CN113501776B - Near infrared luminous free radical cation compound and preparation and application thereof - Google Patents

Near infrared luminous free radical cation compound and preparation and application thereof Download PDF

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CN113501776B
CN113501776B CN202110743372.3A CN202110743372A CN113501776B CN 113501776 B CN113501776 B CN 113501776B CN 202110743372 A CN202110743372 A CN 202110743372A CN 113501776 B CN113501776 B CN 113501776B
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CN113501776A (en
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唐本忠
高蒙
郑莉华
朱文超
周子开
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South China University of Technology SCUT
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Abstract

The invention belongs to the technical field of biological imaging, and discloses a near infrared luminous free radical cationic compound, and preparation and application thereof. The structure of the radical cation compound is formula II, R 1 Is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, heteroaryl; r is R 2 、R 3 、R 4 、R 5 Independently is hydrogen, halogen, substituted or unsubstituted alkyl, alkyloxy, alkylamino, aryl, heteroaryl, aryloxy, arylamino, arylthio, heteroaryloxy, heteroarylamino, heteroarylthio. The method comprises the following steps: and (3) carrying out single electron oxidation on the compound of the formula I to obtain the free radical cationic compound. The free radical cationic compound has the advantages of near infrared luminescence, high generation efficiency and good stability, and can perform fluorescence imaging. The free radical cationic compound is generated through in-situ reaction, does not need to be separated, and can be directly used for bioluminescence imaging.

Description

Near infrared luminous free radical cation compound and preparation and application thereof
Technical Field
The invention belongs to the technical field of luminescent materials and biological imaging, and particularly relates to a free radical cationic compound with near infrared luminescence, a preparation method thereof and application thereof in biological imaging.
Background
The free radical cations are open shell compounds with positive charges, and are easy to generate ionic reactions (nucleophilic addition, elimination reaction and the like) and free radical reactions (free radical coupling, cleavage, electron transfer and the like). In addition, free radical cations have the characteristic of near infrared absorption, and are increasingly attracting attention in the fields of photoelectric devices and biomedicine.
Radical cations can be prepared by single electron oxidation of conjugated systems, but radical cations are generally unstable and are subject to various subsequent reactions, often requiring the addition of either an enlarged conjugated system or multiple electron donating substituents to increase their stability, limiting their use in biomedical applications.
In order to be widely used in biomedical research, development of a method for directly and efficiently generating stable free radical cations in situ based on a simple substrate is urgently needed, near infrared luminescence property is given to the free radical cations, and defects that the traditional free radical cations are difficult to emit light, poor in stability and the like are overcome, so that application and research of biological imaging are facilitated.
Disclosure of Invention
To overcome the disadvantages and shortcomings of the prior art, a primary object of the present invention is to provide a class of free radical cationic compounds. The free radical cationic compound has the advantages of good stability, near infrared absorption, luminescence and the like.
It is another object of the present invention to provide a process for producing the above radical cationic compound.
It is a further object of the present invention to provide the use of the stable free radical cationic compound having near infrared luminescence as described above. The radical cation compound is applied to luminescent materials and/or biological imaging. The biological imaging is applied to organelle and in-vivo fluorescence imaging, and has the advantages of high signal-to-noise ratio, strong in-situ residence capability and the like. In biological imaging, the radical cationic compounds of the present invention are useful as fluorescent imaging agents.
The aim of the invention is achieved by the following technical scheme:
a stable free radical cationic compound having near infrared luminescence, having the structure of formula II:
wherein R is 1 Is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, heteroaryl;
wherein R is 2 、R 3 、R 4 、R 5 Independently hydrogen, halogen, substituted or unsubstituted alkyl, alkyloxy, alkylamino, aryl, heteroaryl, arylOxy (Ar-O-), arylamino (Ar-NH-), arylthio (Ar-S-): heteroaryloxy, heteroarylamino, heteroarylthio;
R 1 wherein the alkyl is a linear or branched alkyl; the substituted alkyl refers to a group formed by a cyclic compound which substitutes hydrogen in the alkyl, and the cyclic compound is preferably a cyclic compound formed by one or more of carbon, hydrogen and N, S, O heteroatoms;
the alkyl group being C 1-30 An alkyl group;
the aryl group refers to a monocyclic or polycyclic aromatic group having 6 to 20 carbon atoms, and representative aryl groups include: phenyl, naphthyl, anthracenyl, pyrenyl;
the substituted aryl refers to that hydrogen on the aryl ring is substituted by more than one of alkoxy, amino and carboxyl; for example: the hydrogen on the phenyl is substituted by one group of alkoxy, amino and carboxyl;
the heteroaryl group refers to a monocyclic or polycyclic heteroaromatic group having 1 to 20 carbon atoms and 1 to 4 heteroatoms selected from N, S, O, representative heteroaryl groups including: pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, thiazolyl, indolyl, naphthyridinyl, azaanthracenyl, and azapyrenyl;
R 2 、R 3 、R 4 、R 5 wherein the alkyl is C 1-30 Alkyl, alkyloxy being C 1-30 Alkyloxy, alkylamino being C 1-30 Alkylamino, alkylthio is C 1-30 Alkylthio;
the substituted alkyl refers to that hydrogen on the alkyl is substituted by hydroxyl, methoxy, carboxyl, halogen and other groups;
the aryl group refers to a monocyclic or polycyclic aromatic group having 6 to 20 carbon atoms, and representative aryl groups include: phenyl, naphthyl, anthracenyl, pyrenyl; aryl groups in aryloxy, arylamino, and arylthio groups are each independently a monocyclic or polycyclic aromatic group having 6 to 20 carbon atoms, and representative aryl groups include: phenyl, naphthyl, anthracenyl, pyrenyl;
the heteroaryl group refers to a monocyclic or polycyclic heteroaromatic group having 1 to 20 carbon atoms and 1 to 4 heteroatoms selected from N, S, O, representative heteroaryl groups including: pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, thiazolyl, indolyl, naphthyridinyl, azaanthracenyl, and azapyrenyl; the heteroaryloxy, heteroarylamino and heteroarylthio groups are each independently a monocyclic or polycyclic heteroaromatic group of 1 to 20 carbon atoms, 1 to 4 heteroatoms selected from N, S, O, representative heteroaryl groups including: pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, thiazolyl, indolyl, naphthyridinyl, azaanthracenyl, and azapyrenyl.
R 2 、R 5 Independently preferably alkyl, aryl; r is R 3 、R 4 Hydrogen, alkyl, substituted alkyl are preferred by themselves.
The free radical cation compound (formula II) with near infrared luminescence is obtained by single electron oxidation of the compound of formula I. Specifically, the catalyst is obtained by oxidation in a solvent.
The preparation method of the cationic compound (formula II) with the near infrared luminescence free radical comprises the following steps: carrying out oxidation reaction on the compound of the formula I to obtain a near infrared luminescent free radical cation compound (formula II);
the oxidation reaction is single electron oxidation; the oxidation reaction is a reaction in which the compound of the formula I is oxidized under the action of an oxidant or a reaction in which the compound of the formula I is oxidized in an electrochemical oxidation mode.
A compound of formula I:R 1 、R 2 、R 3 、R 4 、R 5 as defined in formula II above.
The reaction equation:
the reaction is carried out in a solvent; the solvent is an organic solvent and/or water; the organic solvent is one or more of dimethyl sulfoxide, N-dimethylformamide, acetone, acetonitrile, dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran or 1, 4-dioxane;
the oxidant is oxygen, oxygen-containing atmosphere (such as air), iodine, p-bromotriphenylamine free radical positive ion hexachlorantimonate, tris (2, 4-dibromotriphenylamine) hexachlorantimonate, antimony pentachloride, antimony trichloride, thallium trichloride, cerium nitrate, copper perchlorate, ferric chloride, silver hexafluoroantimonate and silver nitrate;
when the reaction is carried out under the action of the oxidant, the light or no light can be used.
When the oxidant is oxygen or air, the light or no light is irradiated during oxidation;
when illuminated, the oxidation reaction is called photooxidation. The photooxidation refers to illumination under the aerobic condition. The illumination comprises sunlight and ultraviolet light. The concentration of the compound of the formula I in the solvent is 1 mu M-1000 mM; the molar ratio of the oxidant to the compound of formula I is (0.01-10): 1, wherein the oxidant is solid or liquid. The reaction time is 1-300 min.
A method of stabilizing a free radical cationic compound comprising the steps of: and oxidizing the compound in the formula I in a solvent and a stabilizer, or uniformly mixing the stabilizer with the compound in the formula I, and oxidizing to obtain the near infrared luminous free radical cationic compound with better stability.
The stabilizer is a supermolecular host compound or a porous material. By the addition of the stabilizer, the stability of the radical cationic compound (formula II) is better.
The compounds of formula I are as defined above for compounds of formula I. The more stable free radical cationic compound with near infrared luminescence is a stabilizer so that the free radical cationic compound is more stable. The radical cationic compound structure is of formula II, as defined above.
The supermolecule main compound is more than one of cucurbituril, cyclodextrin, calixarene, column arene, molecular tweezers and molecular clips;
porous materials refer to silica gel, zeolite, hydrotalcite, molecular sieve, metal organic frameworks (such as Cu-QC2, co-gap, mg-gap, MUV-10 (Mn), ZIF-8, MIL-53Al-FA, MIL-100 Fe), covalent organic frameworks (such as COF-1, COF-6, COF-300), porous organic polymers (such as super-crosslinked polymers, self-microporous polymers, conjugated microporous polymers), porous molecular solids (such as triptycene cages, porphyrin cages), hydrogels (such as hyaluronic acid hydrogel, chitosan hydrogel).
The solvent is an organic solvent and/or water; the organic solvent is dimethyl sulfoxide, N-dimethylformamide, acetone, acetonitrile, dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran or 1, 4-dioxane;
the oxidation is preferably an oxidant oxidation. The oxidant is oxygen, oxygen-containing atmosphere (such as air), iodine, p-bromotriphenylamine free radical positive ion hexachlorantimonate, tris (2, 4-dibromotriphenylamine) hexachlorantimonate, antimony pentachloride, antimony trichloride, thallium trichloride, cerium nitrate, copper perchlorate, ferric chloride, silver hexafluoroantimonate and silver nitrate. When the reaction is carried out under the action of the oxidant, the light or no light can be used.
When the oxidizing agent is oxygen or an atmosphere containing oxygen, the oxidation is performed in the oxygen or the atmosphere containing oxygen; when the oxidant is more than one of iodine, p-bromotriphenylamine free radical positive ion hexachlorantimonate, tris (2, 4-dibromotriphenylamine hexachlorantimonate, antimony pentachloride, antimony trichloride, thallium trichloride, cerium nitrate, copper perchlorate, ferric chloride, silver hexafluoroantimonate and silver nitrate, the oxidant and each substance are uniformly mixed before oxidation.
The concentration of the compound of the formula I in the solvent is 1 mu M-1000 mM; the molar ratio of the oxidant to the compound of formula I is (0.01-10): 1, wherein the oxidant is solid or liquid. The mass ratio of the stabilizer to the compound of the formula I is (1-100): 1.
taking a stabilizer as a supermolecule main body compound as an example, the method for stabilizing the free radical cationic compound comprises the following specific steps: dissolving a compound of the formula I and a supermolecule main body compound in water, and generating a stable free radical cation compound under the action of air or an oxidant; equation:
a compound containing free radical cation compound with near infrared luminescence, which mainly comprises a free radical cation compound of a formula II and a stabilizer; specifically, the compound of the formula I is oxidized in a solvent and a stabilizer; or mixing stabilizer and compound of formula I in solvent, removing solvent, and oxidizing. The compounds of formula I and the free radical cationic compounds of formula II are as defined above for formulas I and II.
The compound containing the free radical cation compound with near infrared luminescence is specifically prepared by the method for stabilizing the free radical cation compound.
The free radical cation compound with near infrared luminescence or the compound containing the free radical cation compound with near infrared luminescence is used for preparing luminescent materials and/or fluorescent imaging agents and/or fluorescent imaging probes for biological imaging.
The luminescent material is the luminescent material of the photoelectric device.
The use of said free radical cationic compound with near infrared luminescence or complex containing free radical cationic compound with near infrared luminescence in biological imaging, in particular in organelle specific fluorescence imaging. Such as: as imaging agents for mitochondrial-specific fluorescence imaging.
The application of the free radical cation compound with near infrared luminescence or the compound containing the free radical cation compound with near infrared luminescence in tumor imaging is used as a fluorescence imaging agent for tumor imaging.
The compound of the formula I generates electron-losing oxidation reaction to generate a free radical cation compound (formula II) with near infrared luminescence property, and has excellent cell fluorescence imaging effect.
A fluorescent imaging probe comprising the stable free radical cationic compound having near infrared luminescence as described above.
Or a fluorescent imaging probe comprising a complex of the above-described radical cation-containing compound having near infrared luminescence.
The fluorescent probe is prepared by the following method: the compound of formula I is subjected to an oxidation reaction. The oxidation conditions are the same as those described above for the stable radical cationic compound having near infrared luminescence.
Or the preparation method of the fluorescent probe is the same as the preparation conditions of the compound containing the free radical cation compound with near infrared luminescence.
The fluorescent probe is a fluorescent probe for cell organ specific fluorescent imaging and/or tumor imaging, namely a fluorescent imaging agent.
A luminescent material (luminescent material having near infrared luminescence) comprising the above stable radical cation compound having near infrared luminescence or the above complex containing radical cation compound having near infrared luminescence.
Compared with the prior art, the invention has the following advantages and effects:
(1) The free radical cationic compound with near infrared luminescence has the advantages of high generation efficiency, good stability and the like;
(2) The free radical cationic compound with near infrared luminescence is generated through in-situ reaction, does not need to be separated, and can be directly used for living cell fluorescence imaging.
Drawings
FIG. 1 shows the in situ oxidation (365 nm light, air) of compound I-1 on a silica gel plate to free radical cationic compound II-1 ·+ Excitation spectrum, fluorescence emission spectrum, and intensity variation pattern of (a): (A) (B) the fluorescence emission spectrum (lambda) of the compound I-1 on the silica gel plate with time in the air and under 365nm light, respectively ex =550 nm) and fluorescence intensity change pattern (λ ex ＝600nm，λ em =630 nm); (C) Compound II-1 ·+ Excitation spectrum (lambda) on silica gel plate em =750 nm); (D) Normalized fluorescence emission spectra at different excitation wavelengths;
FIG. 2 shows the in situ oxidation (in the absence of light, air) of compound I-1 on a silica gel plate to free radical cationic compound II-1 ·+ Fluorescent emission of (2)Spectrum and intensity change plot: (A) (B) the fluorescence emission spectrum (lambda) of the compound I-1 on the silica gel plate with time in the air and in the dark, respectively ex =550 nm), and a graph (λ) of the change in fluorescence intensity under light and dark conditions ex ＝600nm，λ em ＝630nm)；
FIG. 3 is a graph showing the change of fluorescence emission spectra of compound I-1 on silica gel plate before and after 365nm illumination in air or argon (lambda) ex =550 nm); the inset is a bright field and fluorescence photograph before and after illumination at 365nm in air or argon for 6 minutes;
FIG. 4 is an in situ oxidative conversion of Compound I-2 to free radical cationic Compound II-2 under the action of silver hexafluoroantimonate (1.0 mM) in dichloromethane (1.0 mM) ·+ Absorption spectrum, fluorescence emission spectrum, and intensity variation pattern of (a): (a) a time-dependent absorption spectrum; (B) Time-dependent fluorescence emission spectrum, lambda ex =600 nm; (C) An absorbance intensity ratio profile at 630nm and a fluorescence intensity ratio profile at 670 nm;
FIG. 5 shows the effect of Compound I-2 (300. Mu.M) on cucurbituril [7 ]]And in situ oxidation under the action of air to convert into free radical cation compound II-2 ·+ Absorption spectrum, fluorescence emission spectrum, and intensity variation pattern of (a): (a) a time-dependent absorption spectrum; (B) Time-dependent fluorescence emission spectrum, lambda ex =600 nm; (C) An absorbance intensity ratio profile at 600nm and a fluorescence intensity ratio profile at 670 nm;
FIG. 6 shows the in situ oxidation (365 nm light, air) of compound I-3 to free radical cationic compound II-3 on a silica gel plate ·+ Excitation spectrum, fluorescence emission spectrum, and intensity variation pattern of (a): (A) (B) fluorescence emission spectrum (lambda) of compound I-3 on silica gel plate with time in air and 365nm light respectively ex =550 nm) and a graph (λ) of the change in fluorescence intensity at 686nm ex =650 nm); (C) Compound II-3 ·+ Excitation spectrum, lambda on silica gel plate em ＝750nm；
FIG. 7 shows the in situ oxidation (365 nm light, air) of compound I-4 to free radical cationic compound II-4 on a silica gel plate ·+ Excitation spectrum, fluorescence emission spectrum, and intensity variation pattern of (a): (A) (B) the fluorescence emission spectrum (lambda) of the compound I-4 on the silica gel plate with time in the air and under 365nm light, respectively ex =550 nm) and a graph (λ) of the change in fluorescence intensity at 630nm ex =590 nm); (C) Compound II-4 ·+ Excitation spectrum, lambda on silica gel plate em ＝700nm；
FIG. 8 shows the in situ oxidation (365 nm light, air) of compound I-5 to free radical cationic compound II-5 on a silica gel plate ·+ Excitation spectrum, fluorescence emission spectrum, and intensity variation pattern of (a): (A) (B) the fluorescence emission spectrum (lambda) of the compound I-5 on the silica gel plate with time in the air and under 365nm light, respectively ex =550 nm) and a graph (λ) of the change in fluorescence intensity at 630nm ex =590 nm); (C) Compound II-5 ·+ Excitation spectrum, lambda on silica gel plate em ＝700nm；
FIG. 9 shows the in situ oxidation (365 nm light, air) of compound I-6 to free radical cationic compound II-6 on a silica gel plate ·+ Excitation spectrum, fluorescence emission spectrum, and intensity variation pattern of (a): (A, B) fluorescence emission spectrum (lambda) of Compound I-6 on silica gel plate with time in air and 365nm light ex =550 nm) and a graph of change in fluorescence intensity at 650nm (λ ex =610 nm); (C) Compound II-6 ·+ Excitation spectrum, lambda on silica gel plate em ＝750nm；
FIG. 10 is an in situ oxidation (365 nm light, air) of compound I-7 on a silica gel plate to free radical cationic compound II-7 ·+ Excitation spectrum, fluorescence emission spectrum, and intensity variation pattern of (a): (A) (B) fluorescence emission spectrum (lambda) of Compound I-7 on silica gel plate with time in air and 365nm light respectively ex =550 nm) and a graph of the change in fluorescence intensity at 620nm (λ ex =590 nm); (C) Compound II-7 ·+ Excitation spectrum (lambda) on silica gel plate em ＝680nm)；
FIG. 11 shows the in situ oxidation (365 nm light, air) of compound I-8 to free radical cationic compound II-8 on a silica gel plate ·+ Excitation spectrum, fluorescence emission spectrum, and intensity variation pattern of (a): (A) (B) the fluorescence emission spectrum (lambda) of the compound I-8 on the silica gel plate with time in the air and under 365nm light, respectively ex =550 nm) and at λ em Fluorescence intensity change chart at=630 nm (λ ex =600 nm); (C) Compound II-8 ·+ Excitation spectrum (lambda) on silica gel plate em ＝750nm)；
FIG. 12 is an in situ generated Compound II on silica gel ·+ Electron spin resonance spectrum (EPR) diagram: (A) Is compound II-1 ·+ An EPR map of (c); (B) Is compound II-2 ·+ An EPR map of (c); (C) Is compound II-4 ·+ An EPR map of (c); (D) Is compound II-6 ·+ An EPR map of (c); (E) Is compound II-7 ·+ An EPR map of (c); (F) Is compound II-8 ·+ An EPR map of (c);
FIG. 13 is an oxidation cyclic voltammogram of Compound I: (A) is an oxidation cyclic voltammogram of the compound I-1; (B) is an oxidation cyclic voltammogram of the compound I-2; (C) is an oxidation cyclic voltammogram of the compound I-3; (D) is an oxidation cyclic voltammogram of the compound I-4; (E) is an oxidation cyclic voltammogram of compound I-5; (F) is an oxidation cyclic voltammogram of the compound I-6; (G) is an oxidative cyclic voltammogram of compound I-7; (H) is an oxidation cyclic voltammogram of compound I-8;
FIG. 14 is a reduction cyclic voltammogram of Compound I: (A) is a reduction cyclic voltammogram of the compound I-1; (B) is a reduction cyclic voltammogram of the compound I-2; (C) is a reduction cyclic voltammogram of the compound I-3; (D) is a reduction cyclic voltammogram of the compound I-4; (E) is a reduction cyclic voltammogram of compound I-5; (F) is a reduction cyclic voltammogram of the compound I-6; (G) is a reduction cyclic voltammogram of compound I-7; (H) is a reduction cyclic voltammogram of the compound I-8;
in FIG. 15, (A) is compound I-1 and compound II-1 ·+ Is a theoretical calculation energy level diagram of (1); (B) Is compound II-2 ·+ Is a theoretical calculation energy level diagram of (1);
in FIG. 16, (A) is a compoundFluorescence in HeLa cellsA dyeing chart; (B) Fluorescent staining pattern of mitochondrial dye MitoTracker Green in HeLa cells; (C) is a fluorescence signal superposition diagram of (A) and (B);
in FIG. 17, (A) is a compoundFluorescence staining patterns in a375 cells; (B) Fluorescent staining pattern of mitochondrial dye MitoTracker Green in a375 cells; (C) is a fluorescence signal superposition diagram of (A) and (B);
FIG. 18 is a compoundLambda mode fluorescence imaging and fluorescence spectrogram in HeLa cells: (a) fluorescent staining photographs in Lambda mode; (B) A fluorescence spectrum of the fluorescence-stained area selected in (a);
FIG. 19 is a compoundLambda mode fluorescence imaging and fluorescence spectrogram in a375 cells: (a) fluorescent staining photographs in Lambda mode; (B) A fluorescence spectrum of the fluorescence-stained area selected in (a);
FIG. 20 shows the concentration of the compounds in HeLa cellsCytotoxicity results of the complex;
FIG. 21 shows different concentrations for A375 cellsCytotoxicity results of the complex;
in FIG. 22 (A) is an injection of tumor sites of tumor-bearing miceFluorescence imaging photograph of 0h after the complex; (B) Injection of tumor sites of tumor-bearing mice>Fluorescence imaging photograph 24h after the complex.
Detailed Description
The present invention will be described in further detail with reference to examples and drawings, but embodiments of the present invention are not limited thereto.
Example 1
Compound II-1 under light ·+ In situ generation and photophysical property characterization of (c)
A dichloromethane solution (100 mM) of the compound I-1 (2, 5-dimethyl-1-phenyl-1H-pyrrole) is dripped on a silica gel plate, and the pyrrole compound I-1 is rapidly converted into the corresponding free radical cation compound II-1 under the illumination of 365nm in the air ·+ The generation process can be monitored in situ by testing of fluorescence spectra. The test results are shown in FIG. 1.
In FIG. 1, (A), (B) are the fluorescence emission spectra (lambda) of compound I-1 on a silica gel plate over time in air and under 365nm light, respectively ex =550 nm) and fluorescence intensity change pattern (λ ex ＝600nm，λ em =630 nm); (C) Compound II-1 ·+ Excitation spectrum (lambda) on silica gel plate em =750 nm); (D) Normalized fluorescence emission spectra at different excitation wavelengths. As can be seen from FIG. 1, A, B shows that under irradiation of ultraviolet lamp, the fluorescence intensity at 630nm increases rapidly with the increase of irradiation time, because the compound I-1 easily loses a single electron generating compound II-1 under the action of oxygen ·+ Resulting in the following. In addition, in situ generated Compound II-1 ·+ There is a characteristic excitation peak of the single electron radical compound at 600nm (see C in FIG. 1).
Example 2
The presence of light and oxygen on the compound II-1 ·+ Influence of in situ generation
A dichloromethane solution (100 mM) of compound I-1 (2, 5-dimethyl-1-phenyl-1H-pyrrole) was added dropwise to a silica gel plate in airAnd fluorescence emission spectrum and fluorescence intensity change with time under dark conditions, as shown in fig. 2. In FIG. 2, (A), (B) are the fluorescence emission spectra (lambda) of the compound I-1 on a silica gel plate over time in air and in the absence of light, respectively ex =550 nm), and a graph (λ) of the change in fluorescence intensity under light and dark conditions ex ＝600nm，λ em =630 nm). As can be seen from FIG. 2, the fluorescence intensity gradually increases with time in the air and in the dark, since the compound I-1 can also generate the compound I-1 by losing a single electron under the action of air alone ·+ Resulting in the following.
A dichloromethane solution (100 mM) of compound I-1 (2, 5-dimethyl-1-phenyl-1H-pyrrole) was added dropwise to a silica gel plate, and the fluorescence emission spectra (. Lamda.) of air and argon under light (365 nm) were compared with time ex =550 nm) and the test results are shown in fig. 3. The inset in FIG. 3 shows bright field and fluorescence photographs before and after 6 minutes of 365nm illumination in air or argon. FIG. 3 shows that the presence of inert gas is effective to inhibit the loss of a single electron from Compound I-1 to Compound II-1 ·+ 。
Example 3
Compound II-2 in organic solvent ·+ In situ generation and photophysical property characterization of (c)
Silver hexafluoroantimonate (AgSbF) 6 ) Added into a dichloromethane solution of a compound I-2 (2, 5-dimethyl-3-hydroxymethylene-1-phenyl-1H-pyrrole) (the concentration of the compound I-2 is 1.0mmol/L, the concentration of the silver hexafluoroantimonate is 1.0 mM), and the compound I-2 is rapidly converted into a corresponding free radical cation compound II-2 ·+ The generation process can be monitored in situ by testing the ultraviolet-visible absorption spectrum and the fluorescence spectrum. The test results are shown in fig. 4. FIG. 4 (A) shows an absorption spectrum over time; (B) Time-dependent fluorescence emission spectrum, lambda ex =600 nm; (C) Absorption intensity ratio at 630nm and fluorescence intensity ratio at 670 nm. From the graph4, it can be seen that the fluorescence intensity at 670nm increases gradually within 60 minutes after the addition of silver hexafluoroantimonate, because the compound I-2 easily loses a single electron to form the compound II-2 under the oxidation of silver ions ·+ Resulting in the following. In addition, since the radical cation can further undergo a radical coupling reaction in methylene chloride, the fluorescence intensity thereof gradually decreases after 60 minutes. As can also be seen from the UV-visible absorption spectrum, the intensity of the characteristic absorption peak at 630nm increases rapidly within 60 minutes and then decreases gradually (see (B) in FIG. 4), further confirming that compound I-2 readily loses a single electron to form compound II-2 under oxidation of silver ions ·+ And further, a radical coupling reaction or the like may occur.
Example 4
Compound II-2 in aqueous solution ·+ In situ generation and photophysical property characterization of (c)
The compound I-2 (2, 5-dimethyl-3-hydroxymethylene-1-phenyl-1H-pyrrole) (concentration of the compound I-2: 300. Mu.M) was added to cucurbituril [7 ]]In the aqueous solution of (cucurbituril [ 7)]At a concentration of 300. Mu.M), the pyrrole compound I-2 is rapidly converted into the corresponding radical cation compound II-2 ·+ And further with cucurbituril [7 ]]Forming a stable complexThe generation process can be monitored in situ by testing the ultraviolet-visible absorption spectrum and the fluorescence spectrum. The test results are shown in fig. 5. FIG. 5 (A) shows an absorption spectrum over time; (B) Time-dependent fluorescence emission spectrum, lambda ex =600 nm; (C) Absorption intensity ratio at 600nm and fluorescence intensity ratio at 670 nm. It can also be seen from the ultraviolet-visible absorption spectrum that the intensity of its characteristic absorption peak at 600nm increases rapidly and can exist stably (see (a) in fig. 5). In addition, as can be seen from FIG. 5 (B), the fluorescence intensity at 670nm increases rapidlyPlus, due to cucurbituril [7 ]]Promoting the reaction of the compound I-2 with oxygen to lose a single electron to generate the compound II-2 ·+ Further covered with cucurbituril [7 ]]Package formation->The complex is stabilized (fig. 5 (C)).
Example 5
Compound II-3 under light ·+ In situ generation and photophysical property characterization of (c)
A dichloromethane solution (100 mM) of compound I-3 (2-methyl-1, 5-diphenyl-1H-pyrrole) was added dropwise to a silica gel plate, and the fluorescence intensity at 686nm increased rapidly in air and under 365nm light, since compound I-3 easily lost a single electron generating compound II-3 under the action of oxygen ·+ Resulting (fig. 6 (a) and (B)). In addition, the maximum excitation wavelength at 650nm further confirms Compound II-3 ·+ (FIG. 6C). FIG. 6 (A), (B) are graphs of the fluorescence emission spectra of Compound I-3 over time on silica gel plates in air and 365nm, respectively (lambda ex =550 nm) and a graph (λ) of the change in fluorescence intensity at 686nm ex =650 nm); (C) Compound II-3 ·+ Excitation spectrum, lambda on silica gel plate em ＝750nm。
Example 6
Compound II-4 under light irradiation ·+ In situ generation and photophysical property characterization of (c)
A dichloromethane solution (100 mM) of compound I-4 (2, 5-dimethyl-1- (4-methoxyphenyl) -1H-pyrrole) was added dropwise to a silica gel plate, and its fluorescence intensity at 630nm increased rapidly in air and under 365nm light, due to easy loss of single unit under the action of oxygenGenerating compound II-4 by several electrons ·+ Resulting (a-B in fig. 7). In addition, the maximum excitation wavelength at 590nm further confirms Compound II-4 ·+ Is generated (C in fig. 7). FIG. 7 (A), (B) are graphs of the fluorescence emission spectra of Compound I-4 over time on silica gel plates in air and 365nm, respectively (lambda ex =550 nm) and a graph (λ) of the change in fluorescence intensity at 630nm ex =590 nm); (C) Compound II-4 ·+ Excitation spectrum, lambda on silica gel plate em ＝700nm。
Example 7
Compound II-5 under light ·+ In situ generation and photophysical property characterization of (c)
A dichloromethane solution (100 mM) of the compound I-5 (2, 5-dimethyl-1- (4-aminophenyl) -1H-pyrrole) is dripped on a silica gel plate, and the fluorescence intensity at 630nm is rapidly increased in air and under 365nm illumination, because a single electron generating compound II-5 is easily lost under the action of oxygen ·+ Resulting (a-B in fig. 8). In addition, the maximum excitation wavelength at 590nm further confirms Compound II-5 ·+ Is generated (C in fig. 8). FIG. 8 shows the in situ oxidation (365 nm light, air) of compound I-5 to free radical cationic compound II-5 on a silica gel plate ·+ Excitation spectrum, fluorescence emission spectrum, and intensity variation pattern of (a): (A) (B) the fluorescence emission spectrum (lambda) of the compound I-5 on the silica gel plate with time in the air and under 365nm light, respectively ex =550 nm) and a graph (λ) of the change in fluorescence intensity at 630nm ex =590 nm); (C) Compound II-5 ·+ Excitation spectrum, lambda on silica gel plate em ＝700nm。
Example 8
Compound II-6 under light ·+ In situ generation and photophysical property characterization of (c)
A dichloromethane solution (100 mM) of the compound I-6 (2, 5-dimethyl-1- (4-carboxyphenyl) -1H-pyrrole) is dripped on a silica gel plate, and the fluorescence intensity at 650nm is rapidly increased in air and under 365nm illumination, because a single electron generating compound II-6 is easily lost under the action of oxygen ·+ Resulting (a-B in fig. 9). In addition, the maximum excitation wavelength at 610nm further confirms Compound II-6 ·+ Is generated (C in fig. 9). FIG. 9 shows the in situ oxidation (365 nm light, air) of compound I-6 to free radical cationic compound II-6 on a silica gel plate ·+ Excitation spectrum, fluorescence emission spectrum, and intensity variation pattern of (a): (A, B) fluorescence emission spectrum (lambda) of Compound I-6 on silica gel plate with time in air and 365nm light ex =550 nm) and a graph of change in fluorescence intensity at 650nm (λ ex =610 nm); (C) Compound II-6 ·+ Excitation spectrum, lambda on silica gel plate em ＝750nm。
Example 9
Compound II-7 under light irradiation ·+ In situ generation and photophysical property characterization of (c)
A dichloromethane solution (100 mM) of the compound I-7 (2, 5-dimethyl-1-methyl-1H-pyrrole) is dripped on a silica gel plate, and the fluorescence intensity at 620nm is rapidly increased under the illumination of 365nm in air, because a single electron is easily lost under the action of oxygen to generate the compound II-7 ·+ Resulting (a-B in fig. 10). In addition, the maximum excitation wavelength at 590nm further confirms Compound II-7 ·+ Is generated (C in fig. 10). FIG. 10 is an in situ oxidation (365 nm light, air) of compound I-7 on a silica gel plate to free radical cationic compound II-7 ·+ Excitation spectrum, fluorescence emission spectrum, and intensity variation pattern of (a): (A) (B) fluorescence emission spectrum (lambda) of Compound I-7 on silica gel plate with time in air and 365nm light respectively ex =550 nm) and a graph of the change in fluorescence intensity at 620nm (λ ex =590 nm); (C) Compound II-7 ·+ Excitation spectrum (lambda) on silica gel plate em ＝680nm)。
Example 10
Compound II-8 under light irradiation ·+ In situ generation and photophysical property characterization of (c)
A dichloromethane solution (100 mM) of compound I-8 (2, 5-dimethyl-1H-pyrrole) was added dropwise to a silica gel plate, and its fluorescence intensity at 630nm increased rapidly in air and under 365nm light, due to the easy loss of a single electron generating compound II-8 under the action of oxygen ·+ Resulting (a-B in fig. 11). In addition, the maximum excitation wavelength at 600nm further confirms Compound II-8 ·+ Is generated (C in fig. 11). FIG. 11 shows the in situ oxidation (365 nm light, air) of compound I-8 to free radical cationic compound II-8 on a silica gel plate ·+ Excitation spectrum, fluorescence emission spectrum, and intensity variation pattern of (a): (A) (B) the fluorescence emission spectrum (lambda) of the compound I-8 on the silica gel plate with time in the air and under 365nm light, respectively ex =550 nm) and at λ em Fluorescence intensity change chart at=630 nm (λ ex =600 nm); (C) Compound II-8 ·+ Excitation spectrum (lambda) on silica gel plate em ＝750nm)。
Example 12
Detection of in situ formed Compound II on silica gel plate ·+ The excitation and emission wavelengths, quantum yields and fluorescence lifetime results are shown in table 1.
TABLE 1 Compound II ·+ Maximum excitation wavelength, maximum emission wavelength value, quantum yield and fluorescence lifetime of (a)
Example 13
Detection of in situ formed Compound II on silica gel ·+ Electron spin resonance (EPR) of (a) and the result is shown in fig. 12. A dichloromethane solution of compound I (100 mM,0.5 mL) was mixed with silica gel powder, followed by spin evaporation to remove dichloromethane, and the resulting solid powder was further illuminated with 365nm UV light for 120 minutes, then sealed into a capillary tube and placed in an EPR spectrometer for testing for a period of 5 minutes.
FIG. 12A is Compound II-1 ·+ An EPR map of (c); FIG. 12B is Compound II-2 ·+ An EPR map of (c); FIG. 12C is Compound II-4 ·+ An EPR map of (c); FIG. 12D is Compound II-6 ·+ An EPR map of (c); FIG. 12E is Compound II-7 ·+ An EPR map of (c); FIG. 12F is Compound II-8 ·+ EPR map of (c).
Example 14
The cyclic voltammogram of compound I was measured and the results are shown in fig. 13, fig. 14 and table 2. The test uses a glassy carbon electrode as a working electrode, a platinum wire as a counter electrode, ag/Ag+ as a reference electrode, ferrocene cation/ferrocene as an internal standard, and the scanning rate is 100mV s -1 Anhydrous dimethylformamide and anhydrous dichloromethane (0.1M) containing tetrabutylammonium hexafluorophosphate were used as supporting electrolytes for negative scan and positive scan, respectively. FIG. 13 is an oxidation cyclic voltammogram of compounds I-1 to I-8; FIG. 14 is a reduction cyclic voltammogram of compounds I-1 to I-8.
TABLE 2 redox potential and highest occupied orbital (HOMO), lowest unoccupied orbital (LUMO) energy level values of Compound I
Example 15
Compound I-1 and compound II-1 ·+ Theoretical analysis of photophysical properties of (fig. 15, table 3): calculation of I-1 and cationic free radical II-1 using the Density functional method in Gaussian software (v 16) ·+ Molecular orbital energy of (a). First, I-1 and its radical cation II-1 ·+ Performing structure optimization and frequency calculation under B3LYP/def2-TZVP group, and calculatingThe dispersion effect is corrected using the damped D3 form (GD 3 BJ). Based on the optimized configuration, M06-2X/def2-TZVP and ωB97XD/def2-TZVP pairs I-1 and their free radical cations II-1 are used by time-density functional method (TDDFT) ·+ Theoretical predictions of UV-Vis absorption peaks were made. It should be noted that the program default PCM model (dichloromethane is solvent) is adopted in all the calculation to simulate the solvation effect in the actual process, and the theoretical calculation result is close to the experimental value, thereby further proving that the compound I-1 generates the free radical cationic compound II-1 through the oxidation reaction of losing single electron ·+ . In FIG. 15, (A) is compound I-1 and compound II-1 ·+ Is a theoretical calculation energy level diagram of (1); (B) Is compound II-2 ·+ Is a theoretical calculation energy level diagram of (a).
Table 3 shows compounds I-1 and II-1 ·+ Theoretical and experimental value comparison of excitation wavelength of (c)
Example 16
Use in cell imaging:
compound I-2 (1.2 mg,10 mM) was combined with cucurbituril [7 ]]Is mixed (3.3 mM, 597. Mu.L) and formed in situComplex, then 2.0. Mu.L of the mixture was added to a complete medium containing cells (DMEM medium containing 1% penicillin-streptomycin and 10% fetal bovine serum) (1.0 mL), incubated for 3 hours and then co-stained with the commercial mitochondrial dye Mito-Tracker Green, indicated that @>Can be used for specific fluorescence imaging of mitochondria in HeLa cells and A375 cells (see FIGS. 16-17). />Exciting by using a 633nm laser, and collecting 640-750nm fluorescence signals; mito-Tracker Green was excited with a 488nm laser and fluorescence signals were collected at 500-550 nm.
Using a 633nm laser in Lambda imaging mode, fluorescence signals of 640-750nm were collected (see fig. 18-19). The maximum emission wavelength is found to be about 670nm, and the surface is derived from free radical cation II-2 ·+ Is provided.
In FIG. 16, (A) is a compoundFluorescent staining pattern in HeLa cells; (B) Fluorescent staining pattern of mitochondrial dye MitoTracker Green in HeLa cells; (C) is a fluorescence signal superposition diagram of (A) and (B); in FIG. 17, (A) is the compound +.>Fluorescence staining patterns in a375 cells; (B) Fluorescent staining pattern of mitochondrial dye MitoTracker Green in a375 cells; (C) is a fluorescence signal superposition diagram of (A) and (B); FIG. 18 is a compoundLambda mode fluorescence imaging and fluorescence spectrogram in HeLa cells: (a) fluorescent staining photographs in Lambda mode; (B) A fluorescence spectrum of the fluorescence-stained area selected in (a); FIG. 19 is a compound->Lambda mode fluorescence imaging and fluorescence spectrogram in a375 cells: (a) fluorescent staining photographs in Lambda mode; (B) A fluorescence spectrum of the fluorescence-stained area selected in (A).
Example 17
Is shown in FIGS. 20 to 21):
HeLa or A375 cells (density 0.8X10 per well) were seeded in 96-well plates 4 ～1×10 4 And five wells per concentration. After 24 hours, the cell culture solution was aspirated and the medium containing different concentrations was addedThe well plate was then placed in a cell incubator and the culture was continued for 24 hours at 37 ℃. Subsequently, the culture broth was aspirated, washed once with 100. Mu.L of PBS, and 100. Mu.L of MTT-containing medium (0.5 mg/mL) was added to each well, and incubation was continued for 4 hours at 37 ℃. The medium was aspirated off, and then 100. Mu.L of biological grade dimethyl sulfoxide was added to each well, and the mixture was placed on a shaker for 10 minutes at room temperature to allow the precipitate to dissolve sufficiently. Finally, the absorbance of each well at 570nm was measured with a microplate reader.
FIG. 20 shows the concentration of the compounds in HeLa cellsCytotoxicity results of the complex; FIG. 21 shows the concentration of +.>Cytotoxicity results of the complex.
Example 18
In vivo tumor imaging (see fig. 22):
will be(3 mg/kg) of the aqueous solution was injected into the tumor site of tumor-bearing mice, and it was revealed that the>The complex can be used for long-term fluorescence imaging of mouse tumor>Can be stably stored in the body for a long time.
In FIG. 22 (A) is an injection of tumor sites of tumor-bearing miceFluorescence imaging photograph of 0h after the complex; (B) Injection of tumor sites of tumor-bearing mice>Fluorescence imaging photograph 24h after the complex.
The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.

Claims (6)

1. A complex containing a radical cation compound having near infrared luminescence, characterized in that: mainly comprises a free radical cationic compound of the formula II and a stabilizer;
the structure of the radical cationic compound is shown as a formula II:；
R 1 is hydrogen or alkyl;
R 2 、R 5 are all methyl groups; r is R 3 、R 4 Independently hydrogen, substituted alkyl, the substituted alkyl meaning that the hydrogen on the alkyl is substituted with hydroxy;
the stabilizer is a supermolecular host compound or a porous material.
2. The method for producing a complex of a radical cation compound having near infrared luminescence according to claim 1, characterized in that: the method comprises the following steps: oxidizing the compound of formula I in a solvent and a stabilizer; or uniformly mixing a stabilizer with the compound of the formula I, and oxidizing to obtain a compound of the free radical cation compound with near infrared luminescence;
a compound of formula I: ；
r in formula I 1 Is hydrogen or alkyl;
R 2 、R 5 are all methyl groups; r is R 3 、R 4 Independently hydrogen, substituted alkyl, which means that hydrogen on the alkyl is substituted with hydroxy.
3. The method for producing a complex of a radical cation compound having near infrared luminescence according to claim 2, characterized in that: the stabilizer is a supermolecule main compound or a porous material;
the supermolecule main compound is more than one of cucurbituril, cyclodextrin, calixarene, column arene, molecular tweezers and molecular clips; porous materials refer to silica gel, zeolite, hydrotalcite, molecular sieve, metal organic framework, covalent organic framework, porous organic polymer, porous molecular solid, hydrogel;
when the stabilizer is a porous material, the method comprises the steps of uniformly mixing the stabilizer with the compound of the formula I, and oxidizing;
the solvent is an organic solvent and/or water; the organic solvent is one of dimethyl sulfoxide, N-dimethylformamide, acetone, acetonitrile, dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran and 1, 4-dioxane;
the oxidation is oxidant oxidation; the oxidant is one or more of oxygen, oxygen-containing atmosphere, iodine, p-bromotriphenylamine free radical positive ion hexachlorantimonate, tris (2, 4-dibromotriphenylamine) hexachlorantimonate, antimony pentachloride, antimony trichloride, thallium trichloride, cerium nitrate, copper perchlorate, ferric chloride, silver hexafluoroantimonate and silver nitrate;
when the reaction is carried out under the action of an oxidant, illumination or no illumination is carried out;
when the oxidizing agent is oxygen or an atmosphere containing oxygen, the oxidation is performed in the oxygen or the atmosphere containing oxygen; when the oxidant is more than one of iodine, p-bromotriphenylamine free radical positive ion hexachlorantimonate, tris (2, 4-dibromotriphenylamine hexachlorantimonate, antimony pentachloride, antimony trichloride, thallium trichloride, cerium nitrate, copper perchlorate, ferric chloride, silver hexafluoroantimonate and silver nitrate, the oxidant and each substance are uniformly mixed before oxidation.
4. A fluorescent imaging probe, characterized in that: comprising a complex comprising a radical cation-containing compound having near infrared luminescence;
the complex containing a radical cation compound with near infrared luminescence is as defined in claim 1.
5. The use of a fluorescent imaging probe as claimed in claim 4, wherein: the fluorescent imaging probes are used for organelle specific fluorescent imaging and/or tumor imaging.
6. A luminescent material, characterized in that: comprising a complex comprising a radical cation-containing compound having near infrared luminescence;
the complex containing a radical cation compound with near infrared luminescence is as defined in claim 1.
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