CN113201018B - Mn (II) complex with AIE property and targeted living cell mitochondrial function, and preparation method and application thereof - Google Patents
Mn (II) complex with AIE property and targeted living cell mitochondrial function, and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses an Mn (II) complex with AIE property and targeted living cell mitochondria function, a preparation method and application thereof, relating to the technical field of multiphoton absorption materials, namely FD-MnCl 2 The structural formula is as follows:
the novel terpyridine Mn (II) complex synthesized by the invention is a multiphoton absorption material with a cell development function, and compared with other materials, the complex has the characteristics of larger three-photon absorption section, low excitation energy, long wavelength, strong penetrability, small photodamage and the like, and can be used for multiphoton biological imaging, thereby having obvious application value.
Description
Technical field:
the invention relates to the technical field of multiphoton absorption materials, in particular to an Mn (II) complex with AIE properties and targeted living cell mitochondria functions, a preparation method and application thereof.
The background technology is as follows:
multiphoton absorption is a nonlinear optical effect. Under irradiation of a high intensity laser beam, it is possible for a substance to absorb several, even tens of photons simultaneously, a process known as multiphoton absorption. Compared with the traditional single photon absorption, the multiphoton absorption has obvious advantages in the fields of three-dimensional controllability, photolysis drug release, biological fluorescent labeling, multiphoton fluorescence microscopy imaging (MPFM) and the like, thereby attracting great interest of researchers.
However, the multiphoton absorption cross section of most of the existing organic materials is smaller, the absorption wavelength is short, the application prospect is limited, and the multiphoton absorption materials with large absorption cross section and long wavelength are searched to become hot spots in the nonlinear optical field, so that multiphoton complexes with various structures, unique properties and simple synthesis are attracting the wide attention of researchers.
The transition metal complex has good photophysical properties, such as high quantum yield, large stoke shift, narrow emission peak, long luminescence life and the like (Angew.chem.int.ed., 2020,59,15987-15991), and the longer fluorescence life can effectively eliminate the interference of autofluorescence in organisms. The complex photophysical and other properties are changed by changing the structure of the ligand, so that the simple and effective design and synthesis of the multiphoton optical active complex material are realized.
Based on the above consideration, the terpyridine ligand with strong chelating ability and Mn (II) form a complex, the anilino and butyl introduced on the terpyridine ligand have rich electrons, and halogen is introduced as an auxiliary coordination atom to form a D-A structure, so that the electron-pulling capability is improved, and the multiphoton absorption property of the complex is enhanced.
The invention comprises the following steps:
the technical problem to be solved by the invention is to provide an Mn (II) complex with AIE properties and targeted living cell mitochondrial functions, a preparation method and application thereof, and a tripyridine Mn (II) complex with multiphoton absorption properties is obtained through molecular design, so that the complex has three-photon AIE properties and two-photon cell development is realized.
The technical problems to be solved by the invention are realized by adopting the following technical scheme:
mn (II) complex with AIE property and targeted living cell mitochondria function, called FD-MnCl for short 2 The structural formula is as follows:
the preparation method of Mn (II) complex with AIE property and targeted living cell mitochondrial function uses N, N-dibutylaniline as starting material, firstly uses N, N-dibutylaniline and POCl 3 The compound O is prepared by reaction, the compound O is prepared by reaction with 2-acetyl pyridine, the compound FD is prepared by reaction with MnCl 2 The preparation of the complex FD-MnCl by reaction 2 。
The synthetic route is as follows:
the N, N-dibutylaniline is combined with DMF and POCl 3 The molar ratio of (2) is 1:3:5.
The molar ratio of the compound O to the 2-acetylpyridine is 1:2-5.
The compound FD and MnCl 2 The molar ratio of (2) is 1:1-3.
The use of the above-described Mn (II) complexes having AIE properties and targeted mitochondrial function in living cells as multiphoton absorption materials.
In the invention, 2,2:6', 2' -tripyridine is a compound containing polypyridine heterocycle, has stronger coordination capacity to transition metal ions Mn (II), and N, N-dibutyl radical has strong electron donating capacity, is favorable for intramolecular charge transfer and adjusts complex luminescence. The halogen atom is used as an auxiliary coordination atom, so that the electron-pushing capability of the complex can be improved, and the nonlinear optical property (Dyes and pigments, 2015,117,7-15) can be enhanced. Furthermore, the complexes designed in the present invention have multiphoton aggregation-induced emission (AIE) properties, overcoming fluorescence quenching (ACQ) due to self-aggregation of most complexes at high concentrations. Moreover, the complex can enter cells in a short time under the excitation wavelength of 800nm, penetrate cell membranes, display two-photon fluorescence in the online granulocytes, and can be used for qualitatively tracking liver cancer cells, and the research result has great significance for life science research.
The beneficial effects of the invention are as follows:
1. the novel terpyridine Mn (II) complex synthesized by the invention is a multiphoton absorption material with a cell development function. The anilino and butyl have rich electrons, which are favorable for the transfer of charges in molecules and the adjustment of the luminescence of the complex. Halogen atoms are introduced, so that the electron-pushing and pulling capability is improved, and the nonlinear optical property is enhanced. Compared with other materials, the complex has the characteristics of larger three-photon absorption section, low excitation energy, long wavelength, strong penetrability, small light damage and the like, and the complex material can be used for multiphoton biological imaging and has obvious application value.
2. Investigation of Complex FD-MnCl Using open pore Z-scanning method and fluorescence contrast method 2 Is a multi-photon absorption property of (a). FD-MnCl at 800nm excitation wavelength using an open-pore Z-scan method 2 The maximum two-photon absorption cross section of (2) reaches 1970.63GM; FD-MnCl at 1450nm excitation wavelength 2 The maximum three-photon absorption cross section of (2) is 2.09×10 -75 cm 6 s 2 photon -2 The method comprises the steps of carrying out a first treatment on the surface of the FD-MnCl at 700nm excitation wavelength by fluorescence contrast 2 The maximum two-photon absorption cross section of (2) reaches 121.63GM, and at 1450nm excitation wavelength, FD-MnCl 2 The maximum three-photon absorption cross section of (2.07×10) is reached -81 cm 6 s 2 photon -2 。
3. Mn (II) complexes according to the invention FD-MnCl 2 The three-photon AIE has multiphoton AIE performance, and the three-photon fluorescence during aggregation is obviously enhanced. As the water content increases from 0% to 70%, the fluorescence intensity is unchanged, with the emission position at 525 nm. Solute molecules remain singly dividedIn the sub-state, no polymerization is formed, but the fluorescence intensity is obviously enhanced along with the continuous increase of the water content, when H 2 When O reaches 80%, FD-MnCl is carried out at 1450nm excitation wavelength 2 Is 9.68X10 in three-photon absorption cross section -80 cm 6 s 2 photon -2 46 times the initial absorption cross section. The reason for this phenomenon is due to FD-MnCl 2 Resulting in reduced solubility when the nano-polymer is formed in water, activating an intramolecular spin (RIR) limited process.
4. Co-focusing laser microscope to complex FD-MnCl 2 Cell imaging studies were performed. FD-MnCl in a short time when 800nm is used as an excitation wavelength 2 Enters into HepG2 cells (liver cancer cells) and has two-photon fluorescence signals, which indicates that the complex FD-MnCl 2 Has strong cell permeability. To confirm the complex FD-MnCl 2 Targeting cell sites using commercial dye Mito tracker red TM Co-localized development, results showed FD-MnCl 2 And Mito tracker red TM Is consistent with the coloring part and phenomenon of FD-MnCl 2 Mitochondria of living cells can be targeted. The results of this study demonstrate the potential of the complex in two-photon bioimaging applications.
5. The terpyridyl manganese complex has the advantages of readily available raw materials, low price, short synthetic route and mild synthetic condition.
Description of the drawings:
in FIG. 1, the complex FD-MnCl 2 Crystal structure diagram.
FIG. 2 (a-f) is a diagram of the open-cell Z-scan method and fluorescence contrast method for studying complex FD-MnCl 2 Two/three photon absorption spectrum in DMSO solvent (c=10 -3 mol/L). Panel a uses an open-cell Z-scan method, FD-MnCl at 800nm excitation wavelength 2 Is a maximum two-photon absorption cross-sectional view of (2); panel b shows FD-MnCl at 1450nm excitation wavelength using the open-pore Z-scan method 2 A maximum three-photon absorption cross-sectional view; c, using fluorescence contrast method, taking 680-860nm as excitation wavelength, FD-MnCl 2 Two-photon fluorescence spectrum of (2); the d graph uses fluorescence contrast method, takes 680-860nm as excitation wavelength, FD-MnCl 2 Is a two-photon absorption cross-sectional view of (2); e-chart using fluorescence contrast method, FD-MnCl at 1150-1550nm as excitation wavelength 2 Three-photon fluorescence spectrum of (2); f chart uses fluorescence contrast method, FD-MnCl when 1150-1550nm is used as excitation wavelength 2 Three-photon absorption cross-sectional view.
FIG. 3 (a-b) Complex FD-MnCl 2 At different proportions (0% -90%, 98%) CH 3 OH/H 2 Single photon fluorescence spectrum in O mixed solvent (c=10 -5 mol/L); (c) Under the excitation wavelength of 800nm, the complex FD-MnCl 2 0% -90%,98% CH 3 OH/H 2 Two-photon fluorescence spectrum in O (c=10 -3 mol/L). (d) Under the excitation wavelength of 800nm, the complex FD-MnCl 2 0% -90%,98% CH 3 OH/H 2 Two-photon absorption cross-sectional view in mixed solvent of O; (e) FD-MnCl at 1450nm excitation wavelength 2 0% -90%,98% CH 3 OH/H 2 Three-photon fluorescence spectrum in O (c=10 -3 mol/L); (f) At 1450nm excitation wavelength, the complex FD-MnCl 2 0% -90%,98% CH 3 OH/H 2 Three-photon absorption cross-section in mixed solvent of O.
FIG. 4 is a complex FD-MnCl 2 Two-photon fluorescence development of (a), excitation wavelength=800 nm, scale=20 μm; wherein A is a two-photon visualization using 800nm as excitation wavelength and 450-490nm as emission wavelength; b is Mito tracker red when 405nm is used as excitation wavelength and 560-600nm is used as emission wavelength TM Is a single photon map of (2); c is a single-photon two-photon overlay; d is bright field cell development; all figures were obtained using Image J software.
The specific embodiment is as follows:
the invention is further described below with reference to specific embodiments and illustrations in order to make the technical means, the creation features, the achievement of the purpose and the effect of the implementation of the invention easy to understand.
1. Preparation of Compound O
In a 500mL round bottom flask, purified DMF (4.38 g,0.06 mol) was weighed under ice salt bath conditions and POCl was added dropwise thereto using a constant pressure dropping funnel 3 (15.30 g,0.1 mol) to be treatedAfter the frozen salt was formed, N-dibutylaniline (4.10 g,0.02 mol) was weighed, dissolved in 50mL chloroform, poured into the frozen salt, and after the frozen salt melted, refluxed at 65℃for 6 hours. After the reaction is completed, the reactants are poured into a large amount of ice water, the pH is regulated to be neutral by using NaOH aqueous solution, dichloromethane is used for extraction, and the solvent is distilled out under normal pressure to obtain oily liquid. The crude product is subjected to silica gel column chromatography, petroleum ether is used as developing agent for leaching, the first component is the required product, and the developing agent is distilled out to obtain 3.0g of pale yellow oily liquid, and the yield is 64%.
2. Preparation of Compound FD
2-acetylpyridine (3.03 g,0.025 mol) was weighed into a 500mL round bottom flask, dissolved with a proper amount of ethanol, potassium hydroxide (1.6 g,0.04 mol) was weighed into the above system after dissolved with a small amount of water, compound O (1.17 g,0.005 mol) was weighed into the system after dissolved with a proper amount of ethanol, added into the system after stirring at normal temperature for 1h, 70mL of ammonia water was added dropwise with a constant pressure dropping funnel, reflux was stopped for 6h at 80 ℃ (one ammonia water was added in the middle), part of the solvent was removed by spinning, and 3.00g of a bright yellow solid was recrystallized with ethanol, and the yield was 68%. 1 H NMR(400MHz,d 6 -acetone,ppm)δ8.76(dd,J＝62.4,45.6Hz,4H),8.08–7.90(m,2H),7.44(t,J＝25.5Hz,4H),7.27(t,J＝16.5Hz,1H),7.17–6.94(m,1H),6.69(t,J＝19.6Hz,2H),3.47–3.23(m,4H),1.58(t,J＝18.5Hz,4H),1.38(dt,J＝27.3,13.6Hz,4H),1.13–0.80(m,6H). 13 C NMR(100MHz,d 6 -acetone,ppm)δ154.19,151.80,148.26,139.25,128.79,124.05,119.73,111.53,53.49,30.07,21.77,13.79.MS(ESI-MS):calc:436.60,found:437.27([M]+H + )
3. Complex FD-MnCl 2 Is prepared from
Manganese chloride (0.16 g,1.0 mmol) was weighed into a 100mL round bottom flask, an appropriate amount of anhydrous acetonitrile was added to dissolve it completely, an acetonitrile (10 mL) solution of ligand FD (0.44 g,1.0 mmol) was added dropwise at room temperature, the reaction was stopped after stirring for 2h, and then the mixture was filtered to give an orange solid with a yield of 0.38 g: 76%. 1 H NMR(400MHz,d 6 -DMSO)δ8.75–8.53(m,6H),7.98(d,J＝2.4Hz,2H),7.49(s,2H),6.79(s,2H),5.63–5.05(m,3H),1.83–1.46(m,5H),1.35–1.19(m,6H),0.91(t,J＝7.4Hz,6H). 13 C NMR(100MHz,d 6 -DMSO)δ(ppm):161.14,152.17,151.35,149.58,138.96,138.24,135.23,129.40,128.74,122.89,118.57,117.71,53.72,31.34,21.26,14.26.FT-IR(KBr,cm -1 ):3908(m),3844(s),3768(m),3558(m),3431(s),2962(m),2886(m),2364(m),1583(s),1532(s),1469(s),1418(s),1360(s),1202(s),1017(s),795(s).
Analysis of the drawings:
FIG. 1 is a complex FD-MnCl 2 The exact structure of the molecule is demonstrated by the crystal structure diagram. In order to clearly show the crystal structure, hydrogen atoms and solvent molecules are deleted. Complex FD-MnCl 2 Is obtained by solvent evaporation, and a proper amount of FD-MnCl is added 2 Dissolving in 10mL of dichloromethane, filtering to 25mL of conical flask, covering 5mL of ethanol, and placing in a vibration-free dark environment for two weeks to obtain orange prismatic crystals with the size of 0.30X0.20X0.20 mm. In the complex FD-MnCl 2 The complex belongs to the P ī space group and the triclinic system. N, N-butyl terpyridine is coordinated with the center Mn as a main ligand, and two Cl ions are coordinated with the center Mn as coordination atoms. The ligand after coordination is in the same position as the metal ion the planes, N-Mn portions, are located in the same plane.
FIG. 2, panel a, shows FD-MnCl at an excitation wavelength of 800nm using an open-pore Z-scan method 2 The maximum two-photon absorption cross section of (2) reaches 1970.63GM; panel b shows FD-MnCl at 1450nm excitation wavelength using the open-pore Z-scan method 2 The maximum three-photon absorption cross section reaches 2.09 multiplied by 10 -75 cm 6 s 2 photon -2 The method comprises the steps of carrying out a first treatment on the surface of the C, using fluorescence contrast method, taking 680-860nm as excitation wavelength, FD-MnCl 2 The two-photon fluorescence spectrum of (2) has the strongest two-photon fluorescence intensity when 800nm is used as the excitation wavelength; the d graph uses fluorescence contrast method, takes 680-860nm as excitation wavelength, FD-MnCl 2 The maximum two-photon absorption cross section of (2) reaches 121.63GM; e-chart using fluorescence contrast method, FD-MnCl at 1150-1550nm as excitation wavelength 2 When 1450nm is used as excitation wavelength, the three-photon fluorescence spectrum of the fluorescent probe has the strongest three-photon fluorescence intensity; f chart using fluorescence contrast method with 1500nm as excitation wavelengthWhen FD-MnCl 2 The maximum three-photon absorption cross section reaches 2.55 multiplied by 10 -81 cm 6 s 2 photon -2 。
4. AIE property test: configuring different proportions of CH 3 OH/H 2 Mixed solvent of O (water content from 0% -90%, 98%). Measurement of Complex FD-MnCl 2 At different ratios CH 3 OH/H 2 Single/multiphoton fluorescence spectrum in mixed solvent of O.
FIG. 3 is a complex FD-MnCl 2 At different ratios CH 3 OH/H 2 Single/multiphoton fluorescence spectrum in mixed solvent of O, multiphoton AIE properties thereof were investigated. As can be seen from the a-b diagram, with H 2 The O content is increased from 0% to 50%, the fluorescence intensity is unchanged at 525nm, and when the water content is more than 50%, the fluorescence is enhanced and the water content is 70%, the complex FD-MnCl 2 The fluorescence intensity of (2) is the largest; FIG. c shows the FD-MnCl complex at an excitation wavelength of 800nm 2 At different ratios CH 3 OH/H 2 Two-photon fluorescence spectrum in mixed solvent of O, when H 2 When the O content reaches 70%, the two-photon fluorescence intensity is maximum; d graph illustrates that the maximum two-photon absorption cross section reaches 67.77GM when the water component reaches 70% at 800nm excitation wavelength, calculated using fluorescence contrast method; e graph is the complex FD-MnCl under the excitation wavelength of 1450nm 2 At different ratios CH 3 OH/H 2 Three-photon fluorescence spectrum in mixed solvent of O, when H 2 When the O content reaches 80%, the three-photon fluorescence intensity is maximum; FIG. f illustrates that the maximum three-photon absorption cross section reaches 9.68X10 when the water content reaches 80% at 1450nm excitation wavelength, calculated using fluorescence contrast - 80 cm 6 s 2 photon -2 cm 6 s 2 photon -2 46 times the initial absorption cross section.
5. Cell culture and staining: the cells were cultured in HepG2 cells and DMEM medium for 24 hours. The medium was removed by washing three times with PBS before staining. 200. Mu.L of PBS was added to the petri dish followed by 20. Mu.L of LFD-MnCl 2 Anhydrous DMSO solution (1X 10) - 3 mol/L). After incubation for 15min in the dark, the solution was aspirated with a pipette and washed three times with PBS solutionAnd then carrying out two-photon fluorescence microscopy and imaging.
As can be seen from FIG. 4, FD-MnCl 2 As a two-photon fluorescent probe, the fluorescent probe can penetrate cell membranes and target the mitochondria of HepG2 cells when the fluorescent probe is used as an excitation wavelength at 800nm, and the co-localization coefficient reaches 0.85.
The foregoing has shown and described the basic principles and main features of the present invention and the advantages of the present invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, and that the above embodiments and descriptions are merely illustrative of the principles of the present invention, and various changes and modifications may be made without departing from the spirit and scope of the invention, which is defined in the appended claims. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (6)
1. Mn (II) complex with AIE properties and targeting mitochondrial function in living cells, characterized in that: FD-MnCl for short 2 The structural formula is as follows:
2. a method of preparing a Mn (II) complex having AIE properties and targeting mitochondrial function in living cells according to claim 1, wherein: n, N-dibutylaniline is used as a starting material, and the starting material is prepared from N, N-dibutylaniline and POCl 3 The compound O is prepared by reaction, the compound O is prepared by reaction with 2-acetyl pyridine, the compound FD is prepared by reaction with MnCl 2 The preparation of the complex FD-MnCl by reaction 2 ；
The synthetic route is as follows:
3. according to claim2, the preparation method of the Mn (II) complex with AIE property and targeted living cell mitochondrial function is characterized by comprising the following steps: the N, N-dibutylaniline is combined with DMF and POCl 3 The molar ratio of (2) is 1:3:5.
4. The method of preparing a Mn (II) complex having AIE properties and targeting mitochondrial function in living cells according to claim 2, wherein: the molar ratio of the compound O to the 2-acetylpyridine is 1:2-5.
5. The method of preparing a Mn (II) complex having AIE properties and targeting mitochondrial function in living cells according to claim 2, wherein: the compound FD and MnCl 2 The molar ratio of (2) is 1:1-3.
6. Use of the Mn (II) complex having AIE properties and targeting mitochondrial function of living cells according to claim 1 or the Mn (II) complex having AIE properties and targeting mitochondrial function of living cells obtained by the preparation method according to any one of claims 2 to 5 as a multiphoton absorption material.
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