CN113004186A - Zinc-ligand azapyrrolidone photo-diagnosis and treatment reagent with long-wave absorption characteristic and preparation and application thereof - Google Patents
Zinc-ligand azapyrrolidone photo-diagnosis and treatment reagent with long-wave absorption characteristic and preparation and application thereof Download PDFInfo
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- 238000010521 absorption reaction Methods 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 238000011282 treatment Methods 0.000 title claims abstract description 22
- 239000003446 ligand Substances 0.000 title claims abstract description 14
- 239000003153 chemical reaction reagent Substances 0.000 title claims abstract description 13
- 238000003745 diagnosis Methods 0.000 title claims abstract description 12
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims abstract description 32
- 229910052725 zinc Inorganic materials 0.000 claims abstract description 32
- 239000011701 zinc Substances 0.000 claims abstract description 32
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 60
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 32
- 239000000243 solution Substances 0.000 claims description 32
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 30
- 150000001875 compounds Chemical class 0.000 claims description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 14
- 238000006243 chemical reaction Methods 0.000 claims description 12
- 238000001914 filtration Methods 0.000 claims description 12
- 238000005406 washing Methods 0.000 claims description 12
- -1 cyclic alkyl alkane Chemical class 0.000 claims description 11
- 238000001035 drying Methods 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 8
- 229940125782 compound 2 Drugs 0.000 claims description 8
- 229940126214 compound 3 Drugs 0.000 claims description 8
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 6
- 239000005695 Ammonium acetate Substances 0.000 claims description 6
- 229940043376 ammonium acetate Drugs 0.000 claims description 6
- 235000019257 ammonium acetate Nutrition 0.000 claims description 6
- 229940125904 compound 1 Drugs 0.000 claims description 6
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 230000007935 neutral effect Effects 0.000 claims description 6
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 claims description 6
- ZOIORXHNWRGPMV-UHFFFAOYSA-N acetic acid;zinc Chemical compound [Zn].CC(O)=O.CC(O)=O ZOIORXHNWRGPMV-UHFFFAOYSA-N 0.000 claims description 4
- 229940125898 compound 5 Drugs 0.000 claims description 4
- 238000006482 condensation reaction Methods 0.000 claims description 4
- 230000002140 halogenating effect Effects 0.000 claims description 4
- 150000002576 ketones Chemical class 0.000 claims description 4
- 239000000463 material Substances 0.000 claims description 4
- 239000011259 mixed solution Substances 0.000 claims description 4
- 239000002994 raw material Substances 0.000 claims description 4
- 239000004246 zinc acetate Substances 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- 238000003786 synthesis reaction Methods 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 239000012467 final product Substances 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims 2
- 229940124597 therapeutic agent Drugs 0.000 claims 2
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 231100000433 cytotoxic Toxicity 0.000 claims 1
- 230000001472 cytotoxic effect Effects 0.000 claims 1
- 230000005284 excitation Effects 0.000 abstract description 6
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- 229910052751 metal Inorganic materials 0.000 abstract description 4
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- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 20
- 230000000694 effects Effects 0.000 description 15
- 239000007787 solid Substances 0.000 description 14
- 206010028980 Neoplasm Diseases 0.000 description 11
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- ZKSVYBRJSMBDMV-UHFFFAOYSA-N 1,3-diphenyl-2-benzofuran Chemical compound C1=CC=CC=C1C1=C2C=CC=CC2=C(C=2C=CC=CC=2)O1 ZKSVYBRJSMBDMV-UHFFFAOYSA-N 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 238000001228 spectrum Methods 0.000 description 5
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 238000000862 absorption spectrum Methods 0.000 description 4
- 238000010586 diagram Methods 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 238000001819 mass spectrum Methods 0.000 description 4
- 239000002184 metal Substances 0.000 description 3
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 3
- 238000001931 thermography Methods 0.000 description 3
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 238000002648 combination therapy Methods 0.000 description 2
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- 238000001840 matrix-assisted laser desorption--ionisation time-of-flight mass spectrometry Methods 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene chloride Substances ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
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- 241000282414 Homo sapiens Species 0.000 description 1
- PTFCDOFLOPIGGS-UHFFFAOYSA-N Zinc dication Chemical compound [Zn+2] PTFCDOFLOPIGGS-UHFFFAOYSA-N 0.000 description 1
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- 238000011228 multimodal treatment Methods 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses a zinc ligand azapyrrolidone photo-diagnosis and treatment reagent with long wave absorption characteristics, and preparation and application thereof. The light diagnosis and treatment reagent consists of a metal center and an azapyrrolidone auxiliary ligand, the whole preparation process is simple, and the prepared complex has longer absorption wavelength which can be prolonged along with the change of the azapyrrolidone auxiliary ligand, so that the light diagnosis and treatment reagent has deeper tissue penetration depth in the field of living body application; can be excited by near infrared light and has near infrared light emission, thereby reducing the damage of the excitation light source to the biological sample; the complex can be used in the field of photodynamic photo-thermal combined treatment guided by biological imaging, and has important application prospect.
Description
Technical Field
The invention belongs to the technical field of organic photoelectric and biological materials. In particular to a zinc-dipyrazone-based photo-diagnosis and treatment reagent with a near-infrared absorption function, a preparation method thereof, and applications thereof in the fields of fluorescence imaging, photo-thermal imaging, photo-acoustic imaging, photodynamic and photo-thermal combined treatment and the like.
Background
The tumor is a disease with high fatality rate and seriously threatens the health of human beings. Traditional tumor treatment methods, such as surgery, chemotherapy, radiotherapy and the like, have certain effect on tumor treatment, but are often accompanied by side effects in the implementation process. In contrast, photodynamic and photothermal combined therapy is increasingly favored as a non-invasive, non-toxic, targeted and efficient tumor treatment means, and the therapy can accurately treat tumor parts in real time, so that the tumor treatment effect is greatly improved. The selection of the photodynamic and photothermal combined treatment material has a decisive effect on the effect of the photodynamic and photothermal combined treatment. Therefore, how to select the ideal photodynamic and photothermal combined therapy material has attracted extensive attention in the industry.
Metal complexes have been widely used in multimodal tumor therapy in recent years. However, due to the short absorption wavelength of the metal complex, additional compounds are required to be introduced to achieve multimodal treatment, and most of the metal complexes used for tumor treatment are mostly prepared from noble metals. Therefore, the metal complex has the defects of low penetration depth, complex preparation process and high price in the field of tumor treatment, and further expansion and application of the material in the field of tumor treatment are severely restricted. Therefore, the development of novel inexpensive metal complexes having long-wavelength absorption and simultaneously having a multimodal therapeutic function is the focus of research.
The azapyrrolidone dye can be coordinated with zinc ions due to a proper NN ligand, and is used in the fields of biological marking, imaging, photodynamic therapy and the like, so far, the design and synthesis of the zinc-coordinated azapyrrolidone dye with good photothermal effect by utilizing effective theoretical guidance are rarely reported. Based on the theoretical guidance of photoinduced electron transfer and the excellent performance of the aza-fluoroborane dye, the invention connects electron donating groups to the aza-pyrrolidone dye with near infrared absorption, thereby leading the dye to have good photoacoustic imaging, photothermal imaging and photothermal treatment effect of biological tumors. The zinc-coordinated azapyrrolidone dye can also form a molecular structure with high photodynamic effect of a D-A-D structure through intramolecular charge transfer.
Disclosure of Invention
The invention aims to solve the defects in the prior art and provides a zinc-azapyrrolidone diagnosis and treatment reagent with long-wave absorption characteristics and a preparation method and application thereof.
The technical scheme of the invention is as follows: a zinc ligand azapyrrolidone photo-diagnosis reagent with long wave absorption characteristic has the following structural general formula:
wherein R is1、R2、R4、R5Is any one of the following: :
wherein R is3Is H or a linear, branched or cyclic alkyl alkane having 1 to 16 carbon atoms;
wherein, X1、X2Is H, Cl, Br or I.
The preparation route of the zinc-aza-pyrrolidone photo-diagnosis reagent with the long-wave absorption characteristic is as follows:
the specific synthesis steps are as follows:
1)R1aldehyde of (A) with R2Dissolving the ketone in methanol solution, carrying out aldehyde ketone condensation reaction in the presence of NaOH, adjusting the pH value to be neutral, filtering to remove the methanol solvent, and washing to obtain a compound 1;
2) reacting the compound 1 with nitromethane and diethylamine in methanol for a certain time, removing the solvent by spin-drying, dissolving in ethanol, filtering and washing to obtain a compound 2;
3) dissolving the compound 2 in n-butyl alcohol solution, adding ammonium acetate, stirring for reaction for a period of time, distilling under reduced pressure to remove n-butyl alcohol, and washing with cold ethanol to obtain a compound 3;
4) dissolving the compound 3 in a chloroform solution, and sequentially adding acetic acid and a halogenating raw material to obtain a compound 4;
5)R5aldehyde of (A) with R4Dissolving the ketone in methanol solution, carrying out aldehyde ketone condensation reaction in the presence of NaOH, adjusting the pH value to be neutral, filtering to remove the methanol solvent, and washing to obtain a compound 5;
6) reacting the compound 5 with nitromethane and diethylamine in methanol for a certain time, removing the solvent by spin-drying, dissolving in ethanol, filtering and washing to obtain a compound 6;
7) dissolving the compound 6 in n-butyl alcohol solution, adding ammonium acetate, stirring for reaction for a period of time, distilling under reduced pressure to remove n-butyl alcohol, and washing with cold ethanol to obtain a compound 7;
8) dissolving the compound 7 in a chloroform solution, and sequentially adding acetic acid and a halogenating raw material to obtain a compound 8;
9) dissolving the compound 4 and the compound 8 in a mixed solution of acetic acid, methanol and water, then adding zinc acetate, stirring at room temperature, and spin-drying the reaction solution to obtain the final product of zinc-aza-pyrrolidone.
Further, in step 9), the molar ratio of compound 4 to compound 8 is 1: 1.
Further, in the step 9), the volume ratio of acetic acid, methanol and water is 3:1: 1.
The zinc-ligand azapyrrolidone photo-diagnosis reagent with the long-wave absorption characteristic can generate singlet oxygen with cytotoxicity through laser irradiation; the light diagnosis and treatment reagent has longer absorption wavelength and can be used for biological fluorescence imaging, biological photothermal imaging, biological photoacoustic imaging and time resolution imaging.
The invention has the beneficial effects that:
the zinc-nitrogen-doped pyrrolidone complex disclosed by the invention has long-wave absorption, so that the zinc-nitrogen-doped pyrrolidone complex can have deeper tissue penetration depth in the field of living body application;
the zinc-ligand azapyrrolidone complex disclosed by the invention can be excited by near infrared light and has near infrared light emission, so that the damage of an excitation light source to a biological sample can be reduced;
the zinc ligand azapyrrolidone complex disclosed by the invention can be applied to biological imaging and photothermal and photodynamic combined treatment and has better photothermal and photodynamic effects.
Drawings
FIG. 1 is a mass spectrum of ZnDipy-1, a zinc complex prepared in example one;
FIG. 2 is a nuclear magnetic hydrogen spectrum of ZnDipy-1, a zinc complex prepared in the first example;
FIG. 3 is a UV-VIS absorption spectrum of the zinc complex ZnDipy-1 prepared in the first example;
FIG. 4 is a photothermal diagram of the zinc complex ZnDipy-1 prepared in example one;
FIG. 5 is a photodynamic diagram of the zinc complex ZnDipy-1 prepared in example one;
FIG. 6 is a mass spectrum of ZnDipy-2, a zinc complex prepared in example two;
FIG. 7 is a nuclear magnetic hydrogen spectrum of the zinc complex ZnDipy-2 prepared in example two;
FIG. 8 is a UV-VIS absorption spectrum of the zinc complex ZnDipy-2 prepared in example two;
FIG. 9 is a photothermographic view of the zinc complex ZnDipy-2 prepared in example two;
FIG. 10 is a photodynamic diagram of the zinc complex ZnDipy-2 prepared in example two.
Detailed Description
The following examples further illustrate the present invention but are not to be construed as limiting the invention. Modifications and substitutions to methods, procedures, or conditions of the invention may be made without departing from the spirit of the invention.
The first embodiment is as follows: preparation of zinc-nitrogen-doped pyrrolidone complex with long-wave absorption performance
1. Preparation of azapyrrolidone ancillary ligands
Preparation of compound 2: compound 1(26mmol) and benzaldehyde (26mmol) were dissolved in sodium methoxide solution, followed by addition of 50% by mass aqueous NaOH solution, stirring at room temperature for reaction for 22 hours, pH was adjusted to neutral, and methanol solvent was removed by filtration to give pale yellow solid powder, which was then washed three times with water to remove salts to give white product 2. Yield: 91 percent.
1H NMR(400MHz,CDCl3)δ(ppm):8.01(d,J＝8.4Hz,2H),7.78(d,J＝16.4Hz,1H),7.53(d,J＝8.4Hz,2H),7.35(d,J＝16.4Hz,2H),6.98(d,J＝8.4Hz,2H),6.69(d,J＝8.4Hz,2H),3.66(s,6H).13C NMR(100MHz,CDCl3)δ(ppm):188.85,169.10,162.20,151.91,144.95,131.97,130.49,130.27,122.82,116.63,114.27.
Preparation of compound 3: after 10mL of diethylamine and 15mL of nitromethane were added to a methanol solution of Compound 2(5mmol), and heated under reflux for 24 hours, the solvent was removed by rotary drying and the solid was dissolved in 30mL of ethanol, and a large amount of white solid precipitated, which was obtained by filtration and washed three times with diethyl ether and water to obtain white solid 3. Yield: 83 percent.
1H NMR(400MHz,CDCl3)δ(ppm):8.01(d,J＝8.8Hz,2H),7.78(d,J＝15.2Hz,1H),7.55(d,J＝8.8Hz,2H),7.35(d,J＝15.6Hz,2H),6.98(d,J＝8.8Hz,2H),6.69(d,J＝8.8Hz,2H),4.81–4.60(m,2H),4.18–4.11(m,1H),3.68(s,6H),.13C NMR(100MHz,CDCl3)δ(ppm):188.85,162.20,151.91,144.95,131.97,130.49,130.27,122.82,116.63,111.83,71.92,70.81.
Preparation of compound 4: compound 3(2.50mmol) and 20g ammonium acetate were dissolved in n-butanol solution, stirred at 120 ℃ and refluxed overnight, after the reaction was completed, n-butanol was distilled off under reduced pressure, and the remaining solid was washed with cold ethanol to give a black solid 4. The yield was 69%.
2. Preparation of zinc complex azapyrrolidone complex ZnDipy-1
Preparation of compound ZnDipy-1: compound 4(1.00mmol) was dissolved in acetic acid: methanol: to the mixed solution of 3:1:1 water, zinc acetate (15.0mmol) was added thereto, followed by stirring at room temperature for 48 hours. And finally, spin-drying the reaction solution, and passing through a column to obtain a black solid ZnDipy-1.
1H NMR(400MHz,CDCl3)δ(ppm):7.95(d,J＝7.2Hz,8H),7.46(d,J＝8.8Hz,8H),7.40(t,J＝7.4Hz,8H),7.32(t,J＝6.6Hz,4H),6.71(s,4H),6.39(d,J＝8.8Hz,8H),2.69(s,24H).[m/e](M, MALDI-TOF) theoretical value: 1134.75, experimental value: 1134.60.
And (4) relevant performance test:
1. the mass spectrum of the zinc complex ZnDipy-1 is shown in figure 1.
2. The hydrogen nuclear magnetic resonance spectrum of the zinc complex ZnDipy-1 is shown in figure 2.
3. And (3) testing the absorption spectrum of the zinc complex ZnDipy-1:
the concentration of the spectrum test used was 10. mu.M, and the test solvent was CH2Cl2The excitation wavelength of the solution of (1) is 667 (7) when the emission spectrum is measured53)nm。
The ultraviolet-visible absorption spectrum of the zinc complex ZnDipy-1 is shown in FIG. 3.
The complex shows stronger absorption in 400-500nm of ultraviolet region and 600-800nm of near infrared region, especially the complex can be excited by near infrared light, and the damage of the excitation light source to cells is greatly reduced when cell imaging experiments are performed.
Photothermal effect test of ZnDipy-1
ZnDipy-1 prepared in example 1 was dissolved in THF, diluted to different concentration gradients (0, 5, 10. mu.M) in PBS buffer at pH 7.4 and irradiated with a 660nm laser for 6min (0.4W/cm)2) And recording the change of the solution temperature at different time and different concentration by using a photo-thermal imaging instrument. The photothermal diagram of the zinc complex ZnDipy-1 is shown in figure 4, and the graph 4 shows that the maximum change of the solution temperature reaches 25 ℃ along with the increase of the concentration, so that the zinc complex ZnDipy-1 has better photothermal effect.
Photodynamic effect of ZnDipy-1
The ZnDipy-1 prepared in example 1 was dissolved in THF, the singlet oxygen generation was demonstrated with the singlet oxygen indicator DPBF, the 660nm laser was used for irradiation for different times, and the changes in the absorption peaks of the DPBF at different irradiation times (0min, 1min, 2min, 3min, 4min, 5min, 6min, 7min, 8min, 9min) were recorded by UV-visible spectroscopy. The photodynamic graph of the zinc complex ZnDipy-1 is shown in FIG. 5, and FIG. 5 shows that the indicator DPBF is consumed as the irradiation time is prolonged, thus demonstrating the generation of singlet oxygen.
EXAMPLE two preparation of a Zinc Diazapyrrolidone Complex with Long wavelength absorption Properties
1. Preparation of azapyrrolidone ancillary ligands
Preparation of compound 2: after compound 1(26mmol) and acetophenone (26mmol) were dissolved in sodium methoxide solution and then 50% by mass aqueous NaOH solution was added and stirred at room temperature for reaction for 22 hours, the pH was adjusted to neutral, the methanol solvent was removed by filtration to give pale yellow solid powder, which was then washed three times with water to remove salts to give white product 2. Yield: 91 percent.
1H NMR(400MHz,CDCl3)δ(ppm):7.93(d,J＝8.4Hz,2H),7.62(d,J＝16.4Hz,1H),7.44(d,J＝8.4Hz,2H),7.31(d,J＝16.4Hz,2H),6.90(d,J＝8.4Hz,2H),6.64(d,J＝8.4Hz,2H),3.76(s,6H).13C NMR(100MHz,CDCl3)δ(ppm):189.43,170.22,164.11,150.83,143.11,132.56,131.88,131.00,124.50,118.17,112.45.
Preparation of compound 3: after 10mL of diethylamine and 15mL of nitromethane were added to a methanol solution of Compound 2(5mmol), and heated under reflux for 24 hours, the solvent was removed by rotary drying and the solid was dissolved in 30mL of ethanol, and a large amount of white solid precipitated, which was obtained by filtration and washed three times with diethyl ether and water to obtain white solid 3. Yield: 83 percent.
1H NMR(400MHz,CDCl3)δ(ppm):8.15(d,J＝8.8Hz,2H),7.90(d,J＝15.2Hz,1H),7.63(d,J＝8.8Hz,2H),7.44(d,J＝15.6Hz,2H),7.02(d,J＝8.8Hz,2H),6.80(d,J＝8.8Hz,2H),4.73–4.48(m,2H),4.07–3.99(m,1H),3.60(s,6H).13C NMR(100MHz,CDCl3)δ(ppm):189.76,166.33,154.22,146.61,133.54,130.27,123.95,115.90,113.64,110.80,72.41,71.04.
Preparation of compound 4: compound 3(2.50mmol) and 20g ammonium acetate were dissolved in n-butanol solution, stirred at 120 ℃ and refluxed overnight, after the reaction was completed, n-butanol was distilled off under reduced pressure, and the remaining solid was washed with cold ethanol to give a black solid 4. The yield was 69%.
2. Preparation of zinc complex azapyrrolidone complex ZnDipy-2
Preparation of compound ZnDipy-2: compound 4(1.00mmol) was dissolved in acetic acid: methanol: to the mixed solution of 3:1:1 water, zinc acetate (15.0mmol) was added thereto, followed by stirring at room temperature for 48 hours. And finally, spin-drying the reaction solution, and passing through a column to obtain a black solid ZnDipy-2.
1H NMR(400MHz,CDCl3)δ(ppm):7.90(d,J＝8.8Hz,8H),7.50(d,J＝6.4Hz,8H),7.10–7.01(m,12H),6.82(d,J＝8.4Hz,8H),6.60(s,4H),3.10(s,24H).[m/e](M, MALDI-TOF) theoretical value: 1134.75, experimental value: 1132.44.
Correlation performance testing
1. The mass spectrum of the zinc complex ZnDipy-2 is shown in FIG. 6.
2. The nuclear magnetic hydrogen spectrum of the zinc complex ZnDipy-2 is shown in FIG. 7.
3. Absorption spectrum test of zinc complex ZnDipy-2
The concentration of the spectrum test adopted by the invention is 10 mu M, and the test solvent is CH2Cl2The excitation wavelength of the solution of (1) is 632nm when the emission spectrum is measured.
The ultraviolet-visible absorption spectrum of the zinc complex ZnDipy-2 is shown in FIG. 8.
The complex shows stronger absorption in 400-500nm of ultraviolet region and 600-800nm of near infrared region, especially the complex can be excited by near infrared light, and the damage of the excitation light source to cells is greatly reduced when cell imaging experiments are performed.
Testing of photothermal Effect of ZnDipy-2
ZnDipy-2 prepared in example 2 was dissolved in THF, diluted to different concentration gradients (0, 20, 40. mu.M) in PBS buffer at pH 7.4 and irradiated with a 635nm laser for 6min (0.5W/cm)2) And recording the change of the solution temperature at different time and different concentration by using a photo-thermal imaging instrument. The photothermal graph of the zinc complex ZnDipy-2 is shown in FIG. 9, and the graph in FIG. 9 shows that the maximum change of the solution temperature is as high as 24 ℃ along with the increase of the concentration, so that the solution has better photothermal effect.
And 5, testing the photodynamic effect of ZnDipy-2.
ZnDipy-2 prepared in example 2 was dissolved in THF, singlet oxygen generation was demonstrated with the singlet oxygen indicator DPBF, and changes in the absorption peak of DPBF at different irradiation times (0s, 10s, 20s, 30s, 40s, 50s, 60s, 70s, 80s) were recorded by UV-visible spectroscopy at different times of irradiation with 660nm laser irradiation. The photodynamic graph of the zinc complex ZnDipy-2 is shown in FIG. 10. As shown in fig. 10, the indicator DPBF was consumed with the increase of the irradiation time, demonstrating the generation of singlet oxygen.
The foregoing illustrates and describes the principles, general features, and advantages of the present invention. However, the above description is only an example of the present invention, the technical features of the present invention are not limited thereto, and any other embodiments that can be obtained by those skilled in the art without departing from the technical solution of the present invention should be covered by the claims of the present invention.
Claims (6)
1. The zinc ligand azapyrrolidone photo-diagnosis and treatment reagent with the long-wave absorption characteristic is characterized by comprising the following structural general formula:
wherein R is1、R2、R4、R5Is any one of the following structures:
wherein R is3Is H or a linear, branched or cyclic alkyl alkane having 1 to 16 carbon atoms;
wherein, X1、X2Is H, Cl, Br or I.
2. The preparation method of zinc-diazapyradone photodiagnostic reagent with long-wave absorption characteristic as claimed in claim 1, wherein the specific synthetic route is as follows:
3. the preparation method of zinc-ligand azapyrrolidone photo-therapeutic agent with long-wave absorption characteristic as claimed in claim 2, wherein the specific synthesis steps are as follows:
1)R1aldehyde of (A) with R2Dissolving ketone in sodium methoxide solution, carrying out aldehyde ketone condensation reaction in the presence of NaOH, adjusting the pH to be neutral, filtering to remove methanol solvent, and washing to obtain a compound 1;
2) reacting the compound 1 with nitromethane and diethylamine in methanol for a certain time, removing the solvent by spin-drying, dissolving in ethanol, filtering and washing to obtain a compound 2;
3) dissolving the compound 2 in n-butyl alcohol solution, adding ammonium acetate, stirring for reaction for a period of time, distilling under reduced pressure to remove n-butyl alcohol, and washing with cold ethanol to obtain a compound 3;
4) dissolving the compound 3 in a chloroform solution, and sequentially adding acetic acid and a halogenating raw material to obtain a compound 4;
5)R5aldehyde of (A) with R4Dissolving ketone in sodium methoxide solution, carrying out aldehyde ketone condensation reaction in the presence of NaOH, adjusting the pH value to be neutral, filtering to remove methanol solvent, and washing to obtain a compound 5;
6) reacting the compound 5 with nitromethane and diethylamine in methanol for a certain time, removing the solvent by spin-drying, dissolving in ethanol, filtering and washing to obtain a compound 6;
7) dissolving the compound 6 in n-butyl alcohol solution, adding ammonium acetate, stirring for reaction for a period of time, distilling under reduced pressure to remove n-butyl alcohol, and washing with cold ethanol to obtain a compound 7;
8) dissolving the compound 7 in a chloroform solution, and sequentially adding acetic acid and a halogenating raw material to obtain a compound 8;
9) dissolving the compound 4 and the compound 8 in a mixed solution of acetic acid, methanol and water, then adding zinc acetate, stirring at room temperature, and spin-drying the reaction solution to obtain the final product of zinc-aza-pyrrolidone.
4. The method for preparing a zinc gametophytic aza-pyrrolidone having long-wave absorption characteristics as claimed in claim 3, wherein the molar ratio of the compound 4 to the compound 8 in the step 9) is 1: 1.
5. The method for preparing a zinc gametophytic aza-pyrrolidone photo-therapeutic agent with long wave absorption characteristics as claimed in claim 3, wherein in the step 9), the volume ratio of acetic acid, methanol and water is 3:1: 1.
6. The zinc gametophytic agent having long wave absorption properties of claim 1 wherein the material produces cytotoxic singlet oxygen upon laser irradiation.
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| R.T. KUZNETSOVA等: "Photonics of boron(III) and zinc(II) dipyrromethenates as active media for modern optical devices", 《JOURNAL OF MOLECULAR LIQUIDS》 * |
| THOMAS S. TEETS 等: "Homoleptic, Four-Coordinate Azadipyrromethene Complexes of d10 Zinc and Mercury", 《INORG. CHEM.》 * |
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