CN115010761B - Phosphorescent cyclometalated platinum complex and application thereof - Google Patents

Phosphorescent cyclometalated platinum complex and application thereof Download PDF

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CN115010761B
CN115010761B CN202111461931.8A CN202111461931A CN115010761B CN 115010761 B CN115010761 B CN 115010761B CN 202111461931 A CN202111461931 A CN 202111461931A CN 115010761 B CN115010761 B CN 115010761B
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platinum complex
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杨靖
王鹏超
陈大蕾
高传柱
魏云林
杨波
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Kunming University of Science and Technology
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Abstract

The invention discloses a phosphorescent cyclometallated platinum complex with a structural formula shown as a formula I or a formula II; iII typeIn the cyclometalated platinum complex containing different conjugated systems, the platinum complex coordinated with the monodentate ligand imidazole and the derivative thereof has the characteristics that the self phosphorescence intensity and the service life are enhanced along with the increase of the viscosity in the environment, and the change of the viscosity value in the in-vitro environment and the in-vitro environment can be calculated by utilizing the change of the self phosphorescence service life value of the complex; in addition, the complex has anti-tumor activity and targeting function of specific subcellular organelles such as mitochondria, cell nucleus and the like, and can specifically monitor the viscosity change of the subcellular organelles through two-photon phosphorescence lifetime imaging when living cells undergo apoptosis; the cyclometalated platinum complex can be applied to the fields of fluorescent probes for in-vitro solution viscosity detection, cell imaging, fluorescent chromogenic materials and the like, and has the characteristics of higher sensitivity, lower detection cost, convenient operation, quick measurement and real-time detection.

Description

Phosphorescent cyclometalated platinum complex and application thereof
Technical Field
The invention relates to a phosphorescence cyclometallated platinum complex with viscosity sensitivity and application thereof, belonging to the field of biomedical detection and imaging.
Background
Platinum group metal complexes have the property of an excited state, and these complexes have been widely used in various research fields such as chemical sensors, photocatalysts and asymmetric catalysts for C-H bond functionalization, biomolecular probes, G-quadruplex DNA binding agents, and development of antitumor drugs due to their unique photophysical chemical properties. Among the metal complexes, platinum complexes have higher photostability, longer emission lifetime and luminescence characteristics sensitive to the environment. In particular, better cell membrane permeability and longer phosphorescent lifetime are very advantageous for lifetime-based biosensing and bioimaging in living cells using photoluminescent Phosphorescent Lifetime Imaging Microscopy (PLIM), which can effectively eliminate the unwanted background interference common in biological matrices.
Studies have shown that the introduction of aromatic ring conjugated systems as ligands can result in a rich electronic profile. The rich electronic properties and high coupling energy level complexes of the transition metals result in efficient ISCs to generate phosphorescent electron-emitting triplet excitons. The phosphorescence properties of the transition metal complex may be further enhanced by modification of the ligand molecular structure.
Microenvironment is an extremely important factor in determining the physical or chemical behavior around a molecule, with biological microenvironment viscosity being one of the most important microenvironment parameters that promotes biological function by affecting interactions and transport of biomolecules and chemical signals within living cells. Abnormal changes in viscosity are considered to be important factors or indicators of various serious diseases such as atherosclerosis, diabetes, alzheimer's disease and even cellular malignancies. Sensitive viscosity probes are of great importance in the diagnosis of diseases.
Studies have demonstrated that the emission of molecular rotors with rotating groups is usually quenched by intramolecular rotation processes, whereas the limitation of group rotation can induce recovery of its emission intensity and lifetime. Since the rotation of the molecules is affected by the ambient viscosity, molecular rotors can be used to quantitatively measure viscosity in living cells for lifetime imaging.
Disclosure of Invention
The invention provides a monodentate phosphorescent cyclometalated platinum complex with viscosity sensitivity, which not only has better phosphorus light intensity and phosphorescence service life, but also has the characteristic of viscosity sensitivity.
The structural formula of the phosphorescence cyclometallated platinum complex is shown as formula I or formula II:
iWherein->Selected from->N is selected from
II typeWherein->Selected from-> Selected from the group consisting of
The preparation method of the phosphorescent cyclometallated platinum complex comprises the following steps:
(1) Mixing potassium tetrachloroplatinate with quinoline compounds in the presence of a solvent, carrying out reflux reaction for 48 hours at 80-90 ℃ in an inert atmosphere, separating out a precipitate, washing and drying the precipitate to obtain a platinum bridging precursor;
the molar ratio of the potassium tetrachloroplatinate to the quinoline compound is 1:1-3, and the solvent is a mixed solvent of ethylene glycol diethyl ether and water (the volume ratio is 2:1);
the quinoline compound is selected from
(2) Mixing and refluxing the platinum bridging precursor in the step (1) and silver salt for reaction for 20-24 hours under the condition of inert atmosphere and solvent existence, and filtering to obtain filtrate as an intermediate product;
the molar ratio of the platinum bridging precursor to the silver salt is 1:2-3; silver salt is AgCF 3 SO 3 The method comprises the steps of carrying out a first treatment on the surface of the The solvent is one of acetonitrile, dichloromethane, methanol and acetone;
(3) Mixing the intermediate product of the step (2), the imidazole compound or the biimidazole compound in inert atmosphere, carrying out reflux reaction for 20-24h at 60-80 ℃, and carrying out concentration column chromatography purification or filtration washing to obtain a phosphorescent cyclometallated platinum complex; the molar ratio of the platinum bridging precursor to the imidazole compound or the biimidazole compound is 1:2-4;
the imidazole compound is selected fromThe bisimidazoles are selected from->
The inert atmosphere is N 2 。
The reaction formula of the preparation process is as follows:
(1)、
(2)、
or (b)
The invention also aims to provide the application of the phosphorescence cyclometalated platinum complex, which not only has antineoplastic activity and can be applied to preparing antineoplastic drugs, but also has the characteristics of better phosphorus light intensity and phosphorescence service life, and viscosity sensitivity, wherein the phosphorescence intensity and phosphorescence service life of the complex are enhanced along with the increase of solvent viscosity, and the intracellular microenvironment can change during apoptosis, and the abnormal change of the viscosity is regarded as an important factor or index for causing various serious diseases, so that the change of the viscosity of a specific subcellular organelle in cells during apoptosis can be calculated according to the change of the phosphorescence service life value of the complex, the invention provides an effective detection method for detecting the change of the microenvironment of cells, and can image and trace tumor cells;
the invention has the characteristics of high sensitivity, low detection cost, convenient operation, rapid measurement and real-time detection, and is suitable for industrial production and market popularization and application.
Drawings
FIG. 1 shows the hydrogen nuclear magnetic resonance spectrum of example 1 1 H-NMR，d 6 -DMSO) map;
FIG. 2 shows the hydrogen nuclear magnetic resonance spectrum of example 2 1 H-NMR，d 6 -DMSO) map;
FIG. 3 shows the hydrogen nuclear magnetic resonance spectrum of example 3 1 H-NMR，d 6 -DMSO) map;
FIG. 4 is a high resolution mass spectrum of example 2;
FIG. 5 is a high resolution mass spectrum of example 4;
FIG. 6 is a high resolution mass spectrum of example 5;
FIG. 7 is a single crystal structure of the complex of example 2; a is a single molecular structure diagram, and B is an intermolecular stacking diagram;
FIG. 8 is a graph of UV and fluorescence for example 1 in four different solvents, and graph A is a graph of UV absorption; the diagram B is a fluorescence spectrum diagram;
FIG. 9 is a graph of UV and fluorescence for example 2 in four different solvents, and graph A is a graph of UV absorption; the diagram B is a fluorescence spectrum diagram;
FIG. 10 is a graph of UV and fluorescence for example 3 in four different solvents, and graph A is a graph of UV absorption; the diagram B is a fluorescence spectrum diagram;
FIG. 11 is a graph of UV and fluorescence for example 4 in four different solvents, and graph A is a graph of UV absorption; the diagram B is a fluorescence spectrum diagram;
FIG. 12 is a graph of UV and fluorescence for example 5 in four different solvents, and graph A is a graph of UV absorption; the diagram B is a fluorescence spectrum diagram;
FIG. 13 is a fluorescence plot of complex 1a in a 0% -90% viscosity solution; the upper graph is a fluorescence spectrum graph, and the lower right graph is a test tube color development result;
FIG. 14 is a fluorescence plot of complex 1b in a 0% -90% viscosity solution; the upper graph is a fluorescence spectrum graph, and the lower right graph is a test tube color development result;
FIG. 15 is a fluorescence plot of complex 1c in a 0% -90% viscosity solution; the upper graph is a fluorescence spectrum graph, and the lower right graph is a test tube color development result;
FIG. 16 is a fluorescence plot of complex 2 in a 0% -90% viscosity solution; the upper graph is a fluorescence spectrum graph, and the lower right graph is a test tube color development result;
FIG. 17 is a fluorescence plot of complex 3 in a 0% -90% viscosity solution; the upper graph is a fluorescence spectrum graph, and the lower right graph is a test tube color development result;
FIG. 18 is a bar graph of fluorescence intensity of complex 1b in different ion and protein solutions;
FIG. 19 is a bar graph of fluorescence intensity of complex 2 in different ion and protein solutions;
FIG. 20 is a bar graph of fluorescence intensity of complex 3 in different ion and protein solutions;
FIG. 21 is a bar graph of fluorescence intensity of complex 1B (A), complex 2 (B), complex 3 (C) in different pH environments;
FIG. 22 is a graph of phosphorescent lifetime of complex 1b in a 40% -99% viscosity solution;
FIG. 23 is a graph of phosphorescent lifetime of complex 2 in a 40% -99% viscosity solution;
FIG. 24 is a graph of phosphorescent lifetime of complex 3 in a 40% -99% viscosity solution;
FIG. 25 shows uptake and localization results of complex 1b, complex 2, complex 3 in tumor cells;
FIG. 26 is a graph of phosphorescent lifetime of complex 2 in tumor cells, wherein A is a graph of phosphorescent lifetime imaging of complex in whole cells and B is a range of phosphorescent lifetime values of nuclei;
FIG. 27 is a graph of phosphorescent lifetime of complex 3 in tumor cells, wherein A is a graph of phosphorescent lifetime imaging of complex in whole cells and B is a range of phosphorescent lifetime values for mitochondria.
Detailed Description
The present invention will be described in further detail by way of examples, but the scope of the present invention is not limited to the above description, and the compounds prepared in the examples are determined by nuclear magnetic resonance hydrogen spectroscopy and mass spectrometry; the specific techniques or conditions are not identified in the examples and are performed according to techniques or conditions described in the literature in this field or according to the product specifications. The materials or equipment used are not marked by manufacturers, are all conventional products which can be obtained through purchase, and the methods used are conventional methods unless specified;
example 1: synthesis of Complex 1a (C 23 H 23 F 3 N 5 O 3 PtS; molecular weight: 701.11)
1. Mixing potassium tetrachloroplatinate and 7-benzoquinoline according to the molar ratio of 1:2, dissolving in a mixed solvent (volume ratio of 1:2) of ethylene glycol diethyl ether and ultrapure water, refluxing and stirring for coordination reaction at 80 ℃ under nitrogen atmosphere for 48 hours, concentrating the reaction solution to 2mL after the reaction is finished, adding 20mL of ultrapure water, filtering after 2 hours of ice water bath at 2-4 ℃, washing the obtained solid with diethyl ether for 3 times, washing with ultrapure water for 3 times, drying to obtain a yellowish green platinum bridging precursor, and calculating the yield to be 95%;
2. a50 mL round bottom flask was charged with platinum bridging precursor (60 mg,0.074 mmol) followed by AgCF 3 SO 3 (37.79 mg,0.148 mmol) under nitrogen at ambient temperature for 24h, filtered to remove AgCl precipitate;
3. imidazole (20.15 mg, 0.298 mmol) is added into the filtrate obtained in the step 2, the mixture is condensed and refluxed for 24 hours under the nitrogen atmosphere at the temperature of 60 ℃, after the reaction is finished, the solvent is removed under reduced pressure, the mixture is eluted by a mixed solution of methylene dichloride and methanol (volume ratio is 20:1) through silica gel column chromatography, and the eluent is dried to obtain yellow solid complex 1a with the yield of 52%; 1 H NMR(600MHz,DMSO-d 6 )δ8.72(d,J＝8.0Hz,1H),8.53(d,J＝12.5Hz,2H),8.12(d,J＝5.2Hz,1H),7.95(d,J＝8.8Hz,1H),7.85(d,J＝8.8Hz,1H),7.72–7.67(m,2H),7.58(s,1H),7.52(s,1H),7.46–7.43(m,2H),7.40(s,1H),6.66(d,J＝7.1Hz,1H).ESI-MS m/z:[M] + 509.10. the nuclear magnetic resonance hydrogen spectrum of the complex 1a is shown in figure 1;
ultraviolet absorption and fluorescence emission of Complex 1a in different solvents
1mg of the synthesized complex 1a is weighed, dimethyl sulfoxide is added to prepare mother solutions of 20mmol/L respectively, 3 mu L of the mother solutions are added to 4 centrifuge tubes of 5mL respectively, 27 mu L of dimethyl sulfoxide is added, and CH is used respectively 3 CN、CH 2 Cl 2 、CH 3 Preparing a solution of 20 mu mol/L by OH and PBS buffer solution (pH 7.0-7.4), and detecting by an ultraviolet spectrophotometer to obtain an ultraviolet absorption spectrum, wherein the result is shown in FIG. 8A; adding 6 μl of mother liquor into 45 mL centrifuge tubes, adding 24 μl of dimethyl sulfoxide, and adding glycerol and CH 3 CN、CH 3 OH、CH 2 Cl 2 The solution of 40. Mu. Mol/L was prepared with PBS, and then fluorescence spectrum was measured by a fluorescence spectrophotometer under 375nm excitation light (most probableLarge emission at 497 nm), and as shown in fig. 8B, it can be seen that the optical properties of the complex 1a are not affected by other solvents, the emission intensity in glycerol reaches the maximum, and fluorescence is strongest.
Example 2: synthesis of Complex 1b (C 25 H 27 F 3 N 5 O 3 PtS; molecular weight: 729.14)
1. Steps 1,2 are the same as steps 1,2 of example 1;
2. 1-methylimidazole (24.30 mg, 0.298 mmol) was added to the filtrate, and the mixture was refluxed under nitrogen at 60℃for 24 hours, after the completion of the reaction, the solvent was removed under reduced pressure, and eluted with a mixed solution of methylene chloride and methanol (volume ratio: 20:1) by silica gel column chromatography to give yellow solid complex 1b in 57% yield; 1 H NMR(600MHz,DMSO-d 6 )δ8.72(d,J＝8.0Hz,1H),8.49(d,J＝36.2Hz,2H),8.16(d,J＝5.2Hz,1H),7.95(d,J＝8.7Hz,1H),7.85(d,J＝8.7Hz,1H),7.71(d,J＝7.9Hz,1H),7.67(dd,J＝7.9,5.5Hz,1H),7.58(s,1H),7.52(s,1H),7.45(t,J＝7.5Hz,1H),7.39(d,J＝17.1Hz,2H),6.71(d,J＝7.1Hz,1H),3.82(d,J＝11.5Hz,6H).ESI-MS m/z:[M] + 537.14. the nuclear magnetic resonance hydrogen spectrum of the complex 1b is shown in figure 2, and the high resolution mass spectrum is shown in figure 4;
ultraviolet absorption and fluorescence emission of Complex 1b in different solvents
1mg of the synthesized complex 1b is weighed, dimethyl sulfoxide is added to prepare mother solutions of 20mmol/L respectively, 3 mu L of mother solutions are added to 4 centrifuge tubes of 5mL respectively, 27 mu L of dimethyl sulfoxide is added, and CH is used respectively 3 CN、CH 2 Cl 2 、CH 3 Preparing a solution of 20 mu mol/L by OH and PBS buffer solution (pH 7.0-7.4), and detecting by an ultraviolet spectrophotometer to obtain an ultraviolet absorption spectrum, wherein the result is shown in FIG. 9A; adding 6 μl of mother liquor into 45 mL centrifuge tubes, adding 24 μl of dimethyl sulfoxide, and adding glycerol and CH 3 CN、CH 2 Cl 2 、CH 3 OH, PBS formulation intoAs shown in FIG. 9B, the optical properties of the complex 1B were not affected by the solvent, and the emission intensity in glycerol reached the maximum, with the fluorescence being strongest, as shown by the fluorescence spectrum (maximum emission 500 nm) measured by a fluorescence spectrophotometer at 375 nm.
Single crystal growth of Complex 1b
According to the physicochemical properties of the complex 1b, respectively selecting methanol, dichloromethane and acetonitrile as monocrystal culture solvents, respectively weighing 0.5mg of the complex 1b, putting into 3 glass bottles, respectively adding 2mL of methanol, dichloromethane and acetonitrile, carrying out ultrasonic treatment for 10-15min, sealing with a preservative film, and pricking a small hole on the surface of the preservative film with a needle; placing into a large glass bottle containing diethyl ether solution, standing at room temperature, slowly volatilizing solvent to precipitate single crystal of complex 1B, and analyzing the structure of the obtained single crystal by X-ray single crystal diffractometer at room temperature to obtain the result, as shown in FIG. 7, wherein in FIG. 7B, platinum atom in 1B is in four-coordinate configuration similar to plane, the dihedral angles of CN plane and two imidazole rings are 65.878 (232) DEG and 77.120 (225) DEG respectively, and the distance between platinum and platinum atom between two nearest molecules is
Example 3: synthesis of Complex 1C (C 25 H 25 F 3 N 5 O 3 PtS; molecular weight: 727.13)
1. Steps 1 and 2 are the same as steps 1 and 2 in example 1;
2.1, 1 '-dimethyl-1H, 1' H- [2,2 'is added to the filtrate']Biimidazole (23.84 mg,0.148 mmol), condensing and refluxing for reaction for 24 hours under nitrogen atmosphere at 60 ℃, filtering the reaction liquid after the reaction is finished, washing the obtained solid with diethyl ether for 3 times, washing with ultrapure water for 3 times, and drying to obtain yellow solid with the yield of 54%; 1 H NMR(600MHz,DMSO-d 6 )δ7.88(d,J＝1.2Hz,1H),7.85(d,J＝7.3Hz,1H),7.77(d,J＝8.7Hz,1H),7.74(d,J＝1.4Hz,1H),7.70(d,J＝1.2Hz,1H),7.63(d,J＝7.8Hz,1H),7.52(d,J＝8.7Hz,1H),7.36(t,J＝7.5Hz,1H),7.31(d,J＝1.4Hz,1H),6.78–6.67(m,1H),6.57(d,J＝7.1Hz,1H),6.02(dd,J＝7.9,5.5Hz,1H),4.01(s,3H),3.66(s,3H).ESI-MS m/z:[M] + 535.12. the nuclear magnetic resonance hydrogen spectrum of the complex 1b is shown in figure 3;
ultraviolet absorption and fluorescence emission of Complex 1c in different solvents
1mg of the synthesized complex 1c is weighed, dimethyl sulfoxide is added to prepare mother solutions of 20mmol/L respectively, 3 mu L of the mother solutions are added to 4 centrifuge tubes of 5mL respectively, 27 mu L of dimethyl sulfoxide is added, and CH is used respectively 3 CN、CH 2 Cl 2 、CH 3 Preparing a solution of 20 mu mol/L by OH and PBS buffer solution (pH 7.0-7.4), and detecting by an ultraviolet spectrophotometer to obtain an ultraviolet absorption spectrum, wherein the result is shown in FIG. 10A; adding 6 μl of mother liquor into 45 mL centrifuge tubes, adding 24 μl of dimethyl sulfoxide, and adding glycerol and CH 3 CN、CH 2 Cl 2 、CH 3 OH and PBS were prepared into a 40. Mu. Mol/L solution, and then fluorescence spectrum was measured by a fluorescence spectrophotometer under 375nm excitation light (maximum emission was 500 nm), and as a result, as shown in FIG. 10B, it was seen from the figure that the optical properties of the complex 1B were not affected by the solvent.
Example 4: synthesis of Complex 2 (C 27 H 29 F 3 N 5 O 3 PtS; molecular weight: 755.16)
1. Mixing potassium tetrachloroplatinate with 2-phenylquinoline according to the mol ratio of 1:2, dissolving in a mixed solvent of ethylene glycol diethyl ether and ultrapure water (volume ratio of 1:2), refluxing and stirring for coordination reaction at 80 ℃ under nitrogen atmosphere for 48 hours, concentrating the reaction solution to 2mL after the reaction is finished, adding 20mL of ultrapure water, filtering after 2 hours of ice water bath at 2-4 ℃, washing the obtained solid with diethyl ether for 3 times, washing with ultrapure water for 3 times, drying to obtain a yellowish green platinum bridging precursor, and calculating the yield to 93%;
2. a50 mL round bottom flask was charged with platinum bridging precursor (60 mg,0.069 mmol) followed by AgCF 3 SO 3 (35.52 mg,0.138 mmol) was reacted under nitrogen at room temperature for 24h, filtered to remove AgCl precipitate;
3. 1-methylimidazole (22.66 mg,0.276 mmol) was added to the filtrate, and the mixture was refluxed under nitrogen at 60℃for 24 hours, after the reaction was completed, the solvent was removed under reduced pressure, and eluted with a mixed solution of methylene chloride and methanol (volume ratio: 20:1) by column chromatography to give yellow solid complex 2 in a yield of 56%; 1 H NMR(600MHz,DMSO-d 6 )δ8.74(d,J＝8.7Hz,1H),8.47(s,1H),8.32(d,J＝8.8Hz,1H),8.05(d,J＝7.8Hz,1H),8.01(s,1H),7.94(d,J＝7.7Hz,1H),7.55(t,J＝7.5Hz,1H),7.51(d,J＝8.9Hz,2H),7.39(dd,J＝14.4,10.5Hz,3H),7.18(t,J＝7.4Hz,1H),7.11(s,1H),7.06(t,J＝7.3Hz,1H),6.36(d,J＝7.4Hz,1H),3.80(s,3H),3.64(s,3H).ESI-MS m/z:[M] + 604.14. the high resolution mass spectrum of the complex 2 is shown in figure 5;
ultraviolet absorption and fluorescence emission of complex 2 in different solvents
1mg of the synthesized complex 2 was weighed and mixed with dimethyl sulfoxide to prepare 20mmol/L of mother liquor. mu.L of the mother liquor was added to 45 mL centrifuge tubes, 27. Mu.L of dimethyl sulfoxide was added, and CH was used, respectively 3 CN、CH 3 OH、CH 2 Cl 2 Preparing 20 mu mol/L solution from PBS buffer solution (pH 7.0-7.4), and detecting by ultraviolet spectrophotometer to obtain ultraviolet absorption spectrogram, wherein the result is shown in FIG. 11A; adding 6 μl of mother liquor into 45 mL centrifuge tubes, adding 24 μl of dimethyl sulfoxide, and adding glycerol and CH 3 CN、CH 2 Cl 2 、CH 3 OH and PBS were prepared into a 40. Mu. Mol/L solution, and then fluorescence spectrum was measured by a fluorescence spectrophotometer under 375nm excitation light (maximum emission is 550 nm), as shown in FIG. 11B, it can be seen that the optical properties of the complex 2 are not affected by the solvent, the emission intensity in glycerin reaches the maximum, and the fluorescence is strongest.
Example 5: synthesis of Complex 3 (C 39 H 39 F 3 N 6 O 3 PtS; molecular weight: 923.24)
1. Mixing potassium tetrachloroplatinate with N, N-diphenyl-4- (2-quinoline) aniline according to the mol ratio of 1:2, dissolving in a mixed solvent (volume ratio of 1:2) of ethylene glycol diethyl ether and ultrapure water, refluxing and stirring for coordination reaction at 80 ℃ under a nitrogen atmosphere for 48 hours, concentrating reaction liquid to 2mL after the reaction is finished, adding 20mL of diethyl ether, filtering after 2-4 ℃ ice water bath for 2 hours, washing the obtained solid with diethyl ether for 3 times, washing with ultrapure water for 3 times, and drying to obtain a yellowish green platinum bridging precursor with the yield of 93%;
2. a50 mL round bottom flask was charged with platinum bridging precursor (60 mg,0.050 mmol) followed by AgCF 3 SO 3 (25.65 mg,0.100 mmol) under nitrogen at ambient temperature for 24h, filtered to remove AgCl precipitate;
3. 1-methylimidazole (16.42 mg,0.200 mmol) was added to the filtrate, and the mixture was refluxed under nitrogen at 60℃for 24 hours, after the completion of the reaction, the solvent was removed under reduced pressure, and eluted with a methylene chloride-methanol mixed solution (volume ratio: 20:1) by column chromatography to give a yellow solid in 56% yield; 1 H NMR(600MHz,DMSO-d 6 )δ8.59(d,J＝8.8Hz,1H),8.27(s,1H),8.10(d,J＝8.9Hz,1H),7.99–7.96(m,2H),7.76(d,J＝8.7Hz,1H),7.49–7.46(m,1H),7.42–7.39(m,2H),7.34(t,J＝7.9Hz,5H),7.20–7.17(m,2H),7.15(t,J＝7.4Hz,3H),7.03(d,J＝7.6Hz,4H),6.63(dd,J＝8.6,2.3Hz,1H),5.73(d,J＝2.3Hz,1H),3.63(s,3H),3.56(s,3H).ESI-MS m/z:[M] + 730.23. the high resolution mass spectrum of the complex 3 is shown in figure 6;
ultraviolet absorption and fluorescence emission of complex 3 in different solvents
1mg of the synthesized complex 3 is weighed, dimethyl sulfoxide is added to prepare mother solutions with the concentration of 20mmol/L respectively, 3 mu L of the mother solutions are added to 4 centrifuge tubes with the concentration of 5mL respectively, 27 mu L of the dimethyl sulfoxide is added, and CH is used respectively 3 CN、CH 2 Cl 2 、CH 3 Preparing a solution of 20 mu mol/L by OH and PBS buffer solution (pH 7.0-7.4), and detecting by an ultraviolet spectrophotometer to obtain an ultraviolet absorption spectrum chart, wherein the result is shown in FIG. 12A; adding 6 μl of mother liquor into 45 mL centrifuge tubes, adding 24 μl of dimethyl sulfoxide, and adding glycerol and CH 3 CN、CH 3 OH、CH 2 Cl 2 The fluorescence spectrum of the solution prepared from PBS and 40. Mu. Mol/L was measured by a fluorescence spectrophotometer at 405nm (maximum emission: 625 nm) as shown in FIG. 12B, and it was found that the optical properties of the complex 3 were not affected by the solvent, and that the fluorescence in glycerin was the strongest.
Example 6: viscosity response of complex 1a, complex 1b, complex 1c, complex 2, complex 3 in a solution having a viscosity of 0% to 90%
Weighing 1mg of each of the complex 1a, the complex 1b, the complex 1c, the complex 2 and the complex 3 synthesized in examples 1-5, and adding dimethyl sulfoxide to prepare a mother solution with the concentration of 40 mmol/L; adding 3 mu L of mother solution into a 5mL centrifuge tube, adding 27 mu L of dimethyl sulfoxide, and respectively adding 3mL of methanol solution with the volume concentration of 0%, 20%, 40%, 60%, 70%, 80%, 90% and 99% into the centrifuge tube to prepare a solution with the concentration of 40 mu mol/L; testing the fluorescence spectrum of 5 complexes by a fluorescence spectrophotometer at room temperature;
as a result, as shown in FIGS. 13, 14, 15, 16, 17, the fluorescence intensity gradually increased with an increase in viscosity, and the fluorescence intensity of the complex reached the maximum value (1 a emission wavelength 479nm;1b emission wavelength 500nm;1c emission wavelength 413nm;2 emission wavelength 550nm;3 emission wavelength 625 nm) at 99% of the viscosity, and the fluorescence intensity of the complex 3 increased 53.20 times (fluorescence intensity from 12.16 to 646.96), while the fluorescence intensity of the complex 1c changed negligibly. This is because the solution viscosity increases, and the in-molecule rotation of the monodentate complex (1 a, 1b, 2, 3) is suppressed, which promotes the gradual increase in fluorescence of the complex.
Example 7: luminescent selective detection of Complex 1b, complex 2, complex 3
Weighing complex 1b, complex 2 and complex3 mg each, adding dimethyl sulfoxide to prepare a mother solution with the concentration of 40 mmol/L; adding 3 mu L of mother solution into a 5mL centrifuge tube, adding 27 mu L of dimethyl sulfoxide, and diluting with water to 40 mu mol/L solution; respectively adding Fe 3+ 、Ca 2+ 、Li + 、K + 、F - 、Cl - 、I - Histidine, glutamic acid, glucose, phenylalanine, bovine serum albumin and glutathione, wherein the final concentration is 100 mu mol/L;
adding 3 mu L of mother solution into a 5mL centrifuge tube, adding 27 mu L of dimethyl sulfoxide, adding 3mL of glycerol, preparing a solution with the concentration of 40 mu mol/L as a reference, and measuring the fluorescence spectra of the complex 1b, the complex 2 and the complex 3 at room temperature by using a fluorescence spectrophotometer;
the results are shown in FIGS. 18, 19, 20, with three complexes 1b, 2, 3 being non-responsive in the anion and cation selectivity test and highest in the glycerol solution.
Example 8: effect of pH on luminescence of Complex 1b, complex 2, complex 3
Weighing 1mg of each of the complex 1b, the complex 2 and the complex 3, and adding dimethyl sulfoxide to prepare a mother solution with the concentration of 40 mmol/L; adding 3 mu L of mother solution into a 5mL centrifuge tube, adding 27 mu L of dimethyl sulfoxide, respectively adding 3mL of citric acid and disodium hydrogen phosphate buffer solution to prepare solutions with pH of 5.5, 5.8, 6.2, 6.8, 7.0 and 7.4, and measuring the fluorescence spectra of the complex 1b, the complex 2 and the complex 3 at room temperature by a fluorescence spectrophotometer, wherein the final concentration of the complex is 40 mu mol/L.
In order to further compare the influence of the change of the environmental pH on the luminescence of the complex, adding 3 mu L of mother solution into a 5mL centrifuge tube, adding 27 mu L of dimethyl sulfoxide, adding 3mL of glycerol, preparing a solution with the complex concentration of 40 mu mol/L, and measuring the fluorescence spectrum of the complex 1b, the complex 2 and the complex 3 in the glycerol by a fluorescence spectrophotometer under the condition of room temperature; as a result, as shown in FIG. 21, the fluorescence intensities of the three complexes 1b, 2, 3 were not correlated with the change in environmental pH, but the response was highest in the glycerin solution, further demonstrating that the viscosity was the main cause of affecting the complex luminescence intensity.
Example 9: phosphorescent lifetime detection of Complex 1b, complex 2, complex 3
Weighing 1mg of each of the complex 1b, the complex 2 and the complex 3, and adding dimethyl sulfoxide to prepare a mother solution with the concentration of 40 mmol/L; adding 3 mu L of mother solution into a 5mL centrifuge tube, adding 27 mu L of dimethyl sulfoxide, and respectively adding 3mL of methanol solution with glycerol volume concentration of 40%, 60%, 70%, 80%, 90% and 99% to prepare a solution with concentration of 40 mu mol/L; detecting the phosphorescence lifetime of the complexes 1b, 2, 3 with a phosphorescence lifetime spectrometer at room temperature;
as a result, as shown in fig. 22, 23 and 24, the intramolecular rotation of the complexes 1b, 2 and 3 is continuously inhibited, the fluorescence intensity is continuously increased, and the phosphorescence lifetime is continuously increased with the increase of the viscosity; wherein the phosphorescent lifetime of complex 3 is increased by a factor of 29.77; the longer the life, the more favorable the biological imaging, and the interference of background fluorescence can be greatly reduced;
TABLE 1 lifetime values of complexes 1b, 2, 3 in glycerol concentrations 40% and 99%
Example 10: detection of complex fluorescence quantum yield
The fluorescence quantum yield can be used for characterizing the fluorescence luminescence capacity of a substance, and is calculated according to the following formula:
Y U : quantum yield of the substance to be measured; y is Y S : quantum yield of the reference substance; f (F) U : integrated fluorescence intensity of the substance to be measured; f (F) S : integrated fluorescence intensity of the reference substance; a is that U : ultraviolet absorbance of the substance to be measured; a is that S : ultraviolet absorbance of the reference substance.
Ru (bpy) 3 ](PF 6 ) 2 1mg of reference substance is weighed and added with dimethyl sulfoxide with corresponding volumeTo prepare 20mmol/L, 3 mu L to 45 mL centrifuge tubes are added with 27 mu L of dimethyl sulfoxide and respectively added with CH 3 CN, PBS buffer and glycerol were prepared into a 20 mu mol/L solution, and the ultraviolet absorption value of the prepared solution was measured by an ultraviolet spectrophotometer, so that the absorbance at the maximum absorption wavelength was 0.05 at each solvent. When the absorbance of the solution was 0.05, the fluorescence thereof was measured by excitation with the maximum absorption wavelength, and the fluorescence integrated intensity was calculated.
Weighing 4 complexes 0.5mg respectively, adding into dimethyl sulfoxide to prepare 20mmol/L, adding into centrifuge tube of 3 μL to 5mL, adding into dimethyl sulfoxide of 27 μL, and adding into CH respectively 3 CN, glycerol and PBS buffer solution are prepared into an initial concentration solution with the concentration of 20 mu mol/L for standby, and the concentration of the sample is regulated by using the standby solution so that the absorbance of ultraviolet at the maximum absorption wavelength of the complex under each solvent condition is close to 0.05. When the absorbance of the solution is close to 0.05, the fluorescence spectrum is measured by excitation of the maximum absorption wavelength, and the integral size of the corresponding fluorescence spectrum is calculated. Calculating the fluorescence quantum yield of each complex by using the calculation formula, wherein the data are shown in the following table; the results show that the fluorescence quantum yields of the complex 1b, the complex 2 and the complex 3 in the glycerol are higher than those in other solvents, but the change of the quantum yield of the complex 1c in the glycerol is smaller, and the fluorescence quantum yield of the complex 3 in the glycerol is 5.12 times that in PBS buffer solution, which shows that the intramolecular rotation of the complex with a monodentate structure can be well inhibited in a high-viscosity environment, and the quantum yield is increased.
TABLE 2 maximum absorption and emission wavelengths and corresponding fluorescence quantum yields of the complexes prepared according to the invention in three solvents
Example 11: determination of antitumor Activity of phosphorescent cyclometallated platinum Complex
The cytotoxicity of cisplatin as a control group against HeLa (human cervical cancer cell line) was measured using the cyclometallated platinum complexes prepared in examples 1,2, 3, 4, and 5 as an experimental group, and the specific measurement method was as follows:
measuring by tetrazolium salt (MTT) colorimetric method, respectively digesting tumor cells to obtain single cell suspension by pancreatin, counting by blood cell counting plate, and adjusting cell concentration to5×10 4 Inoculating to 96-well plate at 160 μL per well, culturing for 24 hr, adding different concentrations of drugs, and placing in 5% CO 2 Incubation was performed for 48h in an incubator at 37℃and MTT 20. Mu.L/well was added 4h before the end of incubation. 4h later, the supernatant is discarded, 150 mu L/hole of DMSO is added, after 5min of vibration, an enzyme-labeled instrument is used for measuring an OD value, and the wavelength is set to 492nm; the survival rate of the tested tumor cells is calculated, and the IC is simultaneously plotted and calculated 50 A value, evaluating the antitumor activity of the complex;
the results are shown in Table 3, and the results show that the complex 1b with the benzoquinoline structure has higher toxicity, while the complexes 2 and 3 have lower cytotoxicity, and are more suitable for being used as probes and applied to imaging and tracing of cells relative to the complex 1 b;
TABLE 3 IC of cyclometalated platinum complexes prepared by the present invention 50 Value of
Example 12: uptake and localization of Complex 1b, complex 2, complex 3 in tumor cells
Digestion of HeLa (human cervical cancer cell line) and A549 (human non-small cell lung cancer cell line) with pancreatin, inoculating into confocal culture dish, and culturing with medium containing 5% CO 2 Is cultured at 37 ℃. When HeLa cells are cultured to 70%, washing twice with PBS buffer solution, adding 1mL of PBS buffer solution, respectively adding the complex 1b, the complex 2 and the complex 3, and finally incubating the cells with the drug at the concentration of 20 mu mol/L, continuously culturing for 30-40min, adding subcellular organelle fluorescence (lysosome dark red fluorescent dye (Ex=596 nm, em=619 nm), mitochondrial dark red fluorescent dye (Ex=644 nm, em=665 nm), endoplasmic reticulum blue dye (Ex=374nm, em=430 nm), and fineThe nucleolus red dye Styo59 (Ex=622 nm, em=645 nm) was stained, the medium was removed after 10-15min incubation, washed twice with PBS and immediately observed with a confocal laser microscope.
As shown in fig. 25, the complex 1b, the complex 2 and the cell nucleus red syto59 dye have good co-localization effect, which proves that the complex 1b and the complex 2 can be well taken up by cells and enter the cell nucleus; and the complex 3 has good co-localization effect with the mitochondrial deep red fluorescent dye, so that the complex 3 can enter the subcellular organelle mitochondria.
Example 13:
digestion of well-grown A549 (human non-small cell lung carcinoma cell line) with pancreatin, inoculating into confocal culture dish containing 5% CO 2 Is cultured at 37 ℃; when HeLa cells were cultured to 70% density, washed twice with PBS buffer, 1mL of PBS buffer was added, then complex 2 and complex 3 were added, the final drug-incubated cells were incubated at a concentration of 20. Mu. Mol/L, culturing was continued for 30-40min, then washed twice with PBS, and phosphorescent lifetime imaging of complexes at nucleoli and mitochondria was recorded with a two-photon phosphorescent lifetime imaging (TPPLIM) microscopy apparatus at room temperature, as shown in FIGS. 26A and 27A.
PLIM data was analyzed by SPCImage software on www.becker-hickl.com to obtain organelle lifetime values, as shown in FIG. 26B, with complex 2 monitoring nuclei lifetime values ranging from 8874.94ns to 9920.00ns, and calculating a linear plot of phosphorescence lifetime and viscosity for complex 2 according to example 9 to calculate nuclei viscosity values, wherein nuclei viscosity values range from 180.91cP to 195.02cP. In addition, as shown in FIG. 27B, the range of lifetime values of mitochondria monitored by Complex 3 is 8185.945ns-8585.708ns, the range of viscosity values of mitochondria deduced from the linear curve of phosphorescent lifetime and viscosity of Complex 3 calculated according to example 9 is 58.91cP-62.18cP, which corresponds to the range of organelle viscosity reported in the relevant literature before, indicating that our Complex 3 and Complex 2 can be used for real-time detection of nucleolar and mitochondrial viscosity changes in living cells.

Claims (6)

1. Phosphorescent cyclometallated platinum complexes of formula I or II:
iWherein->Selected from->N is selected from
II typeWherein->Selected from-> Selected from the group consisting of
2. The method for preparing a phosphorescent cyclometallated platinum complex according to claim 1, comprising the steps of:
(1) Mixing potassium tetrachloroplatinate with quinoline compounds in the presence of a solvent, carrying out reflux reaction at 80-90 ℃ under an inert atmosphere for 48-h, separating out a precipitate, washing and drying the precipitate to obtain a platinum bridging precursor;
(2) Under the conditions of inert atmosphere, normal temperature and solvent, the platinum bridging precursor and silver salt in the step (1) are mixed and subjected to reflux reaction for 20-24h for dechlorination, and the filtrate is an intermediate product;
(3) And (3) mixing the intermediate product of the step (2), the imidazole compound or the biimidazole compound in an inert atmosphere, and carrying out reflux reaction at 60-80 ℃ for 20-24h to obtain the phosphorescent cyclometallated platinum complex.
3. The method for preparing a phosphorescent cyclometallated platinum complex according to claim 2, wherein: the molar ratio of the potassium tetrachloroplatinate to the quinoline compound is 1:1-3, the molar ratio of the platinum bridging precursor to the silver salt is 1:2-3, and the molar ratio of the platinum bridging precursor to the imidazole compound or the bisimidazole compound is 1:2-4.
4. Use of a phosphorescent cyclometallated platinum complex of formula i according to claim 1 for the preparation of a reagent for detecting intracellular viscosity.
5. Use of a phosphorescent cyclometallated platinum complex of formula i according to claim 1 for the preparation of a cytological imaging reagent.
6. Use of the phosphorescent cyclometallated platinum complex of claim 1 in the preparation of an antitumor drug.
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