CN111635389A - Hydrogen peroxide responsive compound for imaging and therapy and synthesis method thereof - Google Patents
Hydrogen peroxide responsive compound for imaging and therapy and synthesis method thereof Download PDFInfo
- Publication number
- CN111635389A CN111635389A CN202010378023.1A CN202010378023A CN111635389A CN 111635389 A CN111635389 A CN 111635389A CN 202010378023 A CN202010378023 A CN 202010378023A CN 111635389 A CN111635389 A CN 111635389A
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- hydrogen peroxide
- compound
- imaging
- dichloromethane
- responsive compound
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- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 title claims abstract description 154
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- 238000003384 imaging method Methods 0.000 title claims abstract description 39
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- 238000001308 synthesis method Methods 0.000 title abstract description 9
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims abstract description 48
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- 238000000034 method Methods 0.000 claims abstract description 13
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Abstract
The invention discloses a hydrogen peroxide responsive compound for imaging and therapy and a synthesis method thereof. The chemical structure of the responsive compound is shown in the following figure. The invention also provides a synthesis method of the hydrogen peroxide responsive compound, which comprises the following steps: reacting a monohydroxy compound with oxalyl chloride in an organic solvent containing an acid-binding agent to obtain the hydrogen peroxide responsive compound. The synthesis method of the responsive compound is simple and easy for large-scale synthesis; the nano particles can be prepared by different methods, and the auxiliary chemiluminescence property of the nano particles has hydrogen peroxide responsiveness; when the monohydroxy compound is a micromolecular drug, a hydrogen peroxide responsive prodrug can be obtained and used for preparing nano-drugs for treating inflammation, oxidative stress injury related diseases and hydrogen peroxide high-expression tumor prevention and treatment; the hydrogen peroxide responsive compound has good in-vivo safety.
Description
Technical Field
The invention relates to the field of hydrogen peroxide responsive materials, in particular to a hydrogen peroxide responsive compound with auxiliary chemiluminescence imaging and treatment functions and a synthesis method thereof.
Background
When stimulated by growth factors or immune stimulation, cells produce endogenous hydrogen peroxide1. The hydrogen peroxide has lipophilicity, is easy to pass through cell membranes to realize intercellular diffusion, is used as a second chemical messenger in cells, and plays an important role in regulating physiological reactions such as cell proliferation, differentiation, migration and the like2-3. In addition, hydrogen peroxide is also involved in cellular redox signaling4Regulating the normal physiological functions of the body, and is closely related to the occurrence and development of various diseases, including angiogenesis, oxidative stress, aging, tumor and the like5. During the course of the disease, the expression and activity of hydrogen peroxide affect the pathophysiological changes of the disease, and therefore, studies on the diagnosis and treatment of diseases by means of hydrogen peroxide-responsive materials are receiving increasing attention6-11。
A peroxyoxalate ester chemiluminescence system is a chemiluminescence system mainly composed of diaryl oxalate, hydrogen peroxide, fluorescent agent and solvent12. The light-emitting mechanism is that chemical energy is transferred to fluorophore to transfer to excited state, and the excited state is transferred to ground state to emit light of certain wavelength13. The luminescent system is mainly applied in two aspects: detection application in analytical chemistry and development of chemical cold light source14. The peroxyoxalate ester compound is a small molecular substance sensitive to hydrogen peroxide, when the peroxyoxalate ester compound reacts with the hydrogen peroxide, an oxalate ester bond can be broken to generate intermediate and raw material molecules, and the intermediate can excite a dye to emit light for imaging15The responsiveness can be used for preparing a hydrogen peroxide responsive disease imaging diagnosis material or a hydrogen peroxide responsive drug release material16-18Thereby being applied to the treatment of inflammation, oxidative stress injury and tumor related diseases19-22. However, the in vivo safety of the products of hydrolysis of currently available peroxyoxalate compounds severely limits their use in disease imaging and therapy; meanwhile, the existing peroxy oxalate compounds can only be used for auxiliary chemiluminescence imaging and have no disease treatment function.
Disclosure of Invention
In view of the above-mentioned deficiencies of the prior art, it is a first object of the present invention to provide a hydrogen peroxide-responsive compound having a function of assisting in chemiluminescent imaging and therapy. Another object of the present invention is to provide a method for synthesizing the hydrogen peroxide-responsive compound.
In order to achieve the first object, the invention adopts the technical scheme that: a hydrogen peroxide responsive compound, the chemical structure general formula of which is as follows
Wherein:
in order to achieve the second object, the invention adopts the technical scheme that: the invention provides a synthesis method of a hydrogen peroxide responsive compound, which comprises the following steps: mixing a single hydroxyl compound and an acid-binding agent in an organic solvent, slowly dropwise adding oxalyl chloride into the solution under the ice bath condition under the protection of nitrogen, removing the ice bath after dropwise adding, reacting for 2-12h, adding methanol or ethanol after the raw materials completely react, and quenching the reaction to obtain a crude product of the hydrogen peroxide responsive compound.
In order to further purify the crude product to obtain a final product, the synthesis method of the invention further comprises the following steps: extracting the crude product with dichloromethane/water system for 3 times, collecting dichloromethane solution, extracting with saturated sodium chloride water solution for 1 time, drying the organic phase with anhydrous magnesium sulfate to remove excessive water, vacuum filtering, evaporating to remove dichloromethane, concentrating to obtain crude product, and separating and purifying with silica gel chromatographic column to obtain final product.
Further, the monohydroxy compound is selected from tocopherol, idebenone, camptothecin, zidovudine, 4-hydroxymethylphenylboronic acid pinacol ester, 4-hydroxy-2, 2,6, 6-tetramethylpiperidine nitroxide, 3-methoxy-4-hydroxybenzaldehyde, 4-methoxymethylphenol, 4-ethoxymethylphenol, amyl salicylate, (E) -3, 5-dimethoxy-4' -hydroxystilbene or 2, 4-dinitrophenol.
Further, the acid-binding agent is selected from N, N-diisopropylethylamine or triethylamine.
Further, the organic solvent is dichloromethane.
Further, the concentration of the monohydroxy compound in the organic solvent is between 0.1mmol/ml and 0.4 mmol/ml.
Further, the molar ratio of the monohydroxy compound to the oxalyl chloride is between 1:0.5 and 1:1, and the molar ratio of the monohydroxy compound to the acid-binding agent is between 1:2 and 1: 5.
The technical scheme of the invention also comprises the application of the hydrogen peroxide responsive compound in preparing a medicament and/or an imaging probe for preventing and treating diseases related to inflammation and/or oxidative stress injury.
The inflammation includes allergic inflammation, non-specific inflammation, and infectious inflammation; the nonspecific inflammation comprises red swelling and pain caused by trauma or operation; infectious inflammation includes inflammation caused by bacteria, bacterial products or viruses; allergic inflammation includes inflammatory diseases such as peritonitis, inflammatory bowel disease, arthritis, asthma, atherosclerosis, and non-alcoholic fatty liver disease.
The oxidative stress injury comprises acute heart injury, acute lung injury, acute/chronic liver injury, acute/chronic kidney injury, and acute/chronic intestinal tract injury.
Wherein the hydrogen peroxide-responsive compound is administered by a route selected from the group consisting of oral, intravenous, subcutaneous, intramuscular, and any combination thereof.
By combining the technical scheme, the invention has the beneficial technical effects that:
(1) the responsive compound is simple and convenient in synthesis method, when the selected compound is the monohydroxy active compound, the reaction site is single, namely one equivalent of oxalyl chloride is combined with two equivalents of monohydroxy active compound, the target compound is obtained by room temperature reaction, the condition is mild, and the scale synthesis is easy.
(2) The responsive compounds have significant and sensitive hydrogen peroxide dependent hydrolysis characteristics.
(3) The responsive compounds can be hydrolyzed in the presence of physiological levels of reactive oxygen species to the corresponding starting compounds.
(4) The responsive compound can be prepared into hydrogen peroxide responsive nanoparticles by different methods, and can effectively load fluorescent dye, so that the luminescent imaging nanoprobes with different self-luminescent wavelengths can be conveniently obtained.
(5) The nanoparticles prepared from the responsive compound can effectively load hydrophobic nano-drugs and realize the responsive release of hydrogen peroxide loaded with the drugs.
(6) When the responsive compound is synthesized by selecting the hydroxyl-containing drug, the hydrogen peroxide responsive prodrug can be conveniently prepared, and hydrogen peroxide responsive prodrug nanoparticles are prepared by adopting different methods, so that hydrogen peroxide responsive activation and release of the corresponding drug are realized.
(7) The nanoparticles prepared from the responsive compound have good in-vivo safety.
(8) When the obtained responsive compound is a solid, recrystallization can be used for removing impurities in the purification process, so that the silica gel chromatographic column is not used for separation and purification, and the method is easy to realize industrial production.
Drawings
FIG. 1 is a reaction of tocopherol with hydrogen peroxide responsive tocopherol compounds in deuterated chloroform, obtained by reacting tocopherol with oxalyl chloride1And H NMR spectrum, and the structural correctness is confirmed according to the spectrum.
FIG. 2 is mass spectral data of a compound having a hydrogen peroxide-responsive tocopherol obtained by reacting tocopherol with oxalyl chloride.
FIG. 3 is a graph of light intensity measurements of 0.5mM hydrogen peroxide-responsive tocopherol compound and 0.5mM sulforhodamine 101 under stimulation with different concentrations of hydrogen peroxide; as can be seen, the luminous intensity increases as the hydrogen peroxide concentration increases.
FIG. 4 is a graph showing the luminous intensity test of 0.5mM hydrogen peroxide-responsive tocopherol compound and 0.5mM 1-chloro-9, 10-diphenylethynylanthracene under different concentrations of hydrogen peroxide, and it can be seen that the luminous intensity increases with increasing hydrogen peroxide concentration, and has concentration dependence.
Fig. 5 is a photograph of a sample, a particle size distribution diagram, and a transmission electron microscope photograph of nanoparticles prepared from the hydrogen peroxide-responsive tocopherol compound, the average particle size of which is 188 nm.
Fig. 6 is a graph showing that the sulforhodamine 101 nanoparticle encapsulated by the hydrogen peroxide-responsive tocopherol compound stimulates the light-responsive measurement to different types of active oxygen, and the nanoparticle has selective response to hydrogen peroxide.
Fig. 7 is an imaging diagram of a pore plate with the luminescent responsiveness of hydrogen peroxide-responsive tocopherol compound-loaded 1-chloro-9, 10-diphenylethynyl anthracene nanoparticles to hydrogen peroxide with different concentrations, and it can be seen from the graph that the luminescent intensity of the nanoparticles increases with the increase of the hydrogen peroxide concentration, and the nanoparticles have concentration dependence.
Fig. 8 is an imaging diagram of a pore plate of a hydrogen peroxide-responsive tocopherol compound-loaded 1-chloro-9, 10-diphenylethynyl anthracene nanoparticle in mouse peritoneal neutrophils, wherein the luminous intensity of the nanoparticle is gradually enhanced along with the increase of the number of the neutrophils, and the imaging of the nanoparticle has neutrophil responsiveness.
FIG. 9 shows imaging functional verification of hydrogen peroxide-responsive tocopherol compound-loaded 1-chloro-9, 10-diphenylethynyl anthracene nanoparticles in thioglycollate-induced peritonitis in mice.
Fig. 10 shows imaging functional verification of hydrogen peroxide-responsive tocopherol compound-loaded 1-chloro-9, 10-diphenylethynyl anthracene nanoparticles in alcohol-induced liver injury in mice.
Fig. 11 is an imaging functional test of hydrogen peroxide-responsive tocopherol compound-loaded 1-chloro-9, 10-diphenylethynyl anthracene nanoparticles in subcutaneous tumors.
Detailed Description
The present invention will be described in further detail with reference to specific embodiments. It is to be understood that the embodiments of the present invention are merely for illustrating the present invention and not for limiting the present invention, and that various substitutions and alterations made according to the common knowledge and conventional means in the art without departing from the technical idea of the present invention are included in the scope of the present invention.
Example 1
Under the protection of nitrogen, 4mmol of tocopherol and 20mmol of N, N-diisopropylethylamine are dissolved and mixed in 20mL of anhydrous dichloromethane, 2mmol of oxalyl chloride is slowly dropped under the condition of ice bath, the ice bath is removed after the dropping, the reaction is carried out for 2h at 25 ℃, the reaction process is monitored by a thin-layer chromatographic plate, and methanol is added after the raw materials completely react to quench the reaction. The obtained crude product is extracted by a dichloromethane/water system for 3 times (namely 100mL of dichloromethane is used for dissolving the crude product, the crude product is transferred to a 250mL separating funnel, 15mL of distilled water is added for washing for 3 times), the solution in dichloromethane is collected, then saturated sodium chloride aqueous solution is used for extracting for 1 time, an organic phase is dried by anhydrous magnesium sulfate to remove excessive water in a sample, the organic phase obtained by suction filtration is removed by a rotary evaporator, and dichloromethane is concentrated to obtain the crude product. Concentrating the crude product, and subjecting to silica gel chromatographyThe product (M) was obtained by eluting with ethyl acetate/n-hexane (volume ratio 1/10)1)1.6 g, yield 86%.
Example 2
Under the protection of nitrogen, 4mmol of tocopherol and 20mmol of triethylamine are dissolved and mixed in 20mL of anhydrous dichloromethane, 4mmol of oxalyl chloride is slowly dropped under the condition of ice bath, the ice bath is removed after the dropping, the mixture reacts for 12 hours at 25 ℃, the reaction process is monitored by a thin-layer chromatography plate, and methanol is added after the raw materials completely react to quench the reaction. Extracting the obtained crude product with dichloromethane/water system for 3 times, collecting dichloromethane solution, extracting with saturated sodium chloride water solution for 1 time, drying the organic phase with anhydrous magnesium sulfate to remove excessive water in the sample, vacuum filtering to obtain organic phase, removing dichloromethane with rotary evaporator, and concentrating to obtain crude product. The crude product obtained is concentrated and chromatographed on a silica gel column eluting with ethyl acetate/n-hexane (volume ratio 1/10) to give the product (M)1)1.2 g, yield 66%.
Example 3
Under the protection of nitrogen, 4mmol of tocopherol and 20mmol of N, N-diisopropylethylamine are dissolved and mixed in 40mL of anhydrous dichloromethane, 3mmol of oxalyl chloride is slowly dropped under the condition of ice bath, the ice bath is removed after the dropping, the reaction is carried out for 3h at 25 ℃, the reaction process is monitored by a thin-layer chromatographic plate, and methanol is added after the raw materials completely react to quench the reaction. Extracting the obtained crude product with dichloromethane/water system for 3 times, collecting dichloromethane solution, extracting with saturated sodium chloride water solution for 1 time, drying the organic phase with anhydrous magnesium sulfate to remove excessive water in the sample, vacuum filtering to obtain organic phase, removing dichloromethane with rotary evaporator, and concentrating to obtain crude product. The crude product obtained is concentrated and chromatographed on a silica gel column eluting with ethyl acetate/n-hexane (volume ratio 1/10) to give the product (M)1)1.5 g, 83% yield.
Example 4
Under the protection of nitrogen, 4mmol of tocopherol and 20mmol of N, N-diisopropylethylamine are dissolved and mixed in 10mL of anhydrous dichloromethane, 2mmol of oxalyl chloride is slowly dripped under the condition of ice bath, the ice bath is removed after the dripping is finished, the reaction is carried out for 2h at 25 ℃, a thin-layer chromatographic plate is used for monitoring the reaction process, and ethanol is added after the raw materials are completely reacted to quench the reaction. The crude product obtainedExtracting with dichloromethane/water system for 3 times, collecting dichloromethane solution, extracting with saturated sodium chloride water solution for 1 time, drying the organic phase with anhydrous magnesium sulfate to remove excessive water in the sample, vacuum filtering to obtain organic phase, removing dichloromethane with rotary evaporator, and concentrating to obtain crude product. The crude product obtained is concentrated and chromatographed on a silica gel column eluting with ethyl acetate/n-hexane (volume ratio 1/10) to give the product (M)1)1.5 g, 83% yield.
Product M synthesized in examples 1-4 above1Hydrogen nuclear magnetic resonance1H NMR data:1H NMR(600MHz,CDCl3)(ppm)2.64(t,J=6.0Hz,4H,CH2),2.13(s,9H,CH3),2.08(s,9H,CH3),1.86-1.77(m,4H,CH2),1.62-1.49(m,8H,CH2),1.48-1.37(m,8H,CH2),1.34-1.17(m,24H),1.16-1.12(m,6H,CH2),1.11-1.05(m,6H,CH2),0.88(s,9H,CH3),0.86(s,9H,CH3),0.85(s,6H,CH3);Ms(ESI)m/z:938.0[M+Na]+。
prepared M1The chemical structural formula is as follows:
example 5
Under the protection of nitrogen, 1mmol of idebenone and 2mmol of N, N-diisopropylethylamine are mixed in 5mL of anhydrous dichloromethane, 0.5mmol of oxalyl chloride is slowly dropped under the condition of ice bath, the ice bath is removed after the dropping, the reaction is carried out for 3h at 25 ℃, the reaction process is monitored by a thin-layer chromatographic plate, and methanol is added to quench the reaction after the raw materials are completely reacted. Extracting the obtained crude product with dichloromethane/water system for 3 times, collecting dichloromethane solution, extracting with saturated sodium chloride water solution for 1 time, drying the organic phase with anhydrous magnesium sulfate to remove excessive water in the sample, vacuum filtering to obtain organic phase, removing dichloromethane with rotary evaporator, and concentrating to obtain crude product. The crude product obtained is concentrated and chromatographed on a silica gel column eluting with ethyl acetate/n-hexane (volume ratio 1/15) to give the product (M)2)0.302 g, 83% yield. Hydrogen nuclear magnetic resonance1H NMR data:1H NMR(600MHz,CDCl3)(ppm)4.27(t,J=6.0Hz,2H,CH2),3.97(s,3H,CH3),2.44(t,J=6.0Hz,2H,CH2),1.99(s,3H,CH3),1.72-1.70(t,J=6.0Hz,2H,CH2),1.37-1.25(m,12H,CH2);Ms(ESI)m/z:753.4[M+Na]+。
prepared M2The chemical structural formula is as follows:
example 6
Under the protection of nitrogen, 1mmol of camptothecin and 5mmol of N, N-diisopropylethylamine are mixed in 5mL of anhydrous dichloromethane, 0.5mmol of oxalyl chloride is slowly dropped under the condition of ice bath, the ice bath is removed after the dropping, the reaction is carried out for 4h at 25 ℃, the reaction process is monitored by a thin-layer chromatographic plate, and methanol is added after the raw materials are completely reacted to quench the reaction. Extracting the obtained crude product with dichloromethane/water system for 3 times, collecting dichloromethane solution, extracting with saturated sodium chloride water solution for 1 time, drying the organic phase with anhydrous magnesium sulfate to remove excessive water in the sample, vacuum filtering to obtain organic phase, removing dichloromethane with rotary evaporator, and concentrating to obtain crude product. The crude product obtained is concentrated and chromatographed on a silica gel column eluting with ethyl acetate/n-hexane (volume ratio 1/15) to give the product (M)3)0.296 g, yield 79%. Hydrogen nuclear magnetic resonance1H NMR data:1H NMR(600MHz,CDCl3)(ppm)8.66(s,1H,Ph),8.14(d,J=12.0Hz,1H,Ph),8.10(d,J=12.0Hz,1H,Ph),7.83(t,J=6.0Hz,1H,Ph),7.69(t,J=6.0Hz,1H,Ph),6.52(s,1H,Ph),5.39(s,2H,CH2),5.25(s,2H,CH2),1.87(m,2H,CH2),0.87(t,J=6.0Hz,3H,CH3);Ms(ESI)m/z:751.6[M+H]+。
prepared M3The chemical structural formula is as follows:
example 7
Under the protection of nitrogen, 1mmol of zidovudine and 4mmol of N, N-diAfter mixing isopropyl ethylamine in 5mL of anhydrous dichloromethane, slowly adding 0.5mmol of oxalyl chloride dropwise under the ice bath condition, removing the ice bath after the dropwise adding is finished, heating and refluxing at 40 ℃ for reaction for 4h, monitoring the reaction process by using a thin-layer chromatography plate, and adding methanol to quench the reaction after the raw materials completely react. Extracting the obtained crude product with dichloromethane/water system for 3 times, collecting dichloromethane solution, extracting with saturated sodium chloride water solution for 1 time, drying the organic phase with anhydrous magnesium sulfate to remove excessive water in the sample, vacuum filtering to obtain organic phase, removing dichloromethane with rotary evaporator, and concentrating to obtain crude product. The crude product obtained is concentrated and chromatographed on a silica gel column eluting with ethyl acetate/n-hexane (volume ratio 1/15) to give the product (M)4)0.212 g, yield 72%. Hydrogen nuclear magnetic resonance1H NMR data Ms (ESI) M/z 589.2[ M + H ]]+。
Prepared M4The chemical structural formula is as follows:
example 8
Under the protection of nitrogen, 4mmol of 4-hydroxymethylphenylboronic acid pinacol ester and 20mmol of N, N-diisopropylethylamine are mixed in 20mL of anhydrous dichloromethane, 2mmol of oxalyl chloride is slowly dropped in the mixture under the condition of ice bath, the ice bath is removed after the dropping is finished, the mixture reacts for 2 hours at 25 ℃, a thin-layer chromatographic plate is used for monitoring the reaction process, and methanol is added after the raw materials completely react to quench the reaction. Extracting the obtained crude product with dichloromethane/water system for 3 times, collecting dichloromethane solution, extracting with saturated sodium chloride water solution for 1 time, drying the organic phase with anhydrous magnesium sulfate to remove excessive water in the sample, vacuum filtering to obtain organic phase, removing dichloromethane with rotary evaporator, and concentrating to obtain crude product. The crude product obtained is concentrated and chromatographed on a silica gel column eluting with ethyl acetate/n-hexane (volume ratio 1/15) to give the product (M)5)0.918 g, 88% yield. Hydrogen nuclear magnetic resonance1H NMR data:
1H NMR(600MHz,CDCl3)(ppm)7.92(d,J=6.0Hz,2H,Ph),7.18(d,J=6.0Hz,2H,Ph),4.66(s,2H,CH2),1.27(s,3H,CH3);Ms(ESI)m/z:523.4[M+H]+。
prepared M5The chemical structural formula is as follows:
example 9
Under the protection of nitrogen, 4mmol of 4-hydroxy-2, 2,6, 6-tetramethylpiperidine oxynitride and 12mmol of N, N-diisopropylethylamine are mixed in 20mL of anhydrous dichloromethane, 2mmol of oxalyl chloride is slowly dropped under the condition of ice bath, the ice bath is removed after the dropping, the reaction is carried out for 2h at 25 ℃, the reaction process is monitored by a thin-layer chromatography plate, and methanol is added after the raw materials completely react to quench the reaction. Extracting the obtained crude product with dichloromethane/water system for 3 times, collecting dichloromethane solution, extracting with saturated sodium chloride water solution for 1 time, drying the organic phase with anhydrous magnesium sulfate to remove excessive water in the sample, vacuum filtering to obtain organic phase, removing dichloromethane with rotary evaporator, and concentrating to obtain crude product. The crude product obtained is concentrated and chromatographed on a silica gel column eluting with ethyl acetate/n-hexane (volume ratio 1/15) to give the product (M)6)0.740 g, 93% yield. Hydrogen nuclear magnetic resonance1H NMR data:1H NMR(600MHz,CDCl3)(ppm)3.82(m,1H,CH),2.23(m,2H,CH2),1.95(m,2H,CH2),1.50(s,12H,CH3);Ms(ESI)m/z:422.4[M+Na]+。
prepared M6The chemical structural formula is as follows:
example 10
Under the protection of nitrogen, 4mmol of 3-methoxy-4-hydroxybenzaldehyde and 20mmol of N, N-diisopropylethylamine are dissolved and mixed in 20mL of anhydrous dichloromethane, 2mmol of oxalyl chloride is slowly dropped under the condition of ice bath, the ice bath is removed after the dropping, the mixture reacts for 12 hours at 25 ℃, a thin-layer chromatographic plate is used for monitoring the reaction process, and methanol is added to quench the reaction after the raw materials completely react. Extracting the obtained crude product with dichloromethane/water system for 3 times, collecting dichloromethane solution, extracting with saturated sodium chloride water solution for 1 time, drying the organic phase with anhydrous magnesium sulfate to remove excessive water in the sample, vacuum filtering to obtain organic phase, removing dichloromethane with rotary evaporator, and concentrating to obtain crude product.
Example 11
Under the protection of nitrogen, 4mmol of 4-hydroxybenzaldehyde and 20mmol of N, N-diisopropylethylamine are dissolved and mixed in 20mL of anhydrous dichloromethane, 2mmol of oxalyl chloride is slowly dropped under the condition of ice bath, the ice bath is removed after the dropping, the reaction is carried out for 2h at 25 ℃, the reaction process is monitored by a thin-layer chromatographic plate, and methanol is added to quench the reaction after the raw materials are completely reacted. Extracting the obtained crude product with dichloromethane/water system for 3 times, collecting dichloromethane solution, extracting with saturated sodium chloride water solution for 1 time, drying the organic phase with anhydrous magnesium sulfate to remove excessive water in the sample, vacuum filtering to obtain organic phase, removing dichloromethane with rotary evaporator, and concentrating to obtain crude product.
Example 12
Under the protection of nitrogen, 4mmol of 4-methoxymethylphenol and 20mmol of N, N-diisopropylethylamine are dissolved and mixed in 20mL of anhydrous dichloromethane, 2mmol of oxalyl chloride is slowly dropped under the condition of ice bath, the ice bath is removed after the dropping, the reaction is carried out for 2h at 25 ℃, the reaction process is monitored by a thin-layer chromatography plate, and methanol is added to quench the reaction after the raw materials are completely reacted. Extracting the obtained crude product with dichloromethane/water system for 3 times, collecting dichloromethane solution, extracting with saturated sodium chloride water solution for 1 time, drying the organic phase with anhydrous magnesium sulfate to remove excessive water in the sample, vacuum filtering to obtain organic phase, removing dichloromethane with rotary evaporator, and concentrating to obtain crude product.
Example 13
Under the protection of nitrogen, 4mmol of 4-ethoxymethylphenol and 20mmol of N, N-diisopropylethylamine are dissolved and mixed in 20mL of anhydrous dichloromethane, 2mmol of oxalyl chloride is slowly dropped under the condition of ice bath, the ice bath is removed after the dropping, the reaction is carried out for 2h at 25 ℃, the reaction process is monitored by a thin-layer chromatography plate, and methanol is added to quench the reaction after the raw materials are completely reacted. Extracting the obtained crude product with dichloromethane/water system for 3 times, collecting dichloromethane solution, extracting with saturated sodium chloride water solution for 1 time, drying the organic phase with anhydrous magnesium sulfate to remove excessive water in the sample, vacuum filtering to obtain organic phase, removing dichloromethane with rotary evaporator, and concentrating to obtain crude product.
Example 14
Under the protection of nitrogen, 4mmol of amyl salicylate and 20mmol of N, N-diisopropylethylamine are dissolved and mixed in 20mL of anhydrous dichloromethane, 2mmol of oxalyl chloride is slowly dropped under the condition of ice bath, the ice bath is removed after the dropping, the reaction is carried out for 2h at 25 ℃, the reaction process is monitored by a thin-layer chromatographic plate, and methanol is added after the raw materials are completely reacted to quench the reaction. Extracting the obtained crude product with dichloromethane/water system for 3 times, collecting dichloromethane solution, extracting with saturated sodium chloride water solution for 1 time, drying the organic phase with anhydrous magnesium sulfate to remove excessive water in the sample, vacuum filtering to obtain organic phase, removing dichloromethane with rotary evaporator, and concentrating to obtain crude product.
Example 15
Under the protection of nitrogen, 4mmol of (E) -3, 5-dimethoxy-4' -hydroxystilbene (pterostilbene) and 20mmol of N, N-diisopropylethylamine are dissolved and mixed in 20mL of anhydrous dichloromethane, 2mmol of oxalyl chloride is slowly dripped under the condition of ice bath, the ice bath is removed after the dripping, the reaction is carried out for 2h at 25 ℃, a thin layer chromatography plate is used for monitoring the reaction process, and methanol is added after the raw materials completely react to quench the reaction. Extracting the obtained crude product with dichloromethane/water system for 3 times, collecting dichloromethane solution, extracting with saturated sodium chloride water solution for 1 time, drying the organic phase with anhydrous magnesium sulfate to remove excessive water in the sample, vacuum filtering to obtain organic phase, removing dichloromethane with rotary evaporator, and concentrating to obtain crude product.
Example 16
Under the protection of nitrogen, 4mmol of 2, 4-dinitrophenol and 20mmol of N, N-diisopropylethylamine are dissolved and mixed in 20mL of anhydrous dichloromethane, 2mmol of oxalyl chloride is slowly dropped under the condition of ice bath, the ice bath is removed after the dropping, the reaction is carried out for 2h at 25 ℃, a thin-layer chromatographic plate is used for monitoring the reaction process, and methanol is added to quench the reaction after the raw materials are completely reacted. Extracting the obtained crude product with dichloromethane/water system for 3 times, collecting dichloromethane solution, extracting with saturated sodium chloride water solution for 1 time, drying the organic phase with anhydrous magnesium sulfate to remove excessive water in the sample, vacuum filtering to obtain organic phase, removing dichloromethane with rotary evaporator, and concentrating to obtain crude product.
Preparation of nanoparticles based on hydrogen peroxide-responsive tocopherol compounds: 10mg of tocopherol oxalate and 4mg of DSPE-PEG2000Dissolving in 1.5mL dichloromethane solution, adding 9mL triple distilled water, performing intermittent ultrasound with an ultrasonic probe for 60s at 70% power, stirring at room temperature for 6h to obtain nanoparticles, evaporating dichloromethane with a rotary evaporator, and measuring DLS particle diameter, wherein the sample photograph, particle diameter distribution diagram and transmission electron microscope picture are shown in FIG. 5, and the average particle diameter is 188 nm.
Preparation of hydrogen peroxide-responsive tocopherol compound-encapsulated sulforhodamine 101 nanoparticles: 10mg of tocopherol oxalate, 4mg of DSPE-PEG2000And dissolving 1mg of sulforhodamine 101 in 1.5mL of dichloromethane solution, adding 9mL of triple distilled water, performing intermittent ultrasound for 60s by using an ultrasonic probe with the power of 70%, and then stirring at room temperature for 6h to obtain the sulforhodamine 101 loaded nanoparticle. The photo-responsiveness assay was excited for different types of reactive oxygen species, as can be seen in FIG. 6The nanoparticle has a selective response luminescence characteristic to hydrogen peroxide.
Preparation of hydrogen peroxide-responsive tocopherol compound-encapsulated 1-chloro-9, 10-diphenylethynyl anthracene nanoparticles: 10mg of tocopherol oxalate, 4mg of DSPE-PEG2000And 1mg of 1-chloro-9, 10-diphenylethynyl anthracene is dissolved in 1.5mL of dichloromethane solution, 9mL of triple distilled water is added, intermittent ultrasonic treatment is carried out for 60s by using an ultrasonic probe with the power of 70 percent, and then stirring is carried out for 6h at room temperature to obtain the loaded 1-chloro-9, 10-diphenylethynyl anthracene nanoparticle.
An imaging graph of a pore plate with the light-emitting responsiveness of the hydrogen peroxide-responsive tocopherol compound-loaded 1-chloro-9, 10-diphenylethynyl anthracene nanoparticles to different concentrations is shown in fig. 7, and the light-emitting intensity of the nanoparticles is increased along with the increase of the hydrogen peroxide concentration, so that the nanoparticles have concentration dependence.
As can be seen from fig. 8, the imaging of the pore plate of the hydrogen peroxide-responsive tocopherol compound-loaded 1-chloro-9, 10-diphenylethynyl anthracene nanoparticle in the neutrophil in the abdominal cavity of the mouse shows that the luminescent intensity of the nanoparticle is gradually enhanced with the increase of the number of the neutrophil, and the imaging of the nanoparticle has the neutrophil responsiveness.
As can be seen from fig. 9, the hydrogen peroxide-responsive tocopherol compound loaded 1-chloro-9, 10-diphenylethynyl anthracene nanoparticle can be used for imaging peritonitis in mice. Wherein, the peritonitis model is successfully constructed by injecting thioglycolate into the abdominal cavity of a mouse9. After 300 mu L of nanoparticles (1mg/mL) are injected into the abdominal cavity, the imaging performance of the nanoparticles is verified in a living body imaging system. As a large amount of ROS is generated in abdominal inflammation, the hydrogen peroxide responsive nanoparticles are activated, and energy is transferred to the fluorescent dye to realize chemiluminescence imaging.
As can be seen from fig. 10, the hydrogen peroxide-responsive tocopherol compound loaded 1-chloro-9, 10-diphenylethynyl anthracene nanoparticle can be used for imaging of liver injury in mice. Wherein the liver injury of the mouse is induced and constructed by alcohol according to a literature method23(ii) a Then, 100 mu L of encapsulated 1-chloro-9, 10-diphenylethynyl anthracene nanoparticles (1mg/mL) are injected into the tail vein of the alcoholic liver injury mouse, and the imaging performance of the nanoparticles is verified by a living body imaging system. The oxidative stress generates a large amount of ROS to activate the hydrogen peroxide responsive nanoparticles, and the energy is transferred to fluorescenceDye to realize chemiluminescence imaging.
As can be seen from fig. 11, the hydrogen peroxide-responsive tocopherol compound-loaded 1-chloro-9, 10-diphenylethynyl anthracene nanoparticle can be used for imaging of breast tumors with high hydrogen peroxide expression of 4T1 in mice. Because the 4T1 tumor microenvironment contains a large amount of ROS, the hydrogen peroxide responsive nanoparticles are activated, energy is transferred to the fluorescent dye, and the chemiluminescence imaging of the hydrogen peroxide high-expression tumor is realized.
Reference to the literature
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Claims (10)
2. a method of synthesizing a hydrogen peroxide responsive compound for imaging and therapy comprising the steps of: mixing a single hydroxyl compound and an acid-binding agent in an organic solvent, slowly dropwise adding oxalyl chloride into the solution under the ice bath condition under the protection of nitrogen, removing the ice bath after dropwise adding, reacting for 2-12h, adding methanol or ethanol after the raw materials completely react, and quenching the reaction to obtain a crude product of the hydrogen peroxide responsive compound.
3. A method of synthesizing a hydrogen peroxide responsive compound for imaging and therapy according to claim 2, wherein: extracting the crude product with dichloromethane/water system for 3 times, collecting dichloromethane solution, extracting with saturated sodium chloride water solution for 1 time, drying the organic phase with anhydrous magnesium sulfate to remove excessive water, vacuum filtering, evaporating to remove dichloromethane, concentrating to obtain crude product, and separating and purifying with silica gel chromatographic column to obtain final product.
4. A method of synthesizing a hydrogen peroxide responsive compound for imaging and therapy according to claim 2 or 3, characterized in that: the monohydroxy compound is selected from tocopherol, idebenone, camptothecin, zidovudine, 4-hydroxymethylphenylboronic acid pinacol ester, 4-hydroxy-2, 2,6, 6-tetramethylpiperidine nitroxide, 3-methoxy-4-hydroxybenzaldehyde, 4-methoxymethylphenol, 4-ethoxymethylphenol, amyl salicylate, (E) -3, 5-dimethoxy-4' -hydroxystilbene or 2, 4-dinitrophenol.
5. A method of synthesizing a hydrogen peroxide responsive compound for imaging and therapy according to claim 2 or 3, characterized in that: the acid-binding agent is selected from N, N-diisopropylethylamine or triethylamine.
6. A method of synthesizing a hydrogen peroxide responsive compound for imaging and therapy according to claim 2 or 3, characterized in that: the organic solvent is dichloromethane.
7. A method of synthesizing a hydrogen peroxide responsive compound for imaging and therapy according to claim 2 or 3, characterized in that: the concentration of the monohydroxy compound in the organic solvent is between 0.1mmol/ml and 0.4 mmol/ml.
8. A method of synthesizing a hydrogen peroxide responsive compound for imaging and therapy according to claim 2 or 3, characterized in that: the molar ratio of the monohydroxy compound to the oxalyl chloride is between 1:0.5 and 1:1, and the molar ratio of the monohydroxy compound to the acid-binding agent is between 1:2 and 1: 5.
9. Use of the hydrogen peroxide-responsive compound of claim 1 for the preparation of a medicament and/or an imaging probe for the prevention and treatment of diseases associated with inflammation and/or oxidative stress injury.
10. Use according to claim 9, characterized in that: the inflammation includes allergic inflammation, non-specific inflammation, and infectious inflammation; the oxidative stress injury comprises acute heart injury, acute lung injury, acute/chronic liver injury, acute/chronic kidney injury, and acute/chronic intestinal tract injury.
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