CN114805447A - Iridium complex photosensitizer and preparation method and application thereof - Google Patents
Iridium complex photosensitizer and preparation method and application thereof Download PDFInfo
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- 239000003504 photosensitizing agent Substances 0.000 title claims abstract description 65
- 229910052741 iridium Inorganic materials 0.000 title claims abstract description 59
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 title claims abstract description 59
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 239000003446 ligand Substances 0.000 claims abstract description 41
- 238000006243 chemical reaction Methods 0.000 claims abstract description 26
- 238000002428 photodynamic therapy Methods 0.000 claims abstract description 24
- 229940125782 compound 2 Drugs 0.000 claims abstract description 21
- 229940125904 compound 1 Drugs 0.000 claims abstract description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 60
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic System
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic System compounds of the platinum group
- C07F15/0033—Iridium compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
- C09K11/06—Luminescent, e.g. electroluminescent, chemiluminescent materials containing organic luminescent materials
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/18—Metal complexes
- C09K2211/185—Metal complexes of the platinum group, i.e. Os, Ir, Pt, Ru, Rh or Pd
Abstract
The invention belongs to the technical field of photodynamic therapy, and discloses an iridium complex photosensitizer as well as a preparation method and application thereof. The preparation method comprises the following steps: preparing ligand fmp, compound 1 and compound 2; then preparing the ligand psi by using fmp and the compound 1; and finally, preparing the iridium complex photosensitizer by using the ligand psi and the compound 2. The preparation process is simple, the reaction condition is mild, the yield is high, and the preparation method has the condition of large-scale production. The prepared iridium complex photosensitizer consists of a ring metal ligand, a metal center and an auxiliary ligand containing an N-substituted indole sulfonate structure, the luminous intensity of the iridium complex photosensitizer is enhanced along with the increase of illumination time, and the progress of photodynamic therapy can be monitored.
Description
Technical Field
The invention relates to the technical field of photodynamic therapy, in particular to an iridium complex photosensitizer and a preparation method and application thereof.
Background
Photodynamic therapy (PDT) has received much attention because of its non-invasive, spatio-temporally controllable treatment modalities. During photodynamic therapy, Photosensitizers (PSs) have negligible cytotoxicity in the dark, but generate large amounts of Reactive Oxygen Species (ROS) in the light, resulting in higher cytotoxicity. The mechanism of ROS production can generally be divided into two pathways: type I and type II. The type I pathway is the transfer of electrons from a photosensitizer in an excited state to a surrounding substrate to form a free radical, e.g. O 2 ·- And OH; in the type II pathway, the photosensitizer in the excited state transfers energy to triplet oxygen molecules to form singlet oxygen 1 O 2 . The type I PDT has lower dependence on oxygen content, and has wider development prospect compared with the type II PDT when overcoming the problem of oxygen deficiency in a tumor microenvironment.
ROS, through their strong oxidation, rapidly destroy surrounding biomolecules, including proteins, lipids, and nucleic acids, leading to cell death. ROS generated in the PDT process are short in life (0.03-0.18 ms in a life system) and limited in diffusion distance (0.01-0.02 mu m in the life system), so that the primary position of ROS generation directly influences the PDT treatment effect. Thus, if the photosensitizer is precisely transported to vital or delicate organelles, the accumulated photosensitizer can attack the "lethal site" of these cancer cells, causing greater damage to the tumor tissue. Among them, mitochondria are widely selected as effective targets for cancer therapy because they supply energy to cells, regulate the survival and death of cells, and have very important significance in the research of mitochondria-targeted cancer therapeutic agents.
The long-lived triplet excited states present in the Ir (III) complex provide greater opportunity for them to transfer energy or electrons to surrounding substrates, promoting the generation of reactive oxygen species and reactive free radicals. Through the design of the ligand structure, not only can the excited state property of the Ir (III) complex be adjusted, but also a targeting group can be connected to target important organelles, and a high-efficiency PDT effect is achieved. In addition, the characteristic phosphorescence of the Ir (III) complex has the characteristics of good light stability, large Stokes displacement and long emission life, and has unique advantages in the field of biological imaging.
Therefore, how to apply the iridium complex to photodynamic therapy becomes a problem which needs to be solved by those skilled in the art.
Disclosure of Invention
In view of the above, the invention provides an iridium complex photosensitizer and a preparation method and application thereof. The iridium complex photosensitizer can accurately reach mitochondria, and can overcome the problem of oxygen deficiency in a microenvironment to realize I/II type photodynamic therapy.
In order to achieve the purpose, the invention adopts the following technical scheme:
an iridium complex photosensitizer, wherein the structural formula of the iridium complex photosensitizer is as follows:
the invention provides a preparation method of the iridium complex photosensitizer, which comprises the following steps:
(S1) reacting 1, 10-phenanthroline-5, 6-dione, terephthalaldehyde, ammonium acetate and acetic acid, adjusting the pH of a mixed solution obtained by a reaction solution and water to be neutral to obtain a mixture, and sequentially separating, dissolving, filtering and drying the mixture to obtain a ligand fmp;
s2, reacting 2,3, 3-trimethylindole, 1, 3-propane sultone and o-dichlorobenzene under protective gas to obtain a compound 1;
s3, reacting the ligand fmp, the compound 1, the catalyst and the mixed solvent 1 under the protection of gas, mixing the reaction solution with a saturated sodium chloride solution, and then sequentially separating and drying to obtain the ligand psi;
s4 IrCl 3 ·3H 2 Reacting O, 2-phenylpyridine and the mixed solvent 2 to obtain a compound 2;
s5, under the protection gas, theRemoving dichloromethane after the compound 2, the ligand psi and the mixed solvent 3 are reacted, and obtaining a reaction product, NH 4 PF 6 And mixing the aqueous solution and water, and then sequentially separating, purifying and drying to obtain the iridium complex photosensitizer.
Further, the molar ratio of the 1, 10-phenanthroline-5, 6-diketone to the terephthalaldehyde to the ammonium acetate is 1.8-2.2: 3.8-4.2: 58-65 parts; the molar volume ratio of the ammonium acetate to the acetic acid is 58-65 mmol: 54-66 mL; the volume ratio of acetic acid to water is 54-66: 220 to 280.
Further, the molar ratio of the 2,3, 3-trimethylindole to the 1, 3-propane sultone is 2.8-3.5: 3.0 to 4.0; the molar volume ratio of the 2,3, 3-trimethylindole to the o-dichlorobenzene is 2.8-3.5 mmol: 2.4-4 mL.
Further, the molar ratio of the ligand fmp to the compound 1 is 1.0-1.5: 1.8 to 2.4;
the molar volume ratio of the ligand fmp to the mixed solvent 1 is 1.0-1.5 mmol: 18-25 mL;
the volume ratio of the catalyst to the mixed solvent 1 is 0.8-1.2: 100, respectively;
the volume ratio of the saturated sodium chloride solution to the mixed solvent 1 is 180-220: 18-25;
the catalyst is piperidine, the mixed solvent 1 comprises ethanol and N, N-dimethylformamide, and the volume ratio of the ethanol to the N, N-dimethylformamide is 18-22: 1.
further, said IrCl 3 ·3H 2 The molar ratio of O to 2-phenylpyridine is 1.8-2.2: 4.0 to 6.0;
the IrCl 3 ·3H 2 The molar volume ratio of the O to the mixed solvent 2 is 1.8-2.2 mmol: 45-60 mL;
the mixed solvent 2 comprises ethylene glycol ethyl ether and water, and the volume ratio of the ethylene glycol ethyl ether to the water is (1-5): 1.
further, the molar ratio of the compound 2 to the ligand psi is 0.1-0.2: 0.3 to 0.4;
the molar volume ratio of the compound 2 to the mixed solvent 3 is 0.1-0.2 mmol: 35-45 mL;
the NH 4 PF 6 The volume ratio of the aqueous solution, the water and the mixed solvent 3 is 4-8: 24-35: 35-45;
the mixed solvent 3 comprises dichloromethane and methanol, and the volume ratio of the dichloromethane to the methanol is (1-2): 1 to 2.
Further, the shielding gas in steps S2, S3 and S5 is independently nitrogen, argon, helium, neon or carbon dioxide;
the reaction temperature of the step S1 is 100-130 ℃, and the reaction time is 25-40 min; the reaction temperature of the step S2 is 100-140 ℃, and the reaction time is 20-30 h; the reaction temperature of the step S3 is 80-100 ℃, and the reaction time is 40-55 h; step S4, the reaction temperature is 120-150 ℃, and the reaction time is 20-30 h; the reaction time of the step S5 is 20-30 h.
Further, the structural formulas of the ligand fmp, the compound 1, the ligand psi and the compound 2 are as follows:
the invention also provides application of the iridium complex photosensitizer in preparation of photodynamic therapy medicines.
According to the technical scheme, compared with the prior art, the invention has the following beneficial effects:
1. the luminous intensity of the iridium complex photosensitizer prepared by the invention is enhanced along with the increase of illumination time, and the progress of photodynamic therapy can be monitored.
2. The iridium complex photosensitizer prepared by the invention has low dark cell toxicity, but generates O under illumination 2 ·- Causing cytotoxicity, can be used for I/II type photodynamic therapy, can overcome the problem of oxygen deficiency in microenvironment, and simultaneously improves the photodynamic therapy effect by the mitochondrion targeting function.
3. The preparation method of the iridium complex photosensitizer is simple, the reaction condition is mild, the yield is high, and large-scale production can be realized.
Drawings
FIG. 1 is a fluorescence emission spectrum of an iridium complex photosensitizer Ir-psi prepared in example 3 with luminescence change along with illumination time;
FIG. 2 is a graph of the UV-Vis spectrum of the Ir-psi iridium complex photosensitizer prepared in example 3 with absorption change over time;
FIG. 3 is a fluorescence emission spectrum of a mixed solution of the iridium complex photosensitizer Ir-psi and active oxygen probe 2, 7-Dichlorodihydrofluorescein (DCFH) prepared in example 3 under illumination;
FIG. 4 is an electron paramagnetic resonance signal of superoxide anion generated by the iridium complex photosensitizer Ir-psi prepared in example 3;
FIG. 5 is a graph of electron paramagnetic resonance signals of singlet oxygen production by the iridium complex photosensitizer Ir-psi prepared in example 3;
FIG. 6 is a graph showing the effect of Ir-psi, the iridium complex photosensitizer prepared in example 3, on the viability of HeLa cells under different conditions;
FIG. 7 is a cell co-staining image of the iridium complex photosensitizer Ir-psi prepared in example 3 with mitochondrial probes.
Detailed Description
The invention provides an iridium complex photosensitizer, which has the following structural formula:
the invention provides a preparation method of the iridium complex photosensitizer, which comprises the following steps:
(S1) reacting 1, 10-phenanthroline-5, 6-dione, terephthalaldehyde, ammonium acetate and acetic acid, adjusting the pH of a mixed solution obtained by a reaction solution and water to be neutral to obtain a mixture, and sequentially separating, dissolving, filtering and drying the mixture to obtain a ligand fmp;
s2, reacting 2,3, 3-trimethylindole, 1, 3-propane sultone and o-dichlorobenzene under protective gas to obtain a compound 1;
s3, reacting the ligand fmp, the compound 1, the catalyst and the mixed solvent 1 under protective gas, mixing the reaction solution with a saturated sodium chloride solution, and then sequentially separating and drying to obtain the ligand psi;
s4, mixing IrCl 3 ·3H 2 Reacting O, 2-phenylpyridine and the mixed solvent 2 to obtain a compound 2;
s5, under the protection gas, removing dichloromethane after the compound 2, the ligand psi and the mixed solvent 3 are reacted, and obtaining a reaction product, NH 4 PF 6 The aqueous solution and water are mixed and then are sequentially separated, purified and dried to obtain the iridium complex photosensitizer.
In the invention, the molar ratio of the 1, 10-phenanthroline-5, 6-diketone to the terephthalaldehyde to the ammonium acetate is 1.8-2.2: 3.8-4.2: 58 to 65, preferably 1.9 to 2.1: 3.9-4.1: 59 to 64, and more preferably 2.0: 4.0: 60-62; the molar volume ratio of the ammonium acetate to the acetic acid is 58-65 mmol: 54-66 mL, preferably 60-64 mmol: 57 to 63mL, more preferably 62 to 63 mmol: 60-62 mL; the volume ratio of acetic acid to water is 54-66: 220 to 280, preferably 57 to 63: 230 to 260, more preferably 60 to 62: 240 to 250.
In the present invention, the specific steps of the dissolving and filtering in step S1 are as follows: the crude product obtained after the mixture is separated is heated and dissolved by ethanol; the volume concentration of the ethanol is 99.7%, the dissolving temperature is 70-90 ℃, the preferable temperature is 72-86 ℃, and the further preferable temperature is 75-80 ℃; the time is 20-40 min, preferably 22-38 min, and more preferably 25-35 min; the mass-volume ratio of the crude product to the ethanol is 80-120 mg: 180-220 mL, preferably 90-110 mg: 190-210 mL, more preferably 95-100 mg: 195-200 mL.
In the invention, the molar ratio of the 2,3, 3-trimethylindole to the 1, 3-propane sultone is 2.8-3.5: 3.0 to 4.0, preferably 2.9 to 3.4: 3.2 to 3.8, and more preferably 3.0 to 3.2: 3.4 to 3.6;
the molar volume ratio of the 2,3, 3-trimethylindole to the o-dichlorobenzene is 2.8-3.5 mmol: 2.4-4 mL, preferably 2.9-3.4 mmol: 2.5 to 3.5mL, more preferably 3.0 to 3.2 mmol: 2.8-3.2 mL.
In the invention, the molar ratio of the ligand fmp to the compound 1 is 1.0-1.5: 1.8 to 2.4, preferably 1.1 to 1.4: 1.9 to 2.3, and more preferably 1.2 to 1.3: 2.0 to 2.2;
the molar volume ratio of the ligand fmp to the mixed solvent 1 is 1.0-1.5 mmol: 18-25 mL; preferably 1.1-1.4 mmol: 19 to 24mL, more preferably 1.2 to 1.3 mmol: 20-22 mL;
the volume ratio of the catalyst to the mixed solvent 1 is 0.8-1.2: 100, preferably 0.9 to 1.1: 100, more preferably 1: 100, respectively;
the volume ratio of the saturated sodium chloride solution to the mixed solvent 1 is 180-220: 18-25, preferably 190-210: 19 to 24, more preferably 195 to 200: 21-23;
the catalyst is piperidine, the mixed solvent 1 comprises ethanol and N, N-dimethylformamide, and the volume ratio of the ethanol to the N, N-dimethylformamide is 18-22: 1, preferably 19 to 21: 1, more preferably 20: 1.
in the present invention, the IrCl 3 ·3H 2 The molar ratio of O to 2-phenylpyridine is 1.8-2.2: 4.0 to 6.0, preferably 1.9 to 2.1: 4.2 to 5.5, more preferably 2.0: 4.5 to 5.0;
the IrCl 3 ·3H 2 The molar volume ratio of the O to the mixed solvent 2 is 1.8-2.2 mmol: 45-60 mL, preferably 1.9-2.1 mmol: 48 to 56mL, more preferably 2.0 mmol: 50-54 mL;
the mixed solvent 2 comprises ethylene glycol ethyl ether and water, and the volume ratio of the ethylene glycol ethyl ether to the water is (1-5): 1, preferably 2-4: 1, more preferably 3: 1.
in the invention, the molar ratio of the compound 2 to the ligand psi is 0.1-0.2: 0.3 to 0.4, preferably 0.12 to 0.18: 0.32 to 0.38, and more preferably 0.14 to 0.16: 0.34 to 0.36;
the molar volume ratio of the compound 2 to the mixed solvent 3 is 0.1-0.2 mmol: 35-45 mL, preferably 0.12-0.18 mmol: 38 to 44mL, more preferably 0.14 to 0.16 mmol: 40-42 mL;
the NH 4 PF 6 Dissolving in waterThe volume ratio of the liquid to the water to the mixed solvent 3 is 4-8: 24-35: 35-45, preferably 5-7: 25-32: 36 to 42, more preferably 6: 28-30: 38-40;
the mixed solvent 3 comprises dichloromethane and methanol, and the volume ratio of the dichloromethane to the methanol is (1-2): 1 to 2, preferably 1.2 to 1.8: 1.2 to 1.8, and more preferably 1.4 to 1.6: 1.4 to 1.6.
In the present invention, the shielding gas in steps S2, S3 and S5 is independently nitrogen, argon, helium, neon or carbon dioxide, preferably nitrogen, argon or carbon dioxide, and more preferably nitrogen;
the reaction temperature of the step S1 is 100-130 ℃, preferably 110-125 ℃, and more preferably 115-120 ℃; the time is 25-40 min, preferably 28-36 min, and further preferably 30-35 min;
the reaction temperature of the step S2 is 100-140 ℃, preferably 110-130 ℃, and more preferably 115-125 ℃; the time is 20-30 h, preferably 22-28 h, and further preferably 24-26 h;
the reaction temperature of the step S3 is 80-100 ℃, preferably 85-95 ℃, and more preferably 88-92 ℃; the time is 40-55 h, preferably 42-52 h, and further preferably 45-50 h;
the reaction temperature of the step S4 is 120-150 ℃, preferably 125-140 ℃, and more preferably 130-135 ℃; the time is 20-30 h, preferably 22-28 h, and further preferably 24-26 h;
the reaction time of the step S5 is 20-30 h, preferably 22-28 h, and more preferably 24-26 h.
In the present invention, the structural formulas of the ligand fmp, compound 1, ligand psi, and compound 2 are as follows:
the invention also provides application of the iridium complex photosensitizer in preparation of photodynamic therapy medicines.
The technical solutions in the embodiments of the present invention will be described clearly and completely below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
Dissolving 1, 10-phenanthroline-5, 6-dione (2mmol), terephthalaldehyde (4mmol) and ammonium acetate (60mmol) in acetic acid (60mL), and refluxing at 115 ℃ for 30 min. After cooling to room temperature, 250mL of distilled water was added, and the pH was adjusted to neutral with concentrated ammonia (25% by mass) while stirring, to precipitate a yellow solid. And then carrying out suction filtration, washing the crude product after suction filtration with water for three times, drying at 80 ℃ for 24h to obtain an orange crude product, and heating and dissolving the orange crude product with ethanol at 85 ℃ for 30min, wherein the mass-volume ratio of the orange crude product to the ethanol is 100 mg: 200mL, filtering while hot, putting the filtrate into a rotary dryer, and carrying out rotary drying to obtain a yellow ligand fmp, wherein the yield is 70.0%;
2,3, 3-trimethylindole (3.14mmol) and 1, 3-propanesultone (3.48mmol) were dissolved in 3mL of o-dichlorobenzene and refluxed at 120 ℃ for 24h under an argon atmosphere. Cooling, performing suction filtration, washing with diethyl ether for three times, and drying the obtained crude product in a vacuum drying oven (70 ℃) for 24 hours to obtain a purple black compound 1, wherein the yield is 89.9%;
ligand fmp (1.2mmol) and compound 1(2mmol) were dissolved in 21mL of a mixed solvent (volume ratio of ethanol to DMF 20: 1) and 210. mu.L of piperidine was added, and the mixed solution was refluxed at 90 ℃ for 48h under argon protection. After cooling to room temperature, the reaction mixture was added to 200mL of a saturated sodium chloride solution to precipitate a dark red precipitate. Then, carrying out suction filtration, and drying the crude product after suction filtration in a vacuum drying oven (70 ℃) for 24 hours to obtain black and red ligand psi with the yield of 75.7 percent.
The nuclear magnetic resonance spectrogram of the black-red ligand psi prepared in the embodiment is analyzed, and the technical scheme can be used for efficiently preparing the ligand psi. The specific analysis is as follows:
1 HNMR(400MHz,DMSO-d 6 )δ9.00(ddd,J＝9.2,4.3,1.7Hz,2H),8.91(t,J＝9.5Hz,2H),8.56–8.46(m,3H),8.42(d,J＝8.2Hz,2H),8.10–7.99(m,2H),7.85(dt,J＝8.7,4.7Hz,2H),7.77(dd,J＝8.0,4.4Hz,1H),7.68–7.53(m,2H),4.92(t,J＝8.1Hz,2H),2.70(dd,J＝7.7,4.4Hz,2H),2.22(d,J＝8.6Hz,2H),1.81(s,6H)。
example 2
IrCl is added 3 ·3H 2 Dissolving O (2mmol) and 2-phenylpyridine (4.4mmol) in 50mL of mixed solvent (the volume ratio of ethylene glycol ethyl ether to water is 3: 1), refluxing at 130 ℃ for 24h, cooling to room temperature, performing suction filtration, and drying the crude product after suction filtration at 80 ℃ for 24h to obtain yellow compound 2 (Ir) 2 (ppy) 4 Cl 2 ) The yield is 80%;
example 3
Analysis of the nuclear magnetic resonance spectrogram of the dark red iridium complex photosensitizer Ir-psi prepared in the embodiment shows that the technical scheme of the invention can prepare the iridium complex photosensitizer Ir-psi with high efficiency. The specific analysis is as follows:
1 H NMR(400MHz,DMSO-d 6 )δ9.22(t,J＝8.9Hz,2H),8.68–8.48(m,5H),8.28(d,J＝8.2Hz,2H),8.16(d,J＝14.7Hz,4H),8.05(d,J＝8.4Hz,2H),7.97(d,J＝7.8Hz,2H),7.90(q,J＝7.7,6.8Hz,3H),7.68–7.60(m,2H),7.54(t,J＝7.0Hz,2H),7.08(t,J＝7.5Hz,2H),6.99(dt,J＝19.1,7.0Hz,4H),6.31(d,J＝7.4Hz,2H),4.96(t,J＝8.2Hz,2H),2.73(t,J＝5.9Hz,2H),2.26(s,2H),1.87(d,J＝3.1Hz,6H)；
13 CNMR(101MHz,DMSO-d 6 )δ182.31,167.42,153.13,152.01,150.82,149.75,149.14,144.96,144.65,144.55,141.32,139.25,136.71,133.36,132.19,131.75,130.80,130.14,129.59,127.58,127.40,125.61,124.40,123.63,122.92,120.52,115.79,114.62,52.85,47.66,46.20,26.10,26.02,25.31。
example 4
Example 5
Performance characterization
Spectrum test of iridium complex photosensitizer Ir-psi
The specific operation steps are as follows: the iridium complex photosensitizer Ir-psi prepared in example 3 was dissolved in DMSO to prepare a stock solution of 10 mmol/L. Unless otherwise indicated, the samples used in the following experiments were obtained by dilution of stock solutions. The absorption spectrum and the fluorescence spectrum of the iridium complex photosensitizer Ir-psi (10 mu mol/L) are measured, a 365nm ultraviolet flashlight is used as an external light source, and the ultraviolet spectrum and the fluorescence spectrum are collected once every 1 minute of illumination. Wherein, when the fluorescence spectrum is collected, the excitation wavelength is 400 nm. The test results are shown in FIGS. 1 and 2, and can be obtained from FIGS. 1 to 2: the light emission of the iridium complex photosensitizer Ir-psi gradually increases with increasing illumination time, while the absorption at 550nm gradually decreases. The real-time monitoring of the treatment process can be realized in the photodynamic treatment process.
Determination of active oxygen
The specific operation steps are as follows: ROS production was measured using 2, 7-Dichlorodihydrofluorescein (DCFH) as an index. DCFH was activated with 2, 7-dichlorodihydrofluorescein diacetate (DCFH-DA). DCFH-DA (0.5mL, 1mmol/L) was added to an aqueous NaOH (2mL, 10mmol/L) solution, allowed to stand at room temperature for 30min, and hydrolyzed well. Then neutralized to pH 7.4 with PBS (10mL) buffer to give a stock solution with a concentration of 40 μmol/L. The stock solution was stored under dark freezing conditions.
For testing, the iridium complex photosensitizer Ir-psi (2. mu.L, 10) prepared in example 3 was added to 2mL of activated DCFH solution -2 mol/L) and the fluorescence spectrum is tested every 5s of illumination, and the excitation wavelength is 480 nm. The test results are shown in FIG. 3, from which FIG. 3 can be derived: as the illumination time increases, the light emission of the Ir-psi and DCFH mixed solution at 530nm is gradually enhanced, which indicates that active oxygen is generated in the illumination process.
ESR determination of reactive oxygen species
The specific operation steps are as follows: using 5, 5-dimethyl-1-pyrroline-N-oxidationCapture of superoxide anion radical (O) by substance (DMPO) 2 ·- ) And a hydroxyl radical (. OH). Determination of O 2 ·- In the meantime, DMPO (10mmol/L) was added to a methanol solution of the iridium complex photosensitizer (100. mu. mol/L) prepared in example 3 under a dark condition, an electron paramagnetic resonance signal thereof was measured with an electron paramagnetic resonance spectrometer, and the sample was irradiated with a 365nm ultraviolet torch for 1min, and then the electron paramagnetic resonance signal thereof was measured again. When measuring OH, the solvent is changed to a solvent with a volume ratio of 1: 1, water and acetonitrile, and the other test conditions are the same. The test results are shown in FIG. 4, from which FIG. 4 can be derived: the electron paramagnetic resonance spectrum of the iridium complex photosensitizer Ir-psi prepared in example 3 under the illumination of light shows O when methanol is used as a solvent 2 ·- Indicating that O is generated during the light irradiation 2 ·- (ii) a FIG. 5 is a diagram of electron paramagnetic resonance signals of singlet oxygen generated by Ir-psi iridium complex photosensitizer prepared in example 3, and 2,2,6, 6-Tetramethylpiperidine (TEMP) pair is selected 1 O 2 Capture was performed, as can be taken from fig. 5: electron paramagnetic resonance signal diagram shows 1: 1: 1, indicating that a signal peak is generated 1 O 2 ；
The above results indicate that Ir-psi produces O simultaneously during light exposure 2 ·- And 1 O 2 type I and type II synergistic PDT mechanisms, i/II synergistic mechanism vs. O, compared to type II photosensitizers 2 Has smaller dependence, and is more beneficial to the application of the photodynamic therapy in the anoxic environment.
Cytotoxicity test
The specific operation steps are as follows: digesting the cells at 5X 10 4 The density of each well is inoculated into a 96-well cell culture plate, 3 multiple wells are arranged, and the temperature is 37 ℃ and the CO is added 2 The volume concentration of (2) is 5% in an incubator for 24 h. After the cells grew into a monolayer, the culture solution was discarded, and the iridium complex photosensitizer (0. mu. mol/L, 3.125. mu. mol/L, 6.25. mu. mol/L, 12.5. mu. mol/L, 25. mu. mol/L, 50. mu. mol/L) prepared in example 3 was added at different concentration gradients, and the mixture was incubated at 37 ℃ under CO 2 After incubation for 4h in a 5% volume incubator, 20. mu.L of MTT solution was added to each well and incubation was continued for 4 h. The culture was terminated and,the culture medium in the wells was carefully aspirated. Adding 150 μ L DMSO into each well, oscillating with microplate reader for 10min to dissolve the crystal, and measuring OD value with microplate reader. In the phototoxicity test, cells are incubated for 2h after being added with iridium complex photosensitizer with different concentrations, then are illuminated by a xenon lamp and then are incubated for 2h, and the subsequent treatment method is consistent with the dark toxicity test. The test results are shown in FIG. 5, from which FIG. 5 can be derived: the iridium complex photosensitizer Ir-psi has negligible toxicity in the absence of illumination. After illumination for 5min (400-800 nm), the cell survival rate is obviously reduced. After the illumination time is prolonged to 10min, the cell survival rate is reduced remarkably, and when the concentration of the iridium complex photosensitizer Ir-psi is only 3.125 mu mol/L, the cell survival rate is also reduced to 41.1%. The results show that the cytotoxicity of the iridium complex photosensitizer Ir-psi under the dark condition is negligible, the iridium complex photosensitizer Ir-psi shows larger cytotoxicity after illumination, and when the illumination time is longer, the iridium complex photosensitizer Ir-psi with low concentration can cause obvious cell damage, so that the iridium complex photosensitizer Ir-psi has excellent photodynamic therapy effect.
Co-localization of cells
The specific operation steps are as follows: HeLa cells were grown adherent at 37 ℃ for 24h in a six-well plate, incubated with the iridium complex photosensitizer Ir-psi (50. mu. mol/L) and Mito-Tracker Green (1. mu. mol/L) prepared in example 3 for 20min, then illuminated for 5min and imaged using a confocal microscope. For an iridium complex photosensitizer Ir-psi, the excitation wavelength is 405nm, and the emission wavelength is 550-650 nm. For MTG, the excitation wavelength is 488nm, and the emission wavelength is 500-530 nm. The test results are shown in FIG. 6, from which FIG. 6 can be derived: the Pearson correlation coefficient (Pr) of the iridium complex photosensitizer Ir-psi with MTG was 0.93. The result shows that the complex is mainly targeted to mitochondria after entering cells, so that the iridium complex photosensitizer Ir-psi firstly destroys the mitochondria during the photodynamic therapy process, and the mitochondria are important organelles influencing the vital activities of the cells, thereby improving the efficiency of the photodynamic therapy.
The embodiments in the present description are described in a progressive manner, each embodiment focuses on differences from other embodiments, and the same and similar parts among the embodiments are referred to each other.
The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims (10)
1. An iridium complex photosensitizer is characterized in that the structural formula of the iridium complex photosensitizer is as follows:
2. a method for preparing an iridium complex photosensitizer as claimed in claim 1, comprising the steps of:
(S1) reacting 1, 10-phenanthroline-5, 6-dione, terephthalaldehyde, ammonium acetate and acetic acid, adjusting the pH of a mixed solution obtained by a reaction solution and water to be neutral to obtain a mixture, and sequentially separating, dissolving, filtering and drying the mixture to obtain a ligand fmp;
s2, reacting 2,3, 3-trimethylindole, 1, 3-propane sultone and o-dichlorobenzene under protective gas to obtain a compound 1;
s3, reacting the ligand fmp, the compound 1, the catalyst and the mixed solvent 1 under the protection of gas, mixing the reaction solution with a saturated sodium chloride solution, and then sequentially separating and drying to obtain the ligand psi;
s4 IrCl 3 ·3H 2 Reacting O, 2-phenylpyridine and the mixed solvent 2 to obtain a compound 2;
s5, under the protection gas, removing dichloromethane after the compound 2, the ligand psi and the mixed solvent 3 are reacted, and obtaining a reaction product, NH 4 PF 6 Mixing the aqueous solution and water, and sequentially carrying outAnd separating, purifying and drying to obtain the iridium complex photosensitizer.
3. The preparation method according to claim 2, wherein the molar ratio of 1, 10-phenanthroline-5, 6-dione, terephthalaldehyde and ammonium acetate is 1.8-2.2: 3.8-4.2: 58-65; the molar volume ratio of the ammonium acetate to the acetic acid is 58-65 mmol: 54-66 mL; the volume ratio of acetic acid to water is 54-66: 220 to 280.
4. The preparation method according to claim 2, wherein the molar ratio of the 2,3, 3-trimethylindole to the 1, 3-propanesultone is 2.8-3.5: 3.0 to 4.0; the molar volume ratio of the 2,3, 3-trimethylindole to the o-dichlorobenzene is 2.8-3.5 mmol: 2.4-4 mL.
5. The method according to claim 3, wherein the molar ratio of the ligand fmp to the compound 1 is 1.0 to 1.5: 1.8 to 2.4;
the molar volume ratio of the ligand fmp to the mixed solvent 1 is 1.0-1.5 mmol: 18-25 mL;
the volume ratio of the catalyst to the mixed solvent 1 is 0.8-1.2: 100, respectively;
the volume ratio of the saturated sodium chloride solution to the mixed solvent 1 is 180-220: 18-25;
the catalyst is piperidine, the mixed solvent 1 comprises ethanol and N, N-dimethylformamide, and the volume ratio of the ethanol to the N, N-dimethylformamide is 18-22: 1.
6. the method according to claim 4, wherein said IrCl is present 3 ·3h 2 The molar ratio of O to 2-phenylpyridine is 1.8-2.2: 4.0 to 6.0;
the IrCl 3 ·3h 2 The molar volume ratio of the O to the mixed solvent 2 is 1.8-2.2 mmol: 45-60 mL;
the mixed solvent 2 comprises ethylene glycol ethyl ether and water, and the volume ratio of the ethylene glycol ethyl ether to the water is (1-5): 1.
7. the method of claim 6, wherein the compound 2, ligand psi, is present in a molar ratio of 0.1 to 0.2: 0.3 to 0.4;
the molar volume ratio of the compound 2 to the mixed solvent 3 is 0.1-0.2 mmol: 35-45 mL;
the NH 4 PF 6 The volume ratio of the aqueous solution to the mixed solvent 3 is 4-8: 24-35: 35-45;
the mixed solvent 3 comprises dichloromethane and methanol, and the volume ratio of the dichloromethane to the methanol is (1-2): 1 to 2.
8. The method of claim 7, wherein the shielding gas in steps S2, S3 and S5 is independently nitrogen, argon, helium, neon or carbon dioxide;
the reaction temperature of the step S1 is 100-130 ℃, and the reaction time is 25-40 min; the reaction temperature of the step S2 is 100-140 ℃, and the reaction time is 20-30 h; the reaction temperature of the step S3 is 80-100 ℃, and the reaction time is 40-55 h; step S4, the reaction temperature is 120-150 ℃, and the reaction time is 20-30 h; the reaction time of the step S5 is 20-30 h.
9. The method of any one of claims 2 to 8, wherein the ligand fmp, compound 1, ligand psi, and compound 2 have the following structural formula:
10. use of the iridium complex photosensitizer of claim 1 in the preparation of a photodynamic therapy medicament.
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| CN101787054A (en) * | 2010-03-23 | 2010-07-28 | 上海师范大学 | Water-soluble cationic iridium complex phosphorescence probe and preparation method |
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| CN115505008A (en) * | 2022-09-19 | 2022-12-23 | 兰州大学 | Iridium complex probe and preparation method and application thereof |
| CN115505008B (en) * | 2022-09-19 | 2023-12-22 | 兰州大学 | Iridium complex probe and preparation method and application thereof |
| CN116082658A (en) * | 2023-02-24 | 2023-05-09 | 兰州大学 | Photosensitive MOF and preparation method and application thereof |
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