CN114805447B - 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 60
- 229910052741 iridium Inorganic materials 0.000 title claims abstract description 51
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 title claims abstract description 51
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 239000003446 ligand Substances 0.000 claims abstract description 41
- 238000002428 photodynamic therapy Methods 0.000 claims abstract description 24
- 238000006243 chemical reaction Methods 0.000 claims abstract description 23
- 229940125782 compound 2 Drugs 0.000 claims abstract description 21
- 229940125904 compound 1 Drugs 0.000 claims abstract description 16
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 63
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 51
- 239000012046 mixed solvent Substances 0.000 claims description 41
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 25
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 20
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- 238000001035 drying Methods 0.000 claims description 16
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 claims description 14
- VQGHOUODWALEFC-UHFFFAOYSA-N 2-phenylpyridine Chemical compound C1=CC=CC=C1C1=CC=CC=N1 VQGHOUODWALEFC-UHFFFAOYSA-N 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 13
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- 230000035484 reaction time Effects 0.000 claims description 11
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 10
- 239000005695 Ammonium acetate Substances 0.000 claims description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- 229940043376 ammonium acetate Drugs 0.000 claims description 10
- 235000019257 ammonium acetate Nutrition 0.000 claims description 10
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- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 8
- 239000007864 aqueous solution Substances 0.000 claims description 8
- KCALAFIVPCAXJI-UHFFFAOYSA-N 1,10-phenanthroline-5,6-dione Chemical compound C1=CC=C2C(=O)C(=O)C3=CC=CN=C3C2=N1 KCALAFIVPCAXJI-UHFFFAOYSA-N 0.000 claims description 7
- FSSPGSAQUIYDCN-UHFFFAOYSA-N 1,3-Propane sultone Chemical compound O=S1(=O)CCCO1 FSSPGSAQUIYDCN-UHFFFAOYSA-N 0.000 claims description 7
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- KUCOHFSKRZZVRO-UHFFFAOYSA-N terephthalaldehyde Chemical compound O=CC1=CC=C(C=O)C=C1 KUCOHFSKRZZVRO-UHFFFAOYSA-N 0.000 claims description 7
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 6
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- RKMGAJGJIURJSJ-UHFFFAOYSA-N 2,2,6,6-Tetramethylpiperidine Substances CC1(C)CCCC(C)(C)N1 RKMGAJGJIURJSJ-UHFFFAOYSA-N 0.000 description 1
- RUVJFMSQTCEAAB-UHFFFAOYSA-M 2-[3-[5,6-dichloro-1,3-bis[[4-(chloromethyl)phenyl]methyl]benzimidazol-2-ylidene]prop-1-enyl]-3-methyl-1,3-benzoxazol-3-ium;chloride Chemical compound [Cl-].O1C2=CC=CC=C2[N+](C)=C1C=CC=C(N(C1=CC(Cl)=C(Cl)C=C11)CC=2C=CC(CCl)=CC=2)N1CC1=CC=C(CCl)C=C1 RUVJFMSQTCEAAB-UHFFFAOYSA-M 0.000 description 1
- VCUVETGKTILCLC-UHFFFAOYSA-N 5,5-dimethyl-1-pyrroline N-oxide Chemical compound CC1(C)CCC=[N+]1[O-] VCUVETGKTILCLC-UHFFFAOYSA-N 0.000 description 1
- 206010034972 Photosensitivity reaction Diseases 0.000 description 1
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- AEDZKIACDBYJLQ-UHFFFAOYSA-N ethane-1,2-diol;hydrate Chemical compound O.OCCO AEDZKIACDBYJLQ-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
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- 150000002503 iridium Chemical class 0.000 description 1
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- 102000039446 nucleic acids Human genes 0.000 description 1
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- 229910052724 xenon Inorganic materials 0.000 description 1
- FHNFHKCVQCLJFQ-UHFFFAOYSA-N xenon atom Chemical compound [Xe] FHNFHKCVQCLJFQ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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 Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table 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
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
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Abstract
The invention belongs to the technical field of photodynamic therapy, and discloses an iridium complex photosensitizer and a preparation method and application thereof. The preparation method comprises the following steps: first preparing ligand fmp, compound 1 and compound 2; preparing ligand psi using fmp and compound 1; finally, the iridium complex photosensitizer is prepared using the ligand psi and compound 2. The preparation process is simple, the reaction condition is mild, the yield is high, and the preparation process has the condition of mass production. The prepared iridium complex photosensitizer consists of a cyclometalated ligand, a metal center and an auxiliary ligand containing an N-substituted indole sulfonate structure, the self 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 widespread attention for its non-invasive, spatially and temporally controllable mode of treatment. During photodynamic therapy, photosensitizers (PSs) have negligible cytotoxicity under dark conditions, but generate large amounts of Reactive Oxygen Species (ROS) under light conditions, resulting in higher cytotoxicity. The mechanism of ROS production can be generally 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 radicals, 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 . Type I PDTThe dependence on oxygen content is lower, and the PDT has wider development prospect than the type II PDT when overcoming the hypoxia problem in the tumor microenvironment.
ROS rapidly destroy surrounding biomolecules, including proteins, lipids, and nucleic acids, by its strong oxidation, resulting in cell death. ROS generated in the PDT process has short service life (0.03-0.18 ms in a life system) and limited 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 transported precisely into important or fragile organelles, the accumulated photosensitizer can attack the "deadly" 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 cell survival and death, and have great significance in the study of mitochondria-targeted cancer therapeutics.
The long-lived triplet excited state present in the Ir (iii) complex provides a greater potential for its transfer of 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 the excited state property of the Ir (III) complex can be regulated, but also a targeting group can be connected to target important organelles, so that the efficient PDT effect is achieved. In addition, 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 iridium complexes in photodynamic therapy is a problem to be solved by those skilled in the art.
Disclosure of Invention
In view of the above, the invention provides an iridium complex photosensitizer, a preparation method and application thereof. The iridium complex photosensitizer can accurately reach mitochondria, and can overcome the hypoxia problem in the microenvironment to realize I/II type photodynamic therapy.
In order to achieve the above purpose, the invention adopts the following technical scheme:
an iridium complex photosensitizer having the 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, regulating the pH value of a mixed solution obtained by reaction liquid and water to be neutral to obtain a mixture, and sequentially separating, dissolving, filtering and drying the mixture to obtain a ligand fmp;
s2, under the protection gas, reacting 2, 3-trimethyl indole, 1, 3-propane sultone and o-dichlorobenzene to obtain a compound 1;
s3, under the protection gas, reacting the ligand fmp, the compound 1, the catalyst and the mixed solvent 1, mixing the reaction solution with a saturated sodium chloride solution, and sequentially separating and drying to obtain a ligand psi;
s4, irCl is added 3 ·3H 2 O, 2-phenylpyridine and the mixed solvent 2 react to obtain a compound 2;
s5, under the protection gas, reacting the compound 2, ligand psi and mixed solvent 3, removing dichloromethane, and reacting the reaction product and NH 4 PF 6 And mixing the aqueous solution with water, sequentially separating, purifying and drying to obtain the iridium complex photosensitizer.
Further, the molar ratio of the 1, 10-phenanthroline-5, 6-dione, terephthalaldehyde and ammonium acetate is 1.8-2.2: 3.8 to 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 the acetic acid to the water is 54-66: 220-280.
Further, the molar ratio of the 2, 3-trimethylindole to the 1, 3-propane sultone is 2.8-3.5: 3.0 to 4.0; the mol volume ratio of the 2, 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 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;
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, the IrCl 3 ·3H 2 The mol 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 O to the mixed solvent 2 is 1.8-2.2 mmol: 45-60 mL;
the mixed solvent 2 comprises glycol diethyl ether and water, wherein the volume ratio of the glycol diethyl ether to the water is 1-5: 1.
further, the molar ratio of the compound 2 to the ligand psi is 0.1 to 0.2:0.3 to 0.4;
the mol volume ratio of the compound 2 to the mixed solvent 3 is 0.1-0.2 mmol: 35-45 mL;
the NH is 4 PF 6 The volume ratio of the water solution, water and the mixed solvent 3 is 4-8: 24-35: 35-45;
the mixed solvent 3 comprises dichloromethane and methanol, wherein the volume ratio of the dichloromethane to the methanol is 1-2: 1 to 2.
Further, the shielding gas in the steps S2, S3 and S5 is independently nitrogen, argon, helium, neon or carbon dioxide;
the reaction temperature in the step S1 is 100-130 ℃ and the reaction time is 25-40 min; the reaction temperature in the step S2 is 100-140 ℃ and the reaction time is 20-30 h; the reaction temperature in the step S3 is 80-100 ℃ and the reaction time is 40-55 h; the reaction temperature in the step S4 is 120-150 ℃ and the reaction time is 20-30 h; the reaction time in the step S5 is 20-30 h.
Further, the structural formulas of 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 drugs.
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 cytotoxicity, but generates O under illumination 2 ·- The compound can cause cytotoxicity, can be used for I/II type photodynamic therapy, can overcome the hypoxia problem in microenvironment, and simultaneously has the mitochondria targeting function to improve the photodynamic therapy effect.
3. The iridium complex photosensitizer provided by the invention has the advantages of simple preparation method, mild reaction conditions and higher yield, and can realize large-scale production.
Drawings
FIG. 1 is a graph showing the fluorescence emission spectrum of Ir-psi as a result of luminescence change with time of illumination, which is an iridium complex photosensitizer Ir-psi prepared in example 3;
FIG. 2 is a graph of the ultraviolet-visible spectrum of Ir-psi as a function of time absorption of light for the Ir complex photosensitizer prepared in example 3;
FIG. 3 is a fluorescence emission spectrum of a mixed solution of Ir-psi and 2, 7-Dichlorodihydrofluorescein (DCFH), an iridium complex photosensitizer, prepared in example 3, under illumination;
FIG. 4 is an electron paramagnetic resonance signal of the iridium complex photosensitizer Ir-psi generating superoxide anion prepared in example 3;
FIG. 5 is a graph of electron paramagnetic resonance signals of singlet oxygen generated by Ir-psi, an iridium complex photosensitizer prepared in example 3;
FIG. 6 is a graph showing the effect of Ir-psi as a photosensitizer of Ir complex prepared in example 3 on HeLa cell viability under various conditions;
FIG. 7 is a cell co-dye imaging of Ir-psi as an iridium complex photosensitizer with mitochondrial probes prepared in example 3.
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, regulating the pH value of a mixed solution obtained by reaction liquid and water to be neutral to obtain a mixture, and sequentially separating, dissolving, filtering and drying the mixture to obtain a ligand fmp;
s2, under the protection gas, reacting 2, 3-trimethyl indole, 1, 3-propane sultone and o-dichlorobenzene to obtain a compound 1;
s3, under the protection gas, reacting the ligand fmp, the compound 1, the catalyst and the mixed solvent 1, mixing the reaction solution with a saturated sodium chloride solution, and sequentially separating and drying to obtain a ligand psi;
s4, irCl is added 3 ·3H 2 O, 2-phenylpyridine and the mixed solvent 2 react to obtain a compound 2;
s5, under the protection gas, reacting the compound 2, ligand psi and mixed solvent 3, removing dichloromethane, and reacting the reaction product and NH 4 PF 6 The aqueous solution of the iridium complex is mixed with water, and then sequentially separated, purified and dried, thus obtaining the iridium complex photosensitizer.
In the invention, the molar ratio of the 1, 10-phenanthroline-5, 6-dione, terephthalaldehyde and ammonium acetate is 1.8-2.2: 3.8 to 4.2:58 to 65, preferably 1.9 to 2.1:3.9 to 4.1:59 to 64, 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 63mmol: 60-62 mL; the volume ratio of the acetic acid to the 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 dissolution filtration in the step S1 are as follows: heating and dissolving a crude product obtained after the mixture is separated by ethanol; the volume concentration of the ethanol is 99.7%, the dissolution temperature is 70-90 ℃, preferably 72-86 ℃, and more preferably 75-80 ℃; the time is 20 to 40min, preferably 22 to 38min, and more preferably 25 to 35min; the mass volume ratio of the crude product to the ethanol is 80-120 mg: 180-220 mL, preferably 90-110 mg:190 to 210mL, more preferably 95 to 100mg: 195-200 mL.
In the invention, the molar ratio of the 2, 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, more preferably 3.0 to 3.2:3.4 to 3.6;
the mol volume ratio of the 2, 3-trimethylindole to the o-dichlorobenzene is 2.8-3.5 mmol:2.4 to 4mL, preferably 2.9 to 3.4mmol:2.5 to 3.5mL, more preferably 3.0 to 3.2mmol: 2.8-3.2 mL.
In the present invention, the molar ratio of the ligand fmp to the compound 1 is 1.0 to 1.5:1.8 to 2.4, preferably 1.1 to 1.4:1.9 to 2.3, 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 to 1.4mmol:19 to 24mL, more preferably 1.2 to 1.3mmol: 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, further preferably 1:100;
the volume ratio of the saturated sodium chloride solution to the mixed solvent 1 is 180-220: 18 to 25, preferably 190 to 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, further preferably 20:1.
in the present invention, the IrCl 3 ·3H 2 The mol 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 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 2.0mmol: 50-54 mL;
the mixed solvent 2 comprises glycol diethyl ether and water, wherein the volume ratio of the glycol diethyl ether to the water is 1-5: 1, preferably 2 to 4:1, further preferably 3:1.
in the present invention, the molar ratio of compound 2 to ligand psi is 0.1 to 0.2:0.3 to 0.4, preferably 0.12 to 0.18:0.32 to 0.38, more preferably 0.14 to 0.16:0.34 to 0.36;
the mol 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 0.16mmol: 40-42 mL;
the NH is 4 PF 6 The volume ratio of the aqueous solution, the water and the mixed solvent 3 is 4-8: 24-35: 35 to 45, preferably 5 to 7:25 to 32:36 to 42, more preferably 6: 28-30: 38-40;
the mixed solvent 3 comprises dichloromethane and methanol, wherein 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, more preferably 1.4 to 1.6:1.4 to 1.6.
In the present invention, the shielding gas in the 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 in the step S1 is 100-130 ℃, preferably 110-125 ℃, and more preferably 115-120 ℃; the time is 25 to 40min, preferably 28 to 36min, and more preferably 30 to 35min;
the reaction temperature in the step S2 is 100-140 ℃, preferably 110-130 ℃, and more preferably 115-125 ℃; the time is 20 to 30 hours, preferably 22 to 28 hours, and more preferably 24 to 26 hours;
the reaction temperature in the step S3 is 80-100 ℃, preferably 85-95 ℃, and more preferably 88-92 ℃; the time is 40 to 55 hours, preferably 42 to 52 hours, and more preferably 45 to 50 hours;
the reaction temperature in the step S4 is 120-150 ℃, preferably 125-140 ℃, and more preferably 130-135 ℃; the time is 20 to 30 hours, preferably 22 to 28 hours, and more preferably 24 to 26 hours;
the reaction time in the step S5 is 20 to 30 hours, preferably 22 to 28 hours, and more preferably 24 to 26 hours.
In the present invention, 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 drugs.
The following description of the technical solutions in the embodiments of the present invention will be clear and complete, and it is obvious that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1
1, 10-phenanthroline-5, 6-dione (2 mmol), terephthalaldehyde (4 mmol) and ammonium acetate (60 mmol) were dissolved in acetic acid (60 mL) and refluxed at 115℃for 30min. After cooling to room temperature, 250mL of distilled water was added, and the pH was adjusted to neutral with concentrated ammonia (mass concentration: 25%) while stirring, to precipitate a yellow solid. Then carrying out suction filtration, washing the crude product after suction filtration with water for three times, and drying the crude product at 80 ℃ for 24 hours to obtain an orange crude product, and then heating and dissolving the orange crude product with ethanol at 85 ℃ for 30 minutes, wherein the mass volume ratio of the orange crude product to the ethanol is 100mg:200mL, filtering while the mixture is hot, and putting the filtrate into a rotary dryer for spin drying to obtain yellow ligand fmp with the yield of 70.0%;
2, 3-trimethylindole (3.14 mmol) and 1, 3-propane sultone (3.48 mmol) were dissolved in 3mL o-dichlorobenzene and refluxed at 120℃for 24h under argon protection. Cooling, filtering, 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 purplish black compound 1 with the yield of 89.9%;
ligand fmp (1.2 mmol) and compound 1 (2 mmol) 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 the protection of argon. After cooling to room temperature, the reaction solution was added to 200mL of a saturated sodium chloride solution, and a dark red precipitate was precipitated. And then carrying out suction filtration, and drying the coarse product after suction filtration in a vacuum drying oven (70 ℃) for 24 hours to obtain the black-red ligand psi with the yield of 75.7 percent.
As can be seen from the analysis of the nuclear magnetic resonance spectrum of the black-red ligand psi prepared in the embodiment, the ligand psi can be prepared efficiently by the technical scheme. 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 to 3 ·3H 2 O (2 mmol) and 2-phenylpyridine (4.4 mmol) are dissolved in 50mL of mixed solvent (volume ratio of ethylene glycol diethyl ether and water is 3:1), reflux is carried out for 24h at 130 ℃, suction filtration is carried out after cooling to room temperature, and the crude product after suction filtration is dried for 24h at 80 ℃ to obtain yellow compound 2 (Ir) 2 (ppy) 4 Cl 2 ) The yield was 80%;
example 3
Compound 2 of example 2 (0.187 mmol) and ligand psi of example 1 (0.374 mmol) were dissolved in 40mL of mixed solvent (1:1 by volume of methanol and dichloromethane) and refluxed under argon protection for 24h. After stopping the reaction, the dichloromethane in the reaction solution was removed by spinning, and 5mL of NH was added 4 PF 6 The aqueous solution was stirred for 30min, then additional 30mL of water was added, followed by suction filtration, and the suction-filtered crude product was dried at 80℃for 24h. Purifying the dried crude product by a silica gel chromatographic column, wherein the volume ratio is 60:1 in methylene chloride/methanol, and then the volume ratio of the mixture is 30:1 in methylene chloride/methanol to give an orange-red component. And putting the orange-red component into a rotary dryer for spin drying to obtain the dark red iridium complex photosensitizer Ir-psi, wherein the yield is 62.6%.
As can be seen from the analysis of the nuclear magnetic resonance spectrogram of the dark red iridium complex photosensitizer Ir-psi prepared by the embodiment, the technical scheme of the invention can be used for efficiently preparing the iridium complex photosensitizer Ir-psi. 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
Compound 2 of example 2 (0.19 mmol) and ligand psi of example 1 (0.38 mmol) were dissolved in 40mL of a mixed solvent (methanol and dichloromethane bulk)The product ratio is 1: 1) And (3) refluxing for 25 hours in a dark place under the protection of argon. After stopping the reaction, the dichloromethane in the reaction solution was removed by spinning, and 6mL of NH was added 4 PF 6 The aqueous solution was stirred for 30min, then additional 30mL of water was added, followed by suction filtration, and the suction-filtered crude product was dried at 80℃for 24h. Purifying the dried crude product by a silica gel chromatographic column, wherein the volume ratio is 60:1 in methylene chloride/methanol, and then the volume ratio of the mixture is 30:1 in methylene chloride/methanol to give an orange-red component. And putting the orange-red component into a rotary dryer for spin drying to obtain the dark red iridium complex photosensitizer Ir-psi, wherein the yield is 58.3%.
Example 5
Compound 2 of example 2 (0.195 mmol) and the ligand psi of example 1 (0.365 mmol) were dissolved in 40mL of a mixed solvent (1:1 by volume of methanol and dichloromethane) and refluxed for 25h under argon protection. After stopping the reaction, the dichloromethane in the reaction mixture was removed by spinning, and 7mL of NH was added 4 PF 6 Stirring for 30min, adding 30mL of water, suction filtering, and drying the coarse product at 80 ℃ for 24h. Purifying the dried crude product by a silica gel chromatographic column, wherein the volume ratio is 60:1 in methylene chloride/methanol, and then the volume ratio of the mixture is 30:1 in methylene chloride/methanol to give an orange-red component. And putting the orange-red component into a rotary dryer for spin drying to obtain the dark red iridium complex photosensitizer Ir-psi, wherein the yield is 56.5%.
Characterization of Performance
Spectral testing of Ir-psi as Ir-Complex photosensitizer
The specific operation steps are as follows: ir-psi as a photosensitizer of the iridium complex 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 all obtained by dilution of stock solutions. The absorption spectrum and fluorescence spectrum of Ir-psi (10. Mu. Mol/L) of the iridium complex photosensitizer were measured, using a 365nm UV flashlight as an external light source, and the UV and fluorescence spectra were collected every 1 minute of illumination. Wherein, when the fluorescence spectrum is collected, the excitation wavelength is 400nm. The test results are shown in fig. 1 and 2, and can be obtained from fig. 1 to 2: the iridium complex photosensitizer Ir-psi emits light with increasing illumination time, while the absorption at 550nm 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-Dichlorofluorescein (DCFH) as an indicator. DCFH was obtained by activation of 2, 7-dichlorofluorescein diacetate (DCFH-DA). DCFH-DA (0.5 mL,1 mmol/L) was added to an aqueous solution of NaOH (2 mL,10 mmol/L) and allowed to stand at room temperature for 30min for complete hydrolysis. Then neutralized to ph=7.4 with PBS (10 mL) buffer to give a stock solution at a concentration of 40 μmol/L. The stock solution was kept under dark freezing conditions.
During the test, ir-psi (2. Mu.L, 10) as the iridium complex photosensitizer Ir-psi prepared in example 3 was added to 2mL of the activated DCFH solution -2 mol/L), the fluorescence spectrum is tested once every 5s of illumination, and the excitation wavelength is 480nm. The test results are shown in fig. 3, and can be obtained from fig. 3: as the illumination time increases, the light emission of the mixed solution of Ir-psi and DCFH is gradually enhanced at 530nm, which indicates that active oxygen is generated in the illumination process.
ESR measurement of reactive oxygen species
The specific operation steps are as follows: capturing superoxide anion radical (O) using 5, 5-dimethyl-1-pyrroline-N-oxide (DMPO) 2 ·- ) And hydroxyl radicals (. OH). Determination of O 2 ·- When the electron paramagnetic resonance signal was measured by adding DMPO (10 mmol/L) to a methanol solution of the iridium complex photosensitizer (100. Mu. Mol/L) prepared in example 3 under dark conditions, irradiating the sample with a 365nm ultraviolet torch for 1min, and then measuring the electron paramagnetic resonance signal again. In the measurement of OH, the solvent was changed to a solvent having a volume ratio of 1:1, and other testing conditions were the same. The test results are shown in fig. 4, and can be obtained from fig. 4: the electron paramagnetic resonance spectrum of Ir-psi, an iridium complex photosensitizer of Ir prepared in example 3 under illumination, showed O when methanol was used as solvent 2 ·- Is indicative of O generated during illumination 2 ·- The method comprises the steps of carrying out a first treatment on the surface of the FIG. 5 is an electron generated by singlet oxygen by Ir-psi as a photosensitizer of Ir complex prepared in example 3Paramagnetic resonance signal diagram of 2, 6-tetramethyl piperidine (TEMP) pair 1 O 2 Capturing is performed as can be obtained from fig. 5: the electron paramagnetic resonance signal diagram shows 1:1:1, indicating that a signal peak of 1 is generated 1 O 2 ；
The above results indicate that Ir-psi simultaneously produces O during light 2 ·- And 1 O 2 is a type I and type II synergistic PDT therapeutic mechanism, compared with a type II photosensitizer, the type I/II synergistic mechanism is used for treating O 2 The dependence of the light source is smaller, and the light source is more beneficial to being applied to photodynamic therapy in the anoxic environment.
Cytotoxicity test
The specific operation steps are as follows: the digested cells were treated at 5X 10 4 Density of wells/density of wells was inoculated into 96 well cell culture plates with 3 multiplex wells at 37℃and CO 2 Is cultured in an incubator with a volume concentration of 5% for 24 hours. After the cells grow into a monolayer, the culture solution is 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 with different concentration gradients is added, and the mixture is added at 37℃and CO 2 After incubation for 4h in an incubator with a 5% volume concentration, 20. Mu.L MTT solution was added to each well and incubation was continued for 4h. The culture was terminated and the in-well culture solution was carefully aspirated. 150 μl DMSO is added to each well, and the microplate reader is oscillated for 10min to dissolve the crystals sufficiently, and the OD value is determined by the microplate reader. In the phototoxicity test, after the cells are added with iridium complex photosensitizers with different concentrations for incubation for 2 hours, the cells are subjected to illumination by using a xenon lamp and then are further incubated for 2 hours, and the subsequent treatment method is consistent with the dark toxicity test. The test results are shown in fig. 5, and can be obtained from fig. 5: ir-psi, an iridium complex photosensitizer, has negligible toxicity in the absence of light. And after illumination for 5min (400-800 nm), the cell survival rate is obviously reduced. After the illumination time is prolonged to 10min, the cell viability is remarkably reduced, and when the concentration of Ir-psi serving as the iridium complex photosensitizer is only 3.125 mu mol/L, the cell viability is also reduced to 41.1%. The results show that the iridium complex photosensitizer Ir-psi has negligible cytotoxicity under dark conditions, and shows larger cytotoxicity after illumination, and the iridium complex with low concentration is illuminated when illumination time is longerThe sensitizer Ir-psi can cause obvious cell damage and has excellent photodynamic therapy effect.
Cell co-localization
The specific operation steps are as follows: heLa cells were grown in six well plates at 37℃for 24h, incubated with Ir-psi (50. Mu. Mol/L) and Mito-Tracker Green (1. Mu. Mol/L) as the iridium complex photosensitizer prepared in example 3 for 20min, then illuminated for 5min, and imaged using a confocal microscope. For Ir-psi, the iridium complex photosensitizer has an excitation wavelength of 405nm and an emission wavelength of 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, and can be obtained from fig. 6: the Pearson correlation coefficient (Pr) of Ir-psi and MTG of the iridium complex photosensitizer is 0.93. The result shows that the iridium complex photosensitizer Ir-psi mainly targets mitochondria after entering cells, so that the mitochondria are damaged firstly in the photodynamic treatment process, and the mitochondria are important organelles affecting the vital activities of the cells, thereby improving the photodynamic treatment efficiency.
In the present specification, each embodiment is described in a progressive manner, and each embodiment is mainly described in a different point from other embodiments, and identical and similar parts between the embodiments are all enough to refer 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. The iridium complex photosensitizer is characterized by comprising the following structural formula:
2. the method for preparing the iridium complex photosensitizer as set forth in claim 1, comprising the steps of:
s1, reacting 1, 10-phenanthroline-5, 6-dione, terephthalaldehyde, ammonium acetate and acetic acid, regulating the pH value of a mixed solution obtained by reaction liquid and water to be neutral to obtain a mixture, and sequentially separating, dissolving, filtering and drying the mixture to obtain a ligand fmp;
s2, under the protection gas, reacting 2, 3-trimethyl indole, 1, 3-propane sultone and o-dichlorobenzene to obtain a compound 1;
s3, under the protection gas, reacting the ligand fmp, the compound 1, the catalyst and the mixed solvent 1, mixing the reaction solution with a saturated sodium chloride solution, and sequentially separating and drying to obtain a ligand psi;
s4, irCl is added 3 ·3H 2 O, 2-phenylpyridine and the mixed solvent 2 react to obtain a compound 2;
s5, under the protection gas, reacting the compound 2, ligand psi and mixed solvent 3, removing dichloromethane, and reacting the reaction product and NH 4 PF 6 And mixing the aqueous solution with water, sequentially separating, purifying and drying to obtain the iridium complex photosensitizer.
3. The preparation method of 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 the acetic acid to the water is 54-66:220-280.
4. The preparation method according to claim 2, wherein the molar ratio of the 2, 3-trimethylindole to the 1, 3-propane sultone is 2.8-3.5:3.0-4.0; the molar volume ratio of the 2, 3-trimethylindole to the o-dichlorobenzene is 2.8-3.5 mmol/2.4-4 mL.
5. A process according to claim 3, wherein the molar ratio of ligand fmp to compound 1 is 1.0-1.5:1.8-2.4;
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;
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 is ethanol and N, N-dimethylformamide, and the volume ratio of the ethanol to the N, N-dimethylformamide is 18-22:1.
6. The process according to claim 4, wherein the IrCl is 3 ·3H 2 The mol ratio of O to 2-phenylpyridine is 1.8-2.2:4.0-6.0;
the IrCl 3 ·3H 2 The molar volume ratio of O to the mixed solvent 2 is 1.8-2.2 mmol:45-60 mL;
the mixed solvent 2 is glycol diethyl ether and water, and the volume ratio of the glycol diethyl ether to the water is 1-5:1.
7. The method of claim 6, wherein the molar ratio of compound 2 to ligand psi is 0.1-0.2:0.3-0.4;
the molar volume ratio of the compound 2 to the mixed solvent 3 is 0.1-0.2 mmol:35-45 mL;
the NH is 4 PF 6 The volume ratio of the aqueous solution to the water to the mixed solvent 3 is 4-8:24-35:35-45;
the mixed solvent 3 is dichloromethane and methanol, and the volume ratio of the dichloromethane to the methanol is 1-2:1-2.
8. The method according to claim 7, wherein the shielding gas in steps S2, S3 and S5 is independently nitrogen, argon, helium, neon or carbon dioxide;
the reaction temperature in the step S1 is 100-130 ℃ and the reaction time is 25-40 min; the reaction temperature in the step S2 is 100-140 ℃ and the reaction time is 20-30 h; the reaction temperature in the step S3 is 80-100 ℃ and the reaction time is 40-55 h; the reaction temperature in the step S4 is 120-150 ℃ and the reaction time is 20-30 h; the reaction time in 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 formulas:
10. use of an iridium complex photosensitizer as claimed in claim 1 in the manufacture of a medicament for photodynamic therapy.
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| CN111205335A (en) * | 2020-03-04 | 2020-05-29 | 兰州大学 | Iridium complex and preparation method and application thereof |
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| US9312503B2 (en) * | 2014-05-13 | 2016-04-12 | Shenzhen China Star Optoelectronics Technology Co., Ltd | Green light iridium (III) complex and a method of preparing the same |
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| JP2001270893A (en) * | 2000-03-23 | 2001-10-02 | Takeko Matsumura | Highlight fluorescent iridium complex and rapid and simple synthesis of the complex through microwave heating |
| CN101787054A (en) * | 2010-03-23 | 2010-07-28 | 上海师范大学 | Water-soluble cationic iridium complex phosphorescence probe and preparation method |
| CN103936794A (en) * | 2014-03-18 | 2014-07-23 | 上海师范大学 | Water-soluble cationic phosphorescent iridium complex, preparation method and application thereof |
| CN106188149A (en) * | 2016-07-05 | 2016-12-07 | 上海师范大学 | A kind of near-infrared metal iridium complex and its preparation method and application |
| CN111205335A (en) * | 2020-03-04 | 2020-05-29 | 兰州大学 | Iridium complex and preparation method and application thereof |
| CN113788861A (en) * | 2021-10-14 | 2021-12-14 | 山东普力强生物科技有限公司 | Metal iridium (III) complex and preparation method and application thereof |
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