CN110698514B - Preparation and application of mitochondrion targeted stimulation response photosensitizer - Google Patents

Preparation and application of mitochondrion targeted stimulation response photosensitizer Download PDF

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CN110698514B
CN110698514B CN201910508272.5A CN201910508272A CN110698514B CN 110698514 B CN110698514 B CN 110698514B CN 201910508272 A CN201910508272 A CN 201910508272A CN 110698514 B CN110698514 B CN 110698514B
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photosensitizer
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李昌华
翟文豪
刘明
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Nankai University
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    • 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
    • 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
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6596—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having atoms other than oxygen, sulfur, selenium, tellurium, nitrogen or phosphorus as ring hetero atoms

Abstract

The invention discloses a preparation method and application of a mitochondrion targeted stimulation responsive photosensitizer. Creatively synthesizes a water-soluble mitochondrion targeting agent, and the mitochondrion targeting agent and a photosensitizer reserved with an azide functional group are subjected to click reaction (azidePSSe‑1) Linking and then etherifying the stimuli-responsive group. The photosensitizer has good biocompatibility, stimulation responsiveness and mitochondrial targeting.
Figure DSA0000184446060000011

Description

Preparation and application of mitochondrion targeted stimulation response photosensitizer
Technical Field
The invention relates to preparation and application of a mitochondrion targeting photosensitizer, and belongs to the technical field of photodynamic therapy.
Background
Mitochondria function as organelles essential for cellular respiration, provide energy for cellular metabolism, and play a key role in programmed cell death such as apoptosis. Mitochondria are therefore promising therapeutic targets in clinical applications. Photodynamic therapy is known as an emerging treatment that uses an effective light source to irradiate a photosensitizer, which produces cytotoxic singlet oxygen and thereby irreversibly kills the patient's cells. The two are combined, the mitochondrion targeting photosensitizer is generated at the same time, and the mitochondrion dysfunction is produced to cause the death of patient cells, thereby achieving the treatment purpose. However, most mitochondrial-targeted photosensitizers do not have switching controllability and their use in biological media is limited by their low water solubility, resulting in the formation of large aggregates, reducing singlet oxygen quantum yield. Therefore, it is imperative to design a mitochondrial targeting photosensitizer with controllable switch and good biocompatibility.
Disclosure of Invention
The invention aims to solve the problems in the prior art, and provides a preparation method and application of a mitochondrion targeting stimulus-responsive photosensitizer, wherein the synthetic route is as follows:
Figure GSB0000184749330000011
Figure GSB0000184749330000021
the present invention provides a mitochondrial stimulus-responsive photosensitizer having the formulamito-PNA compound having the structure shown by PS.
Preferably, the molar ratio of compound 1 to gallic acid methyl ester is 1: 1.
Preferably, the molar ratio of the compound 3 to the sodium hydroxide is 1: 10, and the volume ratio of the tetrahydrofuran to the water is 2: 1.
Preferably, the molar ratio of the compound 4 to the propargylamine is 1: 4, the two are dissolved in dichloromethane and uniformly stirred, and then a dichloromethane mixed solution containing EDCI and DMAP is slowly and dropwise added.
Preferably, the molar ratio of the compound 6 to the triphenyl phosphine is 1: 3, and the reaction is stirred at 90 ℃ for 24h without any solvent.
Preferably, compounds 7 andazidePSSe-Ithe molar ratio of the tetrahydrofuran to the water is 1: 1, the volume ratio of the tetrahydrofuran to the water is 4: 1, and the reaction is carried out for 24 hours at room temperature.
Preferably, the compoundsmitoPS and
Figure GSB0000184749330000031
the molar ratio of N, N-dimethylformamide to acetonitrile is 1: 1, the reaction temperature is 80 ℃.
mito-PNROS (OONO) over-expressed in mitochondria and mitochondria of patient cells by compound with structure shown by PS-) Interaction, by self-degrading chemistry, to produce phototoxicmitoThe compound with the structure shown by PS realizes the switching controllability of the mitochondrion targeted photosensitizer.
mito-PNCompounds of the structure PS do not absorb in the visible region, do not have photodynamic ability, and mitochondrial over-expressed ROS (OONO)-) After interaction, produce a compound having phototoxicitymitoJunction of PSThe absorption of the structured compound in the visible region is recovered, and the photodynamic ability is also recovered.
The invention also provides a general preparation strategy of the mitochondrion targeting activation type photosensitizermitoDifferent biological response groups are etherified on the compound with the structure shown by PS, different biological signal molecules are specifically recognized, and photosensitivity is opened.
According to the photosensitizer, iodine atoms are introduced, so that on one hand, the pKa of phenolic hydroxyl groups of the photosensitizer after dephosphorylation is effectively reduced, and the photosensitizer is more suitable for physiological pH value; on the other hand, the device is beneficial to gap crossing and improves the photodynamic ability.
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FIG. 1 synthetic route for mitochondrially targeted photosensitizers.
Figure 2 absorption of mitochondrially targeted photosensitizers before and after stimulus response.
Figure 3 photosensitivity before and after mitochondrially targeted photosensitizer stimulus response.
Figure 4 specific localization of mitochondrially targeted photosensitizers in patient cells (compared to commercial mitochondrial probes).
FIG. 5 Mitochondrially targeted photosensitizer killing (MTT) of patient cells.
FIG. 6 structural formula of mitochondrion targeted photosensitizer.
Detailed Description
In order that those skilled in the art may better understand the present invention, the following further explanation and description are provided in connection with the accompanying drawings and the specific embodiments, but the embodiments are not meant to be limiting, and other embodiments obtained without inventive efforts shall fall within the protection scope of the present invention.
The first embodiment is as follows: synthesis of Compound 7, the synthetic route is shown in figure 1
Methyl boscalid (3.0g, 16.3mmol) was dissolved in dry DMF (15mL), potassium carbonate (4.5g, 32.6mmol) and potassium iodide (0.27g, 1.63mmol) were added, stirred at 80 ℃ for 10min, a solution of compound 1(5.68g, 16.3mmol) in dry DMF (5mL) was added dropwise, and stirred at this temperature overnight. After the reaction is finished, removing the solvent by rotary evaporationThe mixture was dissolved in ethyl acetate, washed 3 times with saturated brine, dried over anhydrous sodium sulfate, the solvent was removed by rotary evaporation, and column chromatography was performed using petroleum ether and ethyl acetate as eluents to give compound 2(1.82g, 31.0%) as a colorless oily substance.1H NMR(400MHz，CDCl3)δ(ppm)7.63(s，2H)，7.15(s，2H)，4.20-4.14(t，J＝3.2Hz，2H)，3.85(s，3H)，3.74(m，8H)，3.69(s，4H)，3.62(t，J＝4.4Hz，2H)，3.48-3.38(s，1H).13C NMR(100MHz，CDCl3)δ(ppm)166.95，149.94，138.14，126.36，109.59，72.88，72.27，70.50，70.43，70.19，70.14，69.89，61.57，52.13.
Compound 3 was synthesized according to the synthesis method of compound 2.1H NMR(400MHz，CDCl3)δ(ppm)7.30(s，2H)，4.22(m，6H)，3.88(m，7H)，3.84-3.78(t，J＝4.8Hz，2H)，3.77-3.70(m，8H)，3.66(m，14H)，3.60(m，2H)，3.57-3.52(m，4H)，3.38(s，6H)，2.80(s，H).13C NMR(100MHz，CDCl3)δ(ppm)166.54，152.23，142.47，124.93，108.94，72.58，72.41，71.89，70.77，70.64，70.59，70.51，70.47，70.29，69.57，68.79，61.64，58.96，52.13.
Compound 3(1.0g, 1.53mmol) was dissolved in THF (10mL), and an aqueous solution (5mL) containing 12% NaOH was slowly added dropwise and stirred at room temperature overnight. Adjusting the pH value to 3 by hydrochloric acid, extracting by ethyl acetate, drying by anhydrous sodium sulfate, and removing the solvent by rotary evaporation. Column chromatography with dichloromethane and methanol as eluents gave compound 4(0.93g, 95.0%) as a pale yellow oil.1H NMR(400MHz，CDCl3)δ(ppm)7.34(s，2H)，4.23(m，6H)，3.88(m，4H)，3.84-3.79(t，J＝5.2Hz，2H)，3.74(m，8H)，3.67(m，14H)，3.61(t，J＝4.8Hz，2H)，3.58-3.53(m，4H)，3.38(s，6H).13C NMR(100MHz，CDCl3)δ(ppm)169.63，152.21，142.80，124.53，109.36，72.57，72.42，71.90，70.76，70.64，70.58，70.50，70.46，70.27，69.62，68.78，61.61，58.97.
Compound 4(1.9g, 2.97mmol) and propargylamine (0.66g, 11.98mmol) were dissolved in dichloromethane (20mL), stirred well, and a solution containing EDCl (0.68g, 3.55mmol) and D was slowly added dropwiseMAP (0.036g, 0.295mmol) in dichloromethane (10mL) was added dropwise and the reaction was allowed to proceed overnight at room temperature. After completion of the reaction, the reaction mixture was washed 3 times with saturated brine, dried over anhydrous sodium sulfate, the solvent was removed by rotary evaporation, and column chromatography was performed using dichloromethane and methanol as eluents to give compound 5(1.51g, 75.2%) as a pale yellow oil.1H NMR(400MHz，CDCl3)δ(ppm)7.14(s，2H)，6.95(t，J＝5.2Hz，1H)，4.21(m，8H)，3.87-3.81(t，J＝4.8Hz，4H)，3.81-3.77(t，J＝4.8Hz，2H)，3.74-3.58(m，24H)，3.57-3.52(m，4H)，3.36(s，6H)，2.80(t，J＝6.0Hz，1H)，2.27(t，J＝2.4Hz，1H).13C NMR(100MHz，CDCl3)δ(ppm)166.66，152.40，141.76，128.85，107.62，79.92，72.50，72.34，71.89，71.39，70.65，70.63，70.61，70.49，70.42，70.37，69.73，69.12，61.71，58.95，29.66.
Compound 5(2.0g, 2.96mmol) and carbon tetrabromide (1.18g, 3.6mmol) were dissolved in dichloromethane (20mL), stirred well, and triphenylphosphine (1.16g, 4.42mmol) in dichloromethane (5mL) was added dropwise at 0 deg.C, after completion of the addition, the reaction was continued for 4 h. After completion of the reaction, column chromatography was performed using dichloromethane and methanol as eluents to obtain compound 6(1.83g, 83.7%) as a pale yellow oil.1H NMR(400MHz，CDCl3)δ(ppm)7.15(s，2H)，7.09(t，J＝5.2Hz，1H)，4.26-4.14(m，8H)，3.87-3.76(m，8H)，3.75-3.61(m，20H)，3.58-3.51(m，4H)，3.47(t，J＝6.4Hz，2H)，3.36(s，6H)，2.27(t，J＝2.4Hz，1H).13C NMR(100MHz，CDCl3)δ(ppm)166.61，152.37，141.65，128.86，107.53，79.97，72.35，71.87，71.33，71.15，70.69，70.63，70.60，70.54，70.49，70.40，69.70，69.05，58.91，30.37，29.61.
Compound 6(1.3g, 1.76mmol) and triphenylphosphine (1.5g, 5.72mmol) were added to a 50mL round bottom flask, heated directly to 90 deg.C and the triphenylphosphine melted and stirred at this temperature for 24 h. After completion of the reaction, column chromatography was performed using dichloromethane and methanol as eluents to give compound 7(1.58g, 97.5%) as a pale yellow oil.1H NMR(400MHz，CDCl3)δ(ppm)8.37(t，J＝5.6Hz，1H)，7.79-7.60(m，15H)，7.33(s，2H)，4.29-4.14(m，8H)，3.97-3.79(m，8H)，3.78-3.73(t，J＝4.8Hz，2H)，3.69(m，4H)，3.67-3.55(m，10H)，3.52(m，4H)，3.42-3.36(m，2H)，3.34(s，6H)，3.33-3.28(m，2H)，3.27-3.22(m，2H)，2.15(t，J＝2.4Hz，1H).13C NMR(100MHz，CDCl3)δ(ppm)166.46，151.89，140.51，134.74，134.72，133.80，133.70，130.11，129.99，128.97，119.00，118.14，107.14，80.85，77.54，72.22，71.75，70.66，70.45，70.40，70.29，70.26，70.16，70.07，69.58，68.78，63.82，63.74，58.85，29.18，25.49，24.96.HRMS(MALDI)：m/z[M]calcd for C50H67NO13P+ 920.4345；found 920.4348.
Example two: synthesis ofmito-PNPS, synthetic route is shown in figure 1
Compound 7(129mg, 0.14mmol),azidePSSe-I(100mg, 0.14mmol), sodium ascorbate (2.8mg, 0.014mmol) and anhydrous copper sulfate (2.2mg, 0.0014mmol) were dissolved in a mixed solution of tetrahydrofuran/water (4mL/1mL) and reacted at room temperature for 24 hours. After the reaction is finished, extracting by dichloromethane, drying by anhydrous sodium sulfate, removing the solvent by rotary evaporation, and carrying out column chromatography by taking dichloromethane and methanol as eluent to obtain a black-green solid compoundmitoPS(0.15g，65.6％)。1H NMR(400MHz，CDCl3)δ(ppm)8.99(s，1H)，8.17(s，1H)，8.08(s，1H)，7.81-7.56(m，18H)，7.53-7.41(m，2H)，7.34(s，2H)，7.13(d，J＝8.8Hz，1H)，6.75(d，J＝15.6Hz，1H)，6.64(d，J＝16.0Hz，1H)，4.86-4.66(m，4H)，4.45(s，2H)，4.15(m，6H)，3.92-3.71(m，10H)，3.66(m，4H)，3.64-3.53(m，10H)，3.50(m，4H)，3.38-3.30(m，8H)，3.26(m，2H)，3.21(m，2H).13C NMR(100MHz，CDCl3)δ(ppm)166.76，158.70，157.36，157.29，151.96，138.39，149.90，145.88，140.51，138.39，134.76，134.74，134.49，133.88，133.78，130.47，130.17，130.04，129.35，128.79，127.21，125.76，124.80，124.44，122.66，122.06，119.19，118.33，117.70，116.19，112.28，107.15，86.12，77.27，72.31，71.88，70.95，70.56，70.50，70.42，70.37，70.20，70.10，69.70，68.75，66.71，63.90，63.83，58.98，49.36，35.64，29.69，25.31，24.78.HRMS(MALDI)：m/z[M]calcd for C72H80I2N6O15SeP+ 1633.2668；found 1633.2675.
Compound (I)mitoPS (0.15g, 91.8. mu. mol) and potassium carbonate (0.051g, 0.37mmol) were added sequentially to dry DMF/CH3CN (2mL/2mL), stirring at 80 ℃ for 10min, slowly adding dropwise a solution containing
Figure GSB0000184749330000061
(54mg, 0.18mmol) of DMF/CH3CN (0.5mL/0.5mL) mixed solution, and after the dropwise addition, the reaction was continued for 4 hours. After completion of the reaction, the solvent was removed by rotary evaporation, and column chromatography was performed using dichloromethane and methanol as eluents to obtain compound 5(0.158g, 93.0%) as a red solid.1H NMR(400MHz，CDCl3)δ(ppm)8.46(t，J＝6.0Hz，1H)，8.15(d，J＝2.4Hz，1H)，8.05(s，1H)，7.98(s，2H)，7.90-7.84(d，J＝8.0Hz，2H)，7.79-7.68(m，9H)，7.68-7.59(m，10H)，7.30(m，2H)，7.25(dd，J＝8.8，2.4Hz，1H)，7.13-7.07(d，J＝16.0Hz，1H)，6.94-6.87(d，J＝16.0Hz，1H)，5.04(s，2H)，4.80-4.68(m，4H)，4.46(t，J＝4.8Hz，2H)，4.27-4.19(t，J＝4.8Hz，4H)，4.17(t，J＝5.2Hz，2H)，3.95-3.84(m，4H)，3.81(t，J＝4.4Hz，4H)，3.78-3.72(t，J＝4.8Hz，2H)，3.68(m，5H)，3.67-3.56(m，10H)，3.55-3.48(m，4H)，3.41-3.32(m，8H)，3.29(m，2H)，3.23(m，2H)，1.36(s，12H).13C NMR(100MHz，CDCl3)δ(ppm)166.65，158.44，157.92，157.58，152.03，148.85，145.84，140.61，138.79，138.73，134.92，134.75，134.72，133.94，133.84，133.52，130.81，130.15，130.02，129.29，128.75，127.51，127.31，126.02，124.19，122.38，119.18，118.32，117.10，115.50，112.40，107.04，91.79，83.86，77.32，74.52，72.32，72.03，71.86，70.85，70.55，70.51，70.42，70.39，70.15，69.66，68.83，66.91，63.93，63.85，59.00，49.31，35.38，29.69，25.49，24.96，24.88.HRMS(MALDI)：m/z[M]calcd for C85H97Bl2N6O17SeP+ 1849.3990；found 1849.4009.
To further explore the ability of mitochondria to target photosensitizers to mitochondria in patients' cells, we compared them using commercial mitochondrial probes with highly coincident fluorescence and Pearson coefficients up to 95%, indicating thatmito-PNThe mitochondrion targeting of PS is very good.
To further explore the photodynamic activity of mitochondrially targeted photosensitizers before and after stimulus response, they were quantitatively tested using 9, 10-Dimethylanthracene (DMA) as a singlet oxygen probe. The test conditions are that the xenon lamp light source 490-700nm and the power is 5mW/cm2The solution contained DMA (60. mu.M),mito-PNPS (2.5. mu.M), DMF (5%), F127 (0.3%), pH 7.4, photodynamic ability before and after stimulus response as shown in FIG. 3, the change of DMA before stimulus response was almost identical to that of the control group (without photosensitizer), and after stimulus response, the change of DMA increased suddenly, indicating that photodynamic was completely inhibited before stimulus response and photodynamic was recovered after stimulus response.
In order to further explore the killing effect of the photosensitizer on patient cells, MTT method is used for researchingmito-PNThe toxicity of PS to RAW264.7 cells under light conditions, the results are shown in FIG. 5,mito-PNOONO with PS over-expressed in mitochondria-Producing phototoxicity upon interactionmitoPS, killing the patient's cells under light conditions.
The foregoing is merely a preferred embodiment of this invention and equivalents thereof (e.g., to the extent that they are equivalent to the alternatives or variations of this invention)mitoPS as a substrate, and different response groups are etherified respectively), are all within the scope of the present invention.

Claims (8)

1. A mitochondrially targeted activated photosensitizer, which is characterized by comprising a compound represented by the structure of formula (I):
Figure FSB0000197151040000011
2. a preparation method of a mitochondrion targeting stimulus responsive photosensitizer is characterized by comprising the following preparation processes:
Figure FSB0000197151040000012
wherein the structural formula of the TEG-OTs is as follows:
Figure FSB0000197151040000013
3. the process according to claim 2, wherein the molar ratio of Compound 1 to methyl gallate is 1: 1.
4. The method according to claim 2, wherein the molar ratio of the compound 3 to the sodium hydroxide is 1: 10, and the volume ratio of the tetrahydrofuran to the water is 2: 1.
5. The process according to claim 2, wherein the molar ratio of compound 4 to propargylamine is 1: 4, the two are dissolved in dichloromethane, stirred until homogeneous, and then a dichloromethane mixed solution containing EDCI and DMAP is slowly added dropwise.
6. The process according to claim 2, wherein the molar ratio of compound 6 to triphenylphosphine is 1: 3, and the reaction temperature is 90 ℃.
7. The process according to claim 2, wherein the molar ratio of the compounds 7 and 8 is 1: 1 and the volume ratio of tetrahydrofuran and water is 4: 1.
8. The method of claim 2, wherein the compound ismitoPS and
Figure FSB0000197151040000021
the molar ratio of N, N-dimethylformamide to acetonitrile is 1: 1.
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Citations (3)

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CN107417714A (en) * 2017-07-06 2017-12-01 南开大学 A kind of highly sensitive fluorescence probe and its synthetic method and application based on BODIPY
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