475 nm passages; (f)
Anoxia state (1 % O2)
The Hela cell cultivated is 500
The fluorescence imaging of-550 nm passages;G () Hela cell that often oxygen condition is cultivated adds the light field imaging of probe (5 μMs);H () Hela cell that often oxygen condition is cultivated adds the probe (5 μMs) fluorescence imaging at 425-475 nm passages;I () Hela cell that often oxygen condition is cultivated adds the probe (5 μMs) fluorescence imaging at 500-550 nm passages;(j) anoxia state (1 %
O2) the Hela cell cultivated adds the light field imaging of probe (5 μMs);(k) anoxia state (1 %
O2) the Hela cell cultivated adds the probe (5 μMs) fluorescence imaging at 425-475 nm passages; (l)
Anoxia state (1 % O2)
The Hela cell cultivated adds the probe (5 μMs) fluorescence imaging at 500-550 nm passages.
Embodiment 8
Compound CNO2The two-photon imaging of tissue test of-HY two-photon weary oxygen fluorescence probe
Preparing two injected in mice tumour cells (mouse source breast cancer cell 4T-1), cultivate mouse breast cancer tumour model, solution takes tumour, and makes tumor biopsy.A part of tumor biopsy is immersed in tissue culture medium, CO2(temperature is 37 DEG C to incubator, 5 % CO2) cultivate；Another part tumor biopsy is immersed in containing in the tissue culture medium that concentration is 5 μMs of probe solutions, CO2(temperature is 37 DEG C to incubator, 5 % CO2) cultivate.After half an hour, tissue culture medium is siphoned away, rinse 3 times with PBS, two groups of tumor tissues are shot under the conditions of two-photon respectively fluoroscopic image, find the fluorescence significantly stronger (result is shown in Fig. 8) that the tissue soaked in the nutrient solution adding probe sends.In Fig. 8, A) for being immersed in the two-photon fluorescence imaging of the tumour of tissue culture medium；B) for the tumour two-photon fluorescence imaging being immersed in the tissue culture medium containing 5 μMs of probe solutions.
Claims (2)
1. a two-photon fluorescence probe for quick detection nitroreductase, its
Chemical structural formula is:
,
Named: 3-nitro-7-diethylaminocoumarin.
Two-photon fluorescence probe the most according to claim 1, it is characterized in that, synthesized by following methods: in 100 milliliters of round-bottomed flasks, add 10 mMs of 4-diethylin salicylides and 30 milliliters of n-butanols, addition lower 11 mM ethyl nitroacetates, then dropping 0.15 milliliter piperidines and 0.3 milliliter glacial acetic acid are stirred at room temperature, reaction system is cooled to room temperature after being heated to reflux 12 hours, filtration under diminished pressure, filter cake ethyl alcohol recrystallization, to obtain final product.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108610319A (en) * | 2018-06-07 | 2018-10-02 | 福建医科大学 | One kind is for detecting Al3+Chalcone Coumarins fluorescence probe synthesis and application |
| CN108727223A (en) * | 2018-07-24 | 2018-11-02 | 南京工业大学 | One kind can two-photon fluorescence detection nitroreductase NTR probes and preparation method thereof |
| CN109694372A (en) * | 2018-12-11 | 2019-04-30 | 湖南大学 | A kind of two-photon fluorescence probe and the preparation method and application thereof |
| US10935498B1 (en) | 2018-11-30 | 2021-03-02 | South China University Of Technology | Fluorescent probe for detecting nitroreductase and preparation method and use thereof in enzymatic reaction |
| CN114736938A (en) * | 2022-03-21 | 2022-07-12 | 华南理工大学 | Hypoxia response type alkyne-amine click polymerization intracellular polymerization method and application thereof |
| CN115873011A (en) * | 2022-12-02 | 2023-03-31 | 安徽大学 | Cancer cell targeted fluorescent probe responding to mitochondrial nitroreductase and preparation method and application thereof |
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108610319A (en) * | 2018-06-07 | 2018-10-02 | 福建医科大学 | One kind is for detecting Al3+Chalcone Coumarins fluorescence probe synthesis and application |
| CN108727223A (en) * | 2018-07-24 | 2018-11-02 | 南京工业大学 | One kind can two-photon fluorescence detection nitroreductase NTR probes and preparation method thereof |
| CN108727223B (en) * | 2018-07-24 | 2020-07-31 | 南京工业大学 | Nitroreductase NTR probe capable of being detected by two-photon fluorescence and preparation method thereof |
| US10935498B1 (en) | 2018-11-30 | 2021-03-02 | South China University Of Technology | Fluorescent probe for detecting nitroreductase and preparation method and use thereof in enzymatic reaction |
| CN109694372A (en) * | 2018-12-11 | 2019-04-30 | 湖南大学 | A kind of two-photon fluorescence probe and the preparation method and application thereof |
| CN109694372B (en) * | 2018-12-11 | 2021-08-24 | 湖南大学 | Two-photon fluorescent probe and preparation method and application thereof |
| CN114736938A (en) * | 2022-03-21 | 2022-07-12 | 华南理工大学 | Hypoxia response type alkyne-amine click polymerization intracellular polymerization method and application thereof |
| CN115873011A (en) * | 2022-12-02 | 2023-03-31 | 安徽大学 | Cancer cell targeted fluorescent probe responding to mitochondrial nitroreductase and preparation method and application thereof |
| CN115873011B (en) * | 2022-12-02 | 2023-09-08 | 安徽大学 | Cancer cell targeted fluorescent probe responding to nitroreductase in mitochondria and preparation method and application thereof |
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