CN110845556A - Target tumor β -galactosidase near-infrared fluorescent probe and preparation method thereof - Google Patents

Target tumor β -galactosidase near-infrared fluorescent probe and preparation method thereof Download PDF

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CN110845556A
CN110845556A CN201911177443.7A CN201911177443A CN110845556A CN 110845556 A CN110845556 A CN 110845556A CN 201911177443 A CN201911177443 A CN 201911177443A CN 110845556 A CN110845556 A CN 110845556A
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compound
galactosidase
reacting
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颜梅
卫先哲
张晶
杨小凤
刘海云
李增军
于京华
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University of Jinan
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Abstract

The invention discloses a preparation method of a near-infrared fluorescent compound which accurately targets tumor cells and is activated by β -galactosidase, wherein the structure of the fluorescent compound is shown as a formula I.the probe compound combines a substrate α D-galactose (α D-gal) which can be identified by β -galactosidase with a cyanine near-infrared fluorophore, introduces α v β 3-integrin receptor targeted ligand c-RGD, utilizes the capacity of the ligand c-RGD to target the tumor cells, is used for near-infrared imaging of live mouse tumors which over-express β -galactosidase, and has the advantages of combining receptor-mediated cell uptake and molecular target activation, being capable of detecting β -galactosidase in live tissues in real time and non-invasively, and being successfully applied to improving cancer imaging and promoting effective cancer diagnosis.

Description

Target tumor β -galactosidase near-infrared fluorescent probe and preparation method thereof
Technical Field
The invention relates to a targeted small molecular fluorescent probe compound, in particular to detection of an important marker β -galactosidase (β -gal) of primary ovarian cancer by a near infrared compound based on a targeted tumor cell surface specific receptor, belonging to the field of fluorescent sensor probe compounds.
Background
However, most of the activatable imaging probes for β -gal are designed by simply linking the substrate α D-galactose (α D-gal) that recognizes β -gal to a quenched fluorophore, resulting in the limitations of small solubility under physiological conditions and low efficiency of delivery to tumor tissues when these probe compounds are imaged in vivo.
Over the past few years, a number of molecular imaging probes have been developed that can target markers in cancer cells, providing important tools for early detection of cancer and rapid monitoring of therapy. These imaging probes are generally classified into two types mainly according to mechanism. The first type of probe typically utilizes a receptor-mediated active delivery mechanism, accumulated and retained in cancer cells through cellular uptake. The second type, called activatable imaging probes, relies on a specific imaging signal that triggers recognition molecules in cancer cells. However, they still have low specificity due to the presence of some cross-reactivity of normal (non-tumor) cells that are similar to the characteristics of cancer cells. To overcome this limitation, strategies have been proposed to construct imaging probes comprising two different targeting ligand molecules simultaneously to enhance cancer cell uptake.
Herein, a new near infrared fluorescent probe (RN-gal) targeting tumor and activated by β -gal was designed and synthesized, which specifically detects β -gal activity in live mouse tumor by introducing α v β 3-integrin receptor targeted ligand c-RGD, probe compounds can be selectively absorbed by tumor cells through α v β 3-integrin receptor mediated endocytosis, and significantly enhanced near infrared fluorescence is observed only in tumor cells.
Disclosure of Invention
The invention aims to solve the technical problems that firstly, the fluorescent probe compound for detecting β -galactosidase and the preparation method thereof are provided, and the probe compound has the advantages of high targeting property, strong selectivity, high detection speed and non-invasive living body imaging for detecting β -galactosidase, and secondly, the method for detecting β -galactosidase is provided, the operation method is simple, and the effect is obvious.
In order to solve the technical problems, the technical scheme is as follows:
the invention provides a near-infrared fluorescent probe of β -galactosidase in a targeted tumor cell, which has the following molecular structural formula:
compound RN-gal
The invention also provides a preparation method of the fluorescent probe compound for detecting β -galactosidase, which comprises the following steps:
(1) reacting indole derivatives with a 2-chloro-1-formyl-3- (hydroxy methylene) compound in a mixed solution of butanol and benzene to obtain a compound I;
compound I
(2) Reacting the compound I with di-tert-butyl carbonate to obtain a compound II;
Figure DEST_PATH_IMAGE003
compound II
(3) Reacting the compound II with 4-chloro-1, 2-dihydroxybenzene to synthesize a compound III;
Figure 200966DEST_PATH_IMAGE004
compound III
(4) Reacting the compound III with trifluoroacetic acid, removing Boc group, and synthesizing a near-infrared fluorescent dye blue compound, namely a compound IV;
Figure DEST_PATH_IMAGE005
compound IV
(5) Reacting a dye compound IV with N-succinimidyl 3-maleimide propionate to synthesize a compound V;
compound five
(6) Reacting the compound five with 2,3,4, 6-tetraacetoxy-alpha-D-pyranose bromide, and hydrolyzing in sodium methoxide to obtain a compound six;
compound six
(7) And stirring the compound six and c-RGD-SH in DMF to obtain a blue product of the near-infrared fluorescent probe compound RN-gal.
The invention has the advantages that:
the fluorescent probe of the invention has a fluorescence emission wavelength of 710 nm, and is a near-infrared fluorescent probe.
The fluorescent probe of the invention has the characteristic of fast response β -galactosidase, and the fluorescence intensity is obviously improved by 240 times after reaction.
The fluorescent probe can be used for distinguishing normal cells from tumor cells over expressing β -galactosidase through cell imaging.
The fluorescent probe can be injected into mice intravenously and actively delivered into tumor tissues through the mediation of α v β 3-integrin receptor.
The fluorescent probe has wide application range of pH and temperature, and is favorable for detecting β -galactosidase in a living system.
The fluorescent probe has good selectivity and strong anti-interference capability on β -galactosidase, and does not influence the response of probe molecules to β -galactosidase in the presence of possibly interfering ions, biomolecules, active enzymes and the like.
Therefore, the invention is a non-invasive, targeted tumor cell, can carry out in-situ and real-time monitoring on β -galactosidase, and is a detection reagent with wide application range, thereby having wide application prospect in the field of chemical analysis and detection.
Detailed Description
The present invention will be described in further detail with reference to specific examples.
Example 1
A method for preparing a fluorescent probe compound for detecting β -galactosidase comprises the following steps:
1) synthesis of compound one:
2-chloro-1-formyl-3- (hydroxymethylene) compound (1.2 mmol, 1 eq) and indole derivative (3 mmol, 2.5 eq) were dissolved in 30 mL of butanol/benzene (5: 2) solution, and after stirring under reflux, water was removed with a water separator. The reaction solution was stirred at 80 ℃ for a further 8 hours. After removal of the solvent by evaporation in vacuo, the residue was purified by silica gel column chromatography using CH2Cl2/CH3OH (20: 1 to 1: 1) as eluent gave compound one as a green solid in 70% yield.
2) Synthesis of compound two:
to a solution of compound one (0.5 mmol, 1 eq) in ethanol was added di-tert-butyl carbonate (1.2 mmol, 2.4 eq) and TEA (1.2 mmol, 2.4 eq) and the mixture was stirred at room temperature for 3 hours. The solvent was removed by evaporation under reduced pressure, and the residue was dissolved in ethyl acetate, washed with saturated brine, and washed with anhydrous Na2SO4And (5) drying. The solvent was evaporated under reduced pressure to give compound two, which was used directly in the next step.
3) Synthesis of compound three:
4-chloro-1, 2-dihydroxybenzene (5 mmol, 1 eq) and TEA (2.5 mmol, 0.5 eq) were dissolved in 5.0 mL of anhydrous DMF, the solution was stirred at room temperature and kept under a nitrogen atmosphere for 20 minutes, and 2.0 mL of Compound two dissolved in anhydrous DMF was added dropwise thereto. The solution was then heated to 85 ℃ and stirred for 6 hours. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography using CH2Cl2/CH3OH (80: 1) as eluent gave compound III as a blue-green solid, which was used directly in the next step.
4) Synthesis of compound four:
compound III was reacted with a dichloromethane/trifluoroacetic acid mixture (1: 1, 20 mL) at room temperature for 1 hour to remove the Boc group. The solvent was evaporated under reduced pressure, ether was added, and the precipitate was collected after filtration to give the near infrared fluorescent dye compound four as a blue solid with a yield of 38%.
5) Synthesis of compound v:
the compound tetrakis (0.5 mmol, 1 eq), N-succinimidyl 3-maleimidopropionate (0.9 mmol, 1.8 eq) and TEA (0.5 mmol, 1 eq) were dissolved in 10 mL of anhydrous THF and the mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography using CH2Cl2/CH3OH (80: 1 to 20: 1) as eluent gave compound five as a blue solid in 85% yield.
6) Synthesis of compound six:
compound five (1.5 mmol, 1)eq) and sodium iodide (1.9 mmol, 1.25 eq) were dissolved in N, N-dimethylformamide, and then 2,3,4, 6-tetraacetoxy-alpha-D-pyranose bromide (1.1 mmol, 0.7 eq) was added to the mixture, stirred at room temperature for 5h, and then heated to 85 ℃ and refluxed for 10 h. The reaction was monitored on a TCL plate, and after completion of the reaction, it was extracted with dichloromethane, anhydrous MgSO4Dried, evaporated under reduced pressure and isolated on silica gel column to give the compound which was used directly in the next step. To the product in dry methanol was added dropwise a solution of sodium methoxide (3 mmol, 2 eq) and the reaction mixture was stirred at room temperature for 6 hours. The pH was adjusted to neutral using hydrochloric acid, after completion of the reaction, the solution was extracted with dichloromethane, the organic phase was evaporated under reduced pressure and the residue was purified by silica gel chromatography to give compound six in 55% yield.
7) Synthesis of the Compound RN-gal:
compound six (0.02 mmol, 1 eq) and c-RGD-SH (0.028 mmol, 1.4 eq) were dissolved in 8mL DMF and stirred at room temperature for 1 hour. The compound RN-gal was obtained as a blue solid in 70% yield.
Example 2
Time response change of probe compound RN-gal to β -gal ultraviolet absorption and fluorescence emission
A5 μ M probe solution was prepared from RN-gal synthesized in example 1, and β -gal (5U/mL) standard solution was added to measure its UV absorption and fluorescence properties.the absorption peak at 608 nm gradually decreased while a new absorption peak at 692 nm appeared, accompanied by a red shift in UV-visible absorption.the fluorescence emission at 710 nm also increased with time with 625 nm as excitation light and reached maximum fluorescence intensity after 60 minutes.the maximum fluorescence at 710 nm for probe RN-gal activated by β -gal was approximately 240 times as large as before the reaction by simultaneous fluorescence scanning.
Example 3
Fluorescence linear range assay for probe compound RN-gal
The fluorescent probe solution (5. mu.M) obtained in example 2 was added with β -gal (0-10U/mL) to conduct fluorescence detection (. lamda.)ex=625 nm), indicating that the probe is linear in the β -gal concentration range of 0-5U/mLRelation, linear correlation coefficient is R2=0.99863。
Example 4
Selectivity of probe compound RN-gal for other representative proteases in tumor cells
The fluorescent probe solution (5. mu.M) of example 2 was pretreated with inhibitor D-galactose (50. mu.M). 100 eq of competitor standard solutions, one of which was added with an equimolar amount of β -gal standard solution, were reacted at 37 ℃ for 30min, and then the fluorescence emission spectrum of the solution was measured with 625 nm excitation light, and it was found that other interfering substances had little effect on the fluorescence of compound RN-gal, while the addition of β -gal significantly enhanced the fluorescence of compound RN-gal.
Example 5
Fluorescence imaging detection of β -gal in living cells by probe compound RN-gal
U87MG cells were incubated with RN-gal (5. mu.M) for various times (0, 1,2, 4,6 h) and imaged for intracellular near infrared fluorescence. The fluorescence intensity increases with increasing incubation time and reaches a maximum after 4 hours of incubation. These results indicate that the probe RN-gal can be activated and enter U87MG cells.
The foregoing is only a preferred embodiment of this invention and is not intended to limit the invention in any way, so that any person skilled in the art may, using the teachings disclosed above, modify or adapt for various equivalent embodiments with equivalent modifications. The design concept of the present invention is not limited thereto, and any insubstantial modifications made to the present invention using this concept shall fall within the scope of infringing upon the present invention.

Claims (3)

1. A target tumor cell is used for detecting β -galactosidase fluorescent probe compound, and the structure of the compound is shown in formula I:
Figure RE-FDA0002312717520000011
the preparation method comprises the following steps:
(1) reacting indole derivatives with a 2-chloro-1-formyl-3- (hydroxy methylene) compound in a mixed solution of butanol and benzene to obtain a compound I;
Figure RE-FDA0002312717520000012
(2) reacting the compound I with di-tert-butyl carbonate to obtain a compound II;
Figure RE-FDA0002312717520000013
(3) reacting the compound II with 4-chloro-1, 2-dihydroxybenzene to synthesize a compound III;
Figure RE-FDA0002312717520000014
(4) reacting the compound III with trifluoroacetic acid, removing Boc group, and synthesizing a near-infrared fluorescent dye blue compound, namely a compound IV;
Figure RE-FDA0002312717520000021
(5) reacting a dye compound IV with N-succinimidyl 3-maleimide propionate to synthesize a compound V;
Figure RE-FDA0002312717520000022
(6) reacting the compound five with 2,3,4, 6-tetraacetoxy-alpha-D-pyranose bromide, and hydrolyzing in sodium methoxide to obtain a compound six;
Figure RE-FDA0002312717520000023
(7) and stirring the compound six and c-RGD-SH in DMF to obtain a blue product of the near-infrared fluorescent probe compound formula I.
2. The method for preparing β -galactosidase fluorescence probe compound for detecting targeted tumor cells according to claim 1, which comprises the following seven steps
Figure RE-FDA0002312717520000031
3. A targeted near infrared fluorescent probe compound, which is characterized in that the compound of claim 1 is used for detecting the content of β -galactosidase in tumor cells, and the detection comprises visual qualitative detection, fluorescence detection, cell imaging detection and living tissue imaging detection.
CN201911177443.7A 2019-11-27 2019-11-27 Target tumor β -galactosidase near-infrared fluorescent probe and preparation method thereof Pending CN110845556A (en)

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CN111690403A (en) * 2020-06-03 2020-09-22 济南大学 Fluorescent probe for detecting beta-galactosidase and preparation method and application thereof
CN113234111A (en) * 2021-02-22 2021-08-10 西北大学 Fluorescent probe for simultaneously detecting beta-galactosidase and lysosome pH, and preparation method and application thereof
CN113264866A (en) * 2021-04-06 2021-08-17 南京大学 Non-fluorescent organic small molecular compound, preparation method of pentamethyl cyanine dye and application of pentamethyl cyanine dye
CN113461770A (en) * 2021-08-06 2021-10-01 南通大学 CDDO-Me targeted prodrug with near-infrared imaging function and preparation method and application thereof
CN114891054A (en) * 2022-03-30 2022-08-12 五邑大学 Lanthanide fluorescent probe and preparation method and application thereof
CN115160391A (en) * 2022-07-20 2022-10-11 湘潭大学 Preparation and application of targeted nitroso peroxide fluorescent probe

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Publication number Priority date Publication date Assignee Title
CN111690403A (en) * 2020-06-03 2020-09-22 济南大学 Fluorescent probe for detecting beta-galactosidase and preparation method and application thereof
CN111690403B (en) * 2020-06-03 2021-09-24 济南大学 Fluorescent probe for detecting beta-galactosidase and preparation method and application thereof
CN113234111A (en) * 2021-02-22 2021-08-10 西北大学 Fluorescent probe for simultaneously detecting beta-galactosidase and lysosome pH, and preparation method and application thereof
CN113264866A (en) * 2021-04-06 2021-08-17 南京大学 Non-fluorescent organic small molecular compound, preparation method of pentamethyl cyanine dye and application of pentamethyl cyanine dye
CN113461770A (en) * 2021-08-06 2021-10-01 南通大学 CDDO-Me targeted prodrug with near-infrared imaging function and preparation method and application thereof
CN114891054A (en) * 2022-03-30 2022-08-12 五邑大学 Lanthanide fluorescent probe and preparation method and application thereof
CN114891054B (en) * 2022-03-30 2023-07-21 五邑大学 Lanthanide fluorescent probe and preparation method and application thereof
CN115160391A (en) * 2022-07-20 2022-10-11 湘潭大学 Preparation and application of targeted nitroso peroxide fluorescent probe
CN115160391B (en) * 2022-07-20 2024-04-26 湘潭大学 Preparation and application of targeted nitrosoperoxide fluorescent probe

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Application publication date: 20200228