CN115160326A - Phthalocyanine complex of targeted IDO enzyme and preparation method and application thereof - Google Patents
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Abstract
The invention discloses a phthalocyanine complex of targeted IDO enzyme and a preparation method and application thereof, the phthalocyanine complex is formed by coupling phthalocyanine zinc and tryptophan, and the phthalocyanine complex takes 3-nitrophthalonitrile, methyl p-hydroxybenzoate, 1-methyl-D-tryptophan and the like as raw materials, obtaining 3- (4-carboxyl methyl ester phenoxy) o-phthalonitrile through nucleophilic reaction, then generating 1- (4-carboxyl phenoxy) phthalocyanine through cyclization reaction and nucleophilic reaction, and finally generating target product through nucleophilic substitution reaction: (
). The obtained phthalocyanine complex can enhance the killing effect of phthalocyanine on triple negative breast cancer cells, and provides a new idea for improving the photodynamic therapy effect.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to an IDO enzyme-targeted phthalocyanine complex and a preparation method and application thereof.
Background
Breast cancer is a common cancer in women and seriously threatens the life and health of women. The triple negative breast cancer is the most malignant breast cancer subtype, is mainly characterized by lacking estrogen receptors, progestogen receptors and human epidermal growth factor receptors-2, and has the characteristics of low onset age, high malignancy and early recurrence and metastasis. To date, treatment of triple negative breast cancer still faces a great challenge, chemotherapy remains its main treatment, but chemotherapy drugs have poor selectivity, cause body dysfunction and damage to normal tissues, and have difficulty in inhibiting metastasis and recurrence at a later stage.
Indoleamine 2, 3-dioxygenase (IDO enzyme) is an enzyme closely related to tumors, is highly expressed in triple negative breast cancer, and the overexpression of the enzyme is closely related to tumor metastasis and poor prognosis of triple negative breast cancer. Inhibition of IDO enzyme can reduce immunosuppression in tumors, thereby enhancing the effectiveness of immunotherapy. 1-methyl-D-tryptophan (1-MT) is a high-efficiency IDO enzyme inhibitor, and is applied to clinical trials of recurrent solid tumors due to the inhibition of tumor immune escape and metastasis.
Disclosure of Invention
Aiming at the problem that the triple negative breast cancer is easy to transfer and invade, the invention provides the phthalocyanine-1-methyl-D-tryptophan complex targeting the IDO enzyme by combining the phthalocyanine and the active structural domain of the 1-methyl-D-tryptophan, which can enhance the killing effect of the phthalocyanine on the triple negative breast cancer cells, enhance the inhibition on the transfer and invasion of the triple negative breast cancer and further improve the treatment efficiency.
In order to realize the purpose of the invention, the invention adopts the following technical scheme:
a phthalocyanine complex targeting IDO enzyme is formed by coupling zinc phthalocyanine and tryptophan, and has a chemical structural formula as follows:
the preparation method of the phthalocyanine complex comprises the following steps:
1) 3-nitrophthalonitrile, methyl p-hydroxybenzoate and K 2 CO 3 Dissolving a mixture of a compound 1a and a compound 2 in dimethyl formamide (DMF) according to a molar ratio of 1; the chemical structural formula of the compound 1a is as follows:
(ii) a Wherein the volume ratio of water to DMF is 5;
2) Dissolving the compound 1a and phthalonitrile in n-amyl alcohol, heating to 110-150 ℃, adding a zinc source, stirring uniformly, and then adding 1, 8-diazabicyclo [5.4.0 ]]Undecyl-7-ene (DUB) is subjected to reflux reaction for 36 to 48h, then n-amyl alcohol is removed by spin drying, an excessive 20wt% sodium hydroxide solution is added, the reflux reaction is carried out for 24 to 48h, after the solution is subjected to spin drying, a 20wt% hydrochloric acid solution is added to adjust the pH value to be about 3.0, a blue solid is obtained by filtration, the blue solid is taken to pass through a silica gel column, a mixed solution of Ethanol (EA) -DMF (100, 1, v/v) is used as an eluent to be washed until no phthalocyanine exists, and then a mixed solution of EA-DMF (20, v/v) is used for elution, so that a target product 2a is obtained by collection; the chemical structural formula of the product 2a is as follows:
(ii) a Wherein the molar ratio of the compound 1a, the phthalonitrile, the DUB and a zinc source is 1;
3) Dissolving 1-methyl-D-tryptophan (1-MT), di-tert-butyl dicarbonate and sodium bicarbonate in a tetrahydrofuran-water (1, v/v) mixed solvent, reacting at normal temperature for 24h to 48h, then spin-drying, passing the obtained product through a neutral silica gel column, eluting with Dichloromethane (DCM), and spin-drying to obtain a white solid product 3a; the chemical structural formula of the product 3a is as follows:
(ii) a Wherein the molar ratio of 1-methyl-D-tryptophan, di-tert-butyl dicarbonate and potassium carbonate is 1;
4) Dissolving the products 2a and 3a, NHS (N-hydroxysuccinimide) and EDCI (carbodiimide) in DMF (N, N-dimethylformamide), reacting at 30 ℃ for 24h to 72h, adding hexamethylenediamine into the reaction solution, refluxing for 1 hour, adding a trifluoroacetic acid (TFA)/Tetrahydrofuran (THF) mixed solution with a volume ratio of 2 3 OH (100 3 Eluting with a mixed solution of OH (30); wherein the molar ratio of product 2a, product 3a, NHS, EDCI, hexamethylenediamine used is 1.
The obtained phthalocyanine complex of the targeted IDO enzyme can be used for preparing photodynamic anti-cancer drugs, wherein the anti-cancer drugs comprise anti-breast cancer drugs, in particular to drugs for resisting triple negative breast cancer.
The invention has the beneficial effects that:
1) The complex synthesized by the invention has stable structure, no isomer and easy synthesis;
2) The introduction of the 1-methyl-D-tryptophan active structural domain can enhance the toxicity of phthalocyanine to tumor cells and effectively inhibit the metastasis and invasion of triple negative breast cancer cells.
Drawings
FIG. 1 is a schematic diagram of a process scheme for synthesizing 1-MT-Pc in an example.
FIG. 2 is a schematic diagram of a comparative example process for Hex-Pc synthesis.
FIG. 3 is a graph comparing the toxicity of 1-MT-Pc and Hex-Pc in light for 4T1 cells and HELF cells.
FIG. 4 is a graph showing the inhibition of 4T1 cell migration and invasion by 1-MT-Pc and Hex-Pc.
FIG. 5 is a graph showing the inhibition of tumors by physiological saline, 1-MT-Pc and Hex-Pc.
Detailed Description
In order to make the content of the present invention more comprehensible, the technical solutions of the present invention are further described below with reference to specific embodiments, but the present invention is not limited thereto.
EXAMPLE 1 preparation of MT-Pc
As shown in figure 1, 3-nitrophthalonitrile is used as an original raw material, 3- (4-carboxy methyl ester phenoxy) phthalonitrile is obtained through a nucleophilic reaction, 1- (4-carboxy phenoxy) zinc phthalocyanine is generated through a ring formation reaction and an alkaline hydrolysis reaction, and a target product of 1-MT-Pc is generated through a nucleophilic substitution reaction between the 1- (4-carboxy phenoxy) zinc phthalocyanine, hexamethylene diamine and 1-methyl-D-tryptophan.
The method comprises the following specific steps:
1) 2.00g (11.6 mmol) of 3-nitrophthalonitrile, 1.757g (11.6 mmol) of methyl p-hydroxybenzoate, 3.202g (23.2 mmol) of K 2 CO 3 Dissolving in 20ml DMF, reacting at room temperature for 24h, adding 100ml water to the reaction solution to precipitate white precipitate, filtering and drying to obtain 2.5 g compound 1a with yield of 78%, and the characterization data is that 1 H NMR (400 MHz, Chloroform-d) δ 8.13 (d, J = 8.2 Hz, 2H), 7.64 (t, J = 8.2 Hz, 1H), 7.54 (d, J = 7.7 Hz, 1H), 7.16 (dd, J = 17.6, 8.2 Hz, 3H), 3.93 (s, 3H)；
2) Dissolving 0.500g (1.8 mmol) of compound 1a and 1.448g (12.6 mmol) of phthalonitrile in 50ml of n-pentanol, heating to 135 ℃, adding 1.318g (7.2 mmol) of zinc acetate, stirring uniformly, adding 2.189g (14.4 mmol) of DBU, wherein the solution turns green, then carrying out reflux reaction for 36h, then carrying out spin-drying on the n-pentanol, adding 20ml of 20wt% sodium hydroxide solution into the solution, carrying out reflux reaction for 24h, adding 50ml of 20wt% hydrochloric acid solution into the solution after the solution is spin-dried to adjust the pH to 3.0, and filtering to obtain a blue solid; the 300 mg blue solid was applied to a silica gel column and washed with EA: DMF =100 (1 v/v) to no zinc phthalocyanine and then eluted with EA: DMF =20 (1 v/v) to collect 200 mg of the target product 2a in 15% yield, characterized by the data of 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.59 (s, 1H), 9.12 – 8.76 (m, 6H), 8.49 (s, 1H), 8.26 – 7.69 (m, 10H), 7.40 (s, 2H)；
3) 1.22 g (5.6 mmol) of 1-methyl-D-tryptophan, 1.22 g (5.6 mmol) of di-tert-butyl dicarbonate and 0.941 g (11.2 mmol) of sodium bicarbonate were added to a tetrahydrofuran-water (1, v/v) mixed solvent, reacted at normal temperature for 24 hours, and the reaction solution was dried and passed through a silica gel column using dichloromethane as an eluent to obtain 1.2 g of white solid powder with a yield of 50%, according to the characterization data, as a 50% white solid powder 1 H NMR (500 MHz，CDCl 3 )：δ=12.52 (s，1H)，7.50 (d，J=7.9 Hz，1H)，7.34 (d，J=8.2 Hz，1H)，7.14-7.06(m，2H)，7.02-6.93(m，2H)，4.10 (td，J=9.0 Hz，4.8Hz,1H)，3.68 (s，3H)，3.08(dd，J=14.6，4.7Hz，1H)，2.98-2.82 (m，1H)，1.29(s，9H)；
4) Dissolving 100mg (0.14 mmol) of 2a, 44mg (0.14 mmol) of 3a, 32mg (0.28 mmol) of NHS and 53mg (0.28 mmol) of EDCI in 20mL of DMF, reacting at 30 ℃ for 24 hours, adding 16mg (0.14 mmol) of hexamethylenediamine to the solution, refluxing for 1 hour, adding a mixed solution of 4mL of trifluoroacetic acid (TFA) and 10mL of Tetrahydrofuran (THF) to a bottle after the solution is dried, reacting at 35 ℃ for 2 hours, drying the solution, passing through a silica gel column, and reacting with DCM: CH 3 OH =100 (v/v) eluting to remove impurities, followed by DCM: CH 3 OH =30 (1) (v/v) and the product was collected and purified by repeating the same elution, impurity removal and purification conditions on the column for 3 times to obtain 15mg of pure product 1-MT-Pc with a yield of 10.6%, characterized by the data of 10.6% of pure product 1 H NMR (500 MHz，DMSO-d 6 )：δ = 9.04 (m，6H)，8.58 (d，J = 7.2 Hz，1H)，8.27(t，J = 5.7 Hz，1H)，8.15 (t，J =7.5 Hz，1H)，8.05-7.94 (m，9H)，7.84 (d，J =7.6 Hz，1H)，7.42 (d，J=8.9 Hz，2H)，7.36 (d，J = 8.7Hz，1H)，7.32 (s，1H)，7.22 (dd，J= 8.5 Hz，1H)，7.16 (d，J=8.2 Hz，2H)，6.93 (t，J=7.7 Hz，1H)，6.75 (t，J= 7.4 Hz，1H)，3.51 (s，3H)，3.19-3.06 (m，4H)，1.91 (d，J =6.0 Hz，1H)，1.30 (d，J=9.9 Hz，2H)，1.26(s，8H),HRMS (ESI) m/z Calcd for C 57 H 46 N 12 O 3 Zn [M+H] + ：1011.3180,found：1011.3231。
Synthesis of comparative example Hex-Pc
Dissolving 100mg (0.14 mmol) of 2a, 16.1mg (0.14 mmol) of NHS and 26.74mg (0.14 mmol) of EDCI in 10ml of DMF, reacting at 30 ℃ for 24h, adding 16mg (0.14 mmol) of n-hexylamine to the solution, refluxing for 1 hour, passing through a silica gel column after spin-drying the solution, and reacting with DCM: CH 3 OH =110 (v/v) eluting to remove impurities, followed by DCM: CH 3 OH =45 (1) (v/v) and the product was collected and purified by repeating the same elution, impurity removal and purification conditions for 3 times on the column to obtain 30mg of a purer product H-Pc with a yield of 30%, which is characterized by the following data 1 H NMR (500 MHz, DMSO-d 6 ) δ 9.08-8.81 (m, 6H), 8.50 (s, 1H), 8.29 (s, 1H), 8.09-7.93 (m, 9H), 7.75 (s, 1H), 7.39 (s, 2H), 3.15 (s, 2H), 1.18 (s, 8H), 0.77 (s, 3H);HRMS (ESI): calcd C 45 H 33 N 9 O 2 Zn[M+H] + 796.2121 and found 796.2083. The chemical structural formula of the obtained Hex-Pc is as follows:
cytotoxicity test
The MTT method is also called colorimetric method, and is a method for detecting the survival state of cells. Succinate dehydrogenase in the mitochondria of living cells can enable exogenous MTT to be reduced into water-insoluble formazan and deposited in the cells, and dead cells can not enable MTT to be reduced into the formazan. Dimethyl sulfoxide can dissolve formazan in cells, the wavelength value of the formazan at the position of 570nm is measured by an enzyme labeling instrument, and the number of the living cells can be indirectly reflected. Within a certain range of cell number, MTT crystals are formed in an amount proportional to the cell number.
Selecting 4T1 cells and HELF cells with good growth state under a microscope, digesting for 3 minutes by 1ml of pancreatin (containing EDTA) when the Cell density is about 90 percent (wherein the HELF cells are digested for 1 minute), adding 2ml of culture medium to stop digestion, blowing uniformly, counting by using a Cell counting plate, diluting a Cell solution to 6 ten thousand cells/ml by using a DMEM culture medium, adding 100 mu L of the Cell culture medium solution into each hole of a 96-pore plate, setting 6 duplicate holes for each concentration of 1-MT-Pc and Hex-Pc medicines, setting a Cell blank group and a solvent blank group (6 duplicate holes in each group), and placing the 96-pore plate in an incubator at 37 ℃ for 24 hours.
Adding medicine: respectively diluting 1-MT-Pc and Hex-Pc to 5 different concentrations by using a DMSO solution of 5% CEL, then diluting the 7 concentrations of drugs by 100 times by using a DMEM culture medium, sucking out the old culture medium in a 96-well plate by using a discharging gun, adding the DMSO solution of the 5% CEL diluted by 100 times into a cell blank group, adding a DMFM culture medium into a solvent control group, respectively adding the prepared solutions into the rest drug control groups, and continuously placing the 96-well plate in an incubator for 24 hours.
Light toxicity: taking out the 96-well plate, sucking out the medicated culture medium in the hole with a gun, washing each hole with physiological saline for 3 times to remove the medicine not taken up, adding 100 μ L culture medium into each hole, irradiating with 670nm LED lamp for 2min, and returning the irradiated plate to the incubator.
And (3) testing OD value: mu.l of 5mg/ml MTT solution was added to each well of the 96-well plate, the 96-well plate was placed in an incubator at 37 ℃ for 4 hours, and then the solution in each well was aspirated by a line gun, 100. Mu.l of DMSO solution was added to each well again, the plate was shaken for 30 minutes by a shaker, and the absorbance at 570nm was measured by a microplate reader.
And (3) calculating: the cell viability was calculated using the measured absorbance by the following formula:
cell survival (%) = (sample group absorbance-solvent blank absorbance)/(cell blank absorbance-solvent blank absorbance) × 100.
FIG. 3 is a graph showing the comparison of the toxicity of 1-MT-Pc and Hex-Pc to 4T1 cells and HELF cells under light. As can be seen from the figure, the introduction of tryptophan can enhance the toxic effect of Hex-Pc on tumor cells.
Cell migration assay:
(1) Selecting 4T1 cells with high transfer potential in a good growth state and a logarithmic growth phase, adding trypsin for digestion and counting, diluting to 30 ten thousand cells/mL by using a prepared DMEM medium, inoculating 1mL of the cells to a 12-well plate (the plate is subjected to streak treatment), and placing the 12-well plate in a 5% carbon dioxide incubator at 37 ℃ overnight until the fusion rate reaches 100%.
(2) The next day, the cell layer was scored perpendicular to the cell plane, at right angles to the previous score, with a 100 μ L sterile tip (the same tip was used as much as possible between different wells).
(3) After the scratch is finished, the membrane is washed three times by using sterile normal saline, cells which do not adhere to the wall and cells floating at the scratch are washed off, the gap after the scratch is clearly visible, and then the medicament prepared by the culture medium containing 1% fetal calf serum is replaced.
(4) The cells were placed in an incubator, and after 24 hours, the 12-well plate was taken out, and the width of the scratch was observed under a microscope and photographed.
(5) The area of the scratch was opened and calculated using Image J software, the data was processed using GraphPad Prism 6.0 statistical analysis software, and the experimental results are expressed as Means ± SD.
Cell invasion assay:
(1) One day prior to the experiment, the dispensed matrigel (16 μ L) was placed in a refrigerator at 4 ℃ overnight from-20 ℃ in advance to change the gel from a solid state to a liquid state, and the chamber was placed under an ultraviolet lamp for overnight sterilization.
(2) 784. Mu.L of serum-free medium was added to 16. Mu.L of matrigel, and the matrigel (100. Mu.L per well) was spread in a chamber, and the chamber was placed in a 5% carbon dioxide incubator at 37 ℃ for 5 hours or longer.
(3) Selecting 4T1 cells which are in good growth state and are in logarithmic phase, adding trypsin for digestion and counting, diluting to 200 ten thousand cells/mL by using a serum-free culture medium, and uniformly blowing.
(4) 100. Mu.L of the counted culture medium and 100. Mu.L of the prepared drug were mixed, 100. Mu.L of the cell suspension was aspirated and added to the upper chamber of the chamber, and 500. Mu.L of a culture medium containing 10% Fetal Bovine Serum (FBS) (note that no air bubbles were generated between the lower medium and the chamber) was added to the 24-well plate, and the mixture was placed in an incubator and cultured for 24 hours.
(5) The next day, the 24-well plate was removed, the chamber was washed twice with 4 ℃ pre-cooled physiological saline, fixed with methanol for 20 minutes, and then removed to air-dry (left in a fume hood for 10 minutes).
(6) 0.1% crystal violet 500. Mu.L was added, the cell was stained at room temperature for 20 minutes, and then the cells in the upper layer of the microporous membrane of the cell were carefully wiped off with a cotton swab and washed twice with physiological saline.
(7) Photographing under an inverted microscope, subsequently adding an aqueous solution containing 33% acetic acid to a 24-well plate, dissolving crystal violet in a chamber under the chamber, mixing uniformly, sucking the solution into a 96-well plate, each set of 5 duplicate wells at 100. Mu.L per well, measuring the OD value at 570nm, and processing the obtained data with GraphPad Prism 6.0 software, and the experimental results are expressed as Means + -SD.
FIG. 4 is a graph showing the inhibition of 4T1 cell migration and invasion by 1-MT-Pc and Hex-Pc. As can be seen from the graph, phthalocyanine (1-MT-Pc) modified with 1-MT significantly enhances inhibition of migration and invasion of triple-negative breast cancer cells, compared to 1-MT and Hex-Pc.
Tumor inhibition experiment of mice
BALB/C female mice bearing 4T1 tumors were randomly divided into 4 groups: target drug 1-MT-Pc, control drug Hex-Pc,1-MT group and blank control group. When the tumor volume grows to 100 mm 3 On the left and right, 200. Mu.L of different drugs (25. Mu.M) were injected into the tail vein, and 200. Mu.L of physiological saline was injected into the tail vein of the blank control group. The tumor sites were irradiated with light (lambda = 670nm, 50 mW/cm) at 12 h and 48h after injection of the drugs 2 10 min). The mice were then monitored and recorded every other day for changes in tumor volume for the next 14 days.
FIG. 5 is a graph showing the inhibition of tumors by physiological saline, 1-MT-Pc and Hex-Pc. As can be seen from the figure, phthalocyanine (1-MT-Pc) modified with 1-MT can significantly enhance the inhibition of tumor growth in tumor-bearing mice compared to 1-MT and Hex-Pc.
The above description is only a preferred embodiment of the present invention, and all the equivalent changes and modifications made according to the claims of the present invention should be covered by the present invention.
Claims (7)
1. An IDO enzyme-targeting phthalocyanine complex, characterized in that: the complex is formed by coupling zinc phthalocyanine and tryptophan, and the chemical structural formula of the complex is as follows:
2. a method for preparing an IDO enzyme targeted phthalocyanine complex as claimed in claim 1, wherein: the method comprises the following steps:
1) 3-nitrophthalonitrile, methyl p-hydroxybenzoate and K 2 CO 3 Dissolving in DMF, reacting at normal temperature for 24-48h, adding a certain amount of water into the reaction solution to separate out white precipitate, filtering and drying to obtain a compound 1a; the chemical structural formula of the compound 1a is as follows:
；
2) Dissolving a compound 1a and phthalonitrile in n-amyl alcohol, heating to 110-150 ℃, adding a zinc source, uniformly stirring, adding DBU, carrying out reflux reaction for 36-48h, then carrying out spin drying to remove n-amyl alcohol, adding an excessive 20wt% sodium hydroxide solution, carrying out reflux reaction for 24-48h, adding a 20wt% hydrochloric acid solution to adjust the pH value to 3.0 after carrying out spin drying on the solution, filtering to obtain a blue solid, passing the blue solid through a silica gel column, washing until no phthalocyanine exists by using an EA-DMF mixed solution with a volume ratio of 100 as an eluent, and then eluting by using an EA-DMF mixed solution with a volume ratio of 20; the chemical structural formula of the product 2a is as follows:
；
3) Dissolving 1-methyl-D-tryptophan, di-tert-butyl dicarbonate and sodium bicarbonate in a tetrahydrofuran-water mixed solvent with the volume ratio of 1; the chemical structural formula of the product 3a is as follows:
；
4) Dissolving the products 2a and 3a, NHS and EDCI with DMF, reacting at 30 ℃ for 24h-72h, adding hexamethylenediamine into the reaction solution, refluxing for 1 h, adding a trifluoroacetic acid/tetrahydrofuran mixed solution with a volume ratio of 2 3 The OH mixture was eluted to remove impurities and then eluted with DCM-CH at a volume ratio of 30 3 And (3) eluting the OH mixed solution, collecting a product, and repeatedly separating and purifying the product for 2 to 3 times by using a silica gel column according to the elution conditions to obtain the pure phthalocyanine complex.
3. The method for preparing an IDO enzyme targeted phthalocyanine complex according to claim 2, wherein: 3-nitrophthalonitrile, methyl p-hydroxybenzoate and K used in step 1) 2 CO 3 1, the volume ratio of water to DMF is 5.
4. The method for preparing an IDO enzyme targeted phthalocyanine complex according to claim 2, wherein: the molar ratio of the compound 1a, phthalonitrile, DBU and zinc source used in step 2) is 1; the zinc source is zinc chloride or zinc acetate.
5. The method for preparing an IDO enzyme targeted phthalocyanine complex according to claim 2, wherein: the molar ratio of 1-methyl-D-tryptophan, di-tert-butyl dicarbonate and potassium carbonate used in the step 3) is 1.
6. The process for preparing phthalocyanine complexes to IDO enzymes as claimed in claim 2, wherein: the molar ratio of product 2a, product 3a, NHS, EDCI, hexamethylenediamine used in step 4) is 1.
7. Use of the IDO enzyme targeted phthalocyanine complex of claim 1 in the preparation of a photodynamic anti-cancer drug.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112209940A (en) * | 2020-10-26 | 2021-01-12 | 福州大学 | COX-2 enzyme-targeted phthalocyanine-indometacin complex and preparation method and application thereof |
| CN113943304A (en) * | 2021-10-21 | 2022-01-18 | 福州大学 | Phthalocyanine-5-bromo-1-benzofuran-2-carboxylic acid complex targeting Pim-1 kinase and preparation method and application thereof |
| CN114409663A (en) * | 2022-01-28 | 2022-04-29 | 福州大学 | Mcl-1 enzyme targeted zinc phthalocyanine 3-chloro-6 methylbenzo [ b ] thiophene-2-carboxylic acid conjugates and methods of making the same |
| CN114751953A (en) * | 2022-04-11 | 2022-07-15 | 福州大学 | Phthalocyanine derivative for targeted photodynamic therapy of postmenopausal breast cancer and preparation method thereof |
| WO2022226052A1 (en) * | 2021-04-20 | 2022-10-27 | The Regents Of The University Of Michigan | Pi3k inhibitors, nanoformulations, and uses thereof |
-
2022
- 2022-07-30 CN CN202210911297.1A patent/CN115160326A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112209940A (en) * | 2020-10-26 | 2021-01-12 | 福州大学 | COX-2 enzyme-targeted phthalocyanine-indometacin complex and preparation method and application thereof |
| WO2022226052A1 (en) * | 2021-04-20 | 2022-10-27 | The Regents Of The University Of Michigan | Pi3k inhibitors, nanoformulations, and uses thereof |
| CN113943304A (en) * | 2021-10-21 | 2022-01-18 | 福州大学 | Phthalocyanine-5-bromo-1-benzofuran-2-carboxylic acid complex targeting Pim-1 kinase and preparation method and application thereof |
| CN114409663A (en) * | 2022-01-28 | 2022-04-29 | 福州大学 | Mcl-1 enzyme targeted zinc phthalocyanine 3-chloro-6 methylbenzo [ b ] thiophene-2-carboxylic acid conjugates and methods of making the same |
| CN114751953A (en) * | 2022-04-11 | 2022-07-15 | 福州大学 | Phthalocyanine derivative for targeted photodynamic therapy of postmenopausal breast cancer and preparation method thereof |
Non-Patent Citations (4)
| Title |
|---|
| GANKUN YUAN等: "Enhanced immunotherapy based on photodynamic therapy for both primary and lung metastasis tumor eradication", 《ACS NANO》, vol. 12, no. 02, pages 1 - 2 * |
| KUNSHAN HUANG等: "A phthalocyanine-based photosensitizer for effectively combating triple negative breast cancer with enhanced photodynamic anticancer activity and immune response", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》, vol. 241, pages 114644 * |
| RI HONG等: "Selective inhibition of IDO1, D-1-methyl-tryptophan (D-1MT), effectively increased EpCAM/CD3-bispecific BiTE antibody MT110 efficacy against IDO1hibreast cancer via enhancing immune cells activity", 《INTERNATIONAL IMMUNOPHARMACOLOGY》, vol. 54, pages 120 * |
| YANG LAN等: "Codelivered chemotherapeutic doxorubicin via a dual-functional immunostimulatory polymeric prodrug for breast cancer immunochemotherapy", 《ACS APPLIED MATERIALS & INTERFACES》, vol. 12, no. 28, pages 2 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115947742A (en) * | 2023-01-05 | 2023-04-11 | 福州大学 | Imidazotetrazine group monosubstituted phthalocyanine conjugate and preparation method and application thereof |
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