Preparation method and application of BODIPY-based nickel porphyrin derivatives

Abstract

The present invention discloses a preparation method and application of a BODIPY-based nickel porphyrin derivative, wherein the BODIPY-based nickel porphyrin derivative is shown in formula (I). Porphyrin derivative 1 is used as a starting material, and compound I is obtained through metalation reaction, Vilsmeier reaction, bromination reaction, Suzuki coupling reaction and Knoevenagel condensation reaction. Compound I has good stability and good in vitro anti-tumor biological activity, and has good anti-tumor activity against IC1 in Jeko-1 and Rec-1 lymphoma cells. 50 The values are 13.09mM and 9.87mM respectively, showing good application prospects in the field of anti-tumor.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis and relates to a preparation method and application of a BODIPY-based nickel porphyrin derivative. Background Art

[0002] Malignant tumors currently threaten human health and life. Radiotherapy and chemotherapy are commonly used clinically to treat tumors, inhibiting their growth and metastasis to a certain extent. Traditional chemotherapy drugs lack targeting and have significant side effects. Furthermore, most chemotherapy drugs are poorly water-soluble, resulting in limited efficacy. Repeated high-dose administration can lead to drug resistance.

[0003] Porphyrins and their derivatives are a class of conjugated macromolecular heterocyclic compounds with an 18-electron system, consisting of four pyrrole rings connected by methine groups. They are a series of bioactive molecules widely present in life forms in nature. Porphyrins combine with anticancer agents or other groups to form new porphyrin compounds with anticancer activity. Using porphyrins as tumor-targeting agents can enhance anticancer activity or mitigate the toxic side effects of anticancer agents. Porphyrin compounds have a special affinity for tumor tissue.

[0004] Based on the advantages of the metal nickel porphyrin complex itself and the introduction of the BODIPY group, a BODIPY-based nickel porphyrin derivative was designed for use in anti-tumor activity. It has a good inhibitory effect on both Jeko-1 and Rec-1 lymphoma cells, and has better anti-tumor activity against Jeko-1 lymphoma cells. It also has good in vivo cell stability within 48 hours, giving it a good application prospect in the field of anti-tumor activity. Summary of the Invention

[0005] Purpose of the invention: In view of the deficiencies in the prior art, the purpose of the present invention is to provide a preparation method and application of BODIPY-based nickel porphyrin derivatives.

[0006] Technical solution: In order to achieve the above purpose, the technical solution adopted by the present invention is:

[0007] A BODIPY-based nickel porphyrin derivative of the present invention is characterized in that its structural formula is shown in the following formula (I):

[0008]

[0009] A method for preparing a BODIPY-based nickel porphyrin derivative comprises the following steps:

[0010] 1) Compound 1 was dissolved in a chloroform solution and a methanol solution of Ni(OAc)2·4H2O was added dropwise thereto. The mixture was heated to 60°C and reacted for 18 hours. After the reaction, the organic solvent was removed by distillation under reduced pressure, and the product was separated and purified by silica gel column chromatography using dichloromethane-petroleum ether as the eluent to obtain compound 2;

[0011] 2) Under argon protection, a 1,2-dichloroethane solution of compound 2 was added dropwise to a solution of phosphorus trichloride (POCl3) in N,N-dimethylformamide (DMF), and the mixed solution was heated to 50°C for 2 h. After the reaction, the mixture was cooled to 0°C and quenched with a saturated aqueous NaOAc solution. The mixture was extracted with CH2Cl2, washed with water, dried over anhydrous Na2SO4, and the solvent was removed by distillation under reduced pressure. The product was separated and purified by silica gel column chromatography using dichloromethane-petroleum ether as eluent to obtain compound 3;

[0012] 3) NBS was added to a dichloromethane solution of compound 3 at 0°C, stirred at room temperature for 2 h, diluted with CH2Cl2, washed with water, and the organic layer was dried over anhydrous Na2SO4. The solvent was removed by distillation under reduced pressure, and purified by silica gel column chromatography using dichloromethane-petroleum ether as eluent to obtain compound 4;

[0013] 4) Under argon protection, Pd(PPh3)4 was added to a mixed solution of compound 4, BODIPY derivative BDP, Na2CO3, THF, and MeOH. The mixed solution was heated to 65°C and stirred for 18 hours, cooled to room temperature, quenched with water, extracted with CH2Cl2, dried over anhydrous Na2SO4, and the solvent was removed by distillation under reduced pressure. The product was separated and purified by silica gel column chromatography using dichloromethane-petroleum ether as eluent to obtain compound 5;

[0014] 5) Under argon protection, a drop of pyridine was added dropwise to a chloroform solution of compound 5 and 2-(3-oxo-2,3-dihydroindan-1-ylidene)malononitrile. The mixed solution was heated to 65° C. and stirred for 18 h. The solvent was distilled off under reduced pressure, and the product was separated and purified by silica gel column chromatography using dichloromethane-petroleum ether as eluent to obtain compound (I).

[0015] The specific chemical reaction formula is as follows:

[0016]

[0017] In the above step 2), the molar ratio of compound 2, POCl3, and DMF is 0.1 mmol: 9 mmol: 9 mmol;

[0018] In the above steps 2), 4) and 5), all are carried out under argon protection conditions;

[0019] In the above step 3), the molar ratio of compound 3 to NBS is 1 mmol:1 mmol;

[0020] In the above step 4), the volume ratio of THF and MeOH and the amount of compound 4, BDP, Na2CO3, and Pd(PPh3)4 is 8 mL: 1 mL: 0.04 mmol: 0.04 mmol: 0.66 mmol: 0.004 mmol;

[0021] In the above step 5), the molar ratio of compound 5, 2-(3-oxo-2,3-dihydroindan-1-ylidene)malononitrile and pyridine is 0.04 mmol:0.66 mmol:0.004 mmol.

[0022] Beneficial effects of the present invention

[0023] Compared with the prior art, the BODIPY-based nickel porphyrin derivative of the present invention has the following advantages: (1) simple reaction conditions and mature technology; (2) good inhibitory effect on Jeko-1 and Rec-1 lymphoma cells, and the IC of compound (I) in Jeko-1 and Rec-1 lymphoma cells is 50 The values were 13.09mM and 9.87mM respectively; (3) It had better anti-tumor activity against Jeko-1 lymphoma cells and good in vivo cell stability within 48h. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 This is a graph showing the inhibitory effect of compound (I) of Example 6 of the present invention on the proliferation of Jeko-1 and Rec-1 lymphoma cells in vitro;

[0025] Figure 2 This is an immunofluorescence image of Jeko-1 lymphoma cells treated with compound (I) of Example 7 of the present invention. DETAILED DESCRIPTION

[0026] The present invention will be further described below with reference to specific examples.

[0027] use 1 H NMR, MALDI-TOF-MS, and UV-Vis spectroscopy were used to characterize and confirm the structure of BODIPY-based nickel porphyrin derivative I. The instruments used for detection were: a Bruker ARX600 NMR spectrometer (TMS as the internal standard, deuterated chloroform or deuterated acetone as the solvent), an ABI Voyager De Pro spectrometer, and a TECAN Infinite M200 Pro multi-function microplate reader.

[0028] Example 1

[0029] Preparation of compound 2

[0030] Compound 1 (0.16 mmol, 192 mg) was dissolved in chloroform solution, and 10 mL of Ni(OAc)2·4H2O methanol solution was added dropwise. The mixed solution was heated to 60°C and reacted for 18 h; cooled to room temperature, diluted with water, extracted with dichloromethane, and the combined organic layers were dried over anhydrous Na2SO4. The solvent was removed by distillation under reduced pressure, and the product was separated and purified by silica gel column chromatography using dichloromethane-petroleum ether as eluent to obtain 137 mg of compound 2 (yield 68%). 1 H NMR (CDCl3, 400MHz, ppm): δ9.95 (s, 2H), 9.20 (d, J=4Hz, 4H), 9.07 (d, J=4Hz, 4H), 7.26 (s, 4H), 6.88 (s, 2H), 4.12 (t, J=6Hz, 8H), 1.90-1.86 (m, 8H), 1.55-1.46 (m, 8H), 1.46-1.23 (m, 64H), 0.91-0.83 (t, J=5.6Hz, 12H).

[0031] Example 2

[0032] Preparation of compound 3

[0033] Under argon protection, POCl3 (9 mmol, 0.84 mL) was added dropwise to DMF (0.73 mL, 9 mmol) and stirred at room temperature for 0.5 h; compound 2 (0.106 mmol, 137 mg) was dissolved in 20 mL of 1,2-dichloroethane and added dropwise to the above solution, and then the mixed solution was heated to 50°C for 2 h; after the reaction, the solution was cooled to 0°C and quenched with NaOAc solution, diluted with water, extracted with dichloromethane, dried over anhydrous Na2SO4, and the solvent was distilled off under reduced pressure. The product was separated and purified by silica gel column chromatography using dichloromethane-petroleum ether as eluent to obtain 90 mg of compound 3 (yield 78%). 1 H NMR (CDCl3, 400MHz, ppm): δ12.16 (s, 1H), 9.88 (d, J=5.2Hz, 2H), 9.76 (s, 1H), 9.08-9.02 (m, 4H), 8.88 (d, J=4.8Hz, 2H), 7 .15 (s, 4H), 6.85 (d, J=2.4Hz, 2H), 4.10 (t, J=6.8Hz, 8H), 1.87 (t, J=6.8Hz, 8H), 1.41-1.20 (m, 72H), 0.88 (t, J=6Hz, 12H).

[0034] Example 3

[0035] Preparation of compound 4

[0036] Compound 3 (0.07 mmol, 90 mg) was dissolved in dichloromethane solution, and the temperature was lowered to 0°C. NBS (0.07 mmol, 14 mg) was added and stirred at 25°C for 2 h. After the reaction was completed, water was added to quench the solution, and the solution was extracted with dichloromethane. The organic layers were combined and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and purified by silica gel column chromatography using dichloromethane-petroleum ether as eluent to obtain 85 mg of compound 4 (yield 88%). 1 H NMR (CDCl3, 400MHz, ppm): δ12.01 (s, 1H), 9.75 (d, J=5.2Hz, 2H), 9.39 (d, J=4.8Hz, 2H), 8.92 (d, J=5.2Hz, 2H), 8.75 (d, J=5.2Hz, 2H), 7. 09 (s, 4H), 6.83 (s, 2H), 4.08 (t, J=6.4Hz, 8H), 1.86 (t, J=7.6Hz, 10H), 1.53-1.47 (m, 10H), 1.30-1.25 (m, 60H), 0.88 (t, J=5.6Hz, 12H).

[0037] Example 4

[0038] Preparation of compound 5

[0039] Under argon protection, Pd(PPh3)4 (0.004mmol, 6mg) was added to a mixed solution of compound 4 (0.04mmol, 60mg), BDP (0.04mmol, 54mg), Na2CO3 (0.66mmol, 66mg), THF (8mL) and MeOH (1mL). The mixed solution was heated to 65°C and reacted for 18h. The mixture was quenched with water and extracted with CH2Cl2. The organic layers were combined, dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. The product was separated and purified by silica gel column chromatography using dichloromethane-petroleum ether as eluent to obtain 48mg of compound 5 (yield 65%). 1 HNMR (CDCl3, 400MHz, ppm): δ12.10 (s, 1H), 9.84 (d, J=5.2Hz, 2H), 9.02 (d, J=4.8Hz, 2H ), 8.78 (d, J=4.8Hz, 2H), 8.62 (d, J=5.2Hz, 2H), 8.11 (d, J=7.6Hz, 2H), 7.69 (d, J=8.8H z, 3H), 7.66-7.55 (m, 6H), 7.14 (s, 4H), 6.84 (s, 2H), 6.79-6.62 (m, 7H), 4.09 (t, J=6.8 Hz, 8H), 3.08 (s, 12H), 1.92-1.82 (m, 14H), 1.36-1.22 (m, 72H), 0.87 (t, J=5.6Hz, 12H).

[0040] Example 5

[0041] Preparation of Compound I

[0042] Under argon protection, a drop of pyridine was added dropwise to a chloroform solution of compound 5 (0.04 mmol, 60 mg) and 2-(3-oxo-2,3-dihydroindan-1-ylidene)malononitrile (0.66 mmol, 66 mg). The mixed solution was heated to 65°C and stirred for 18 h. The solvent was distilled off under reduced pressure and the product was separated and purified by silica gel column chromatography using dichloromethane-petroleum ether as eluent to obtain 40 mg of compound (I) (yield 61%). 1 H NMR (CDCl3, 400MHz, ppm): δ10.87 (s, 1H), 9.12 (d, J=5.2Hz, 2H), 8.84-8.79 (m, 4H), 8.62 (d, J=4.8Hz, 2H), 8.48 (d, J=4.8Hz, 2H), 7.89-7.52 (m, 14H), 7.31 (s, 2H), 6.92-6.46 (m, 10H), 4.29-3.86 (m, 8H), 3.08 (s, 12H), 1.86 (s, 14H), 1.40-1.21 (m, 72H), 0.90-0.85 (m, 12H)MADLI-TOF MASS:C 130 H 155 BF2N 10 NiO5 calculated for: 2043.16; found: 2043.70.

[0043] Example 6

[0044] The anti-tumor activity of compound I against Jeko-1 and Rec-1 lymphoma cells was evaluated. Jeko-1 and Rec-1 lymphoma cells were cultured to an appropriate cell density and incubated at compound concentrations of 1 μM, 5 μM, 10 μM, 50 μM and 100 μM for 24 h or 48 h. The viability of Jeko-1 and Rec-1 lymphoma cells was determined by the MTT assay. The absorbance values were measured at 550 nm and 630 nm using a microplate reader. The relative cell survival rate was calculated using the formula. The results are shown in FIG. Figure 1 shown.

[0045] Example 7

[0046] The anti-tumor stability of compound I against Jeko-1 lymphoma cells was evaluated. The cells were incubated with the compound for 24 h or 48 h, the supernatant was removed by centrifugation, and the cells were fixed with 4% paraformaldehyde for 10 min, washed with PBS, and stained with 1 μg / μL DAPI at 25°C for 5 min. After washing with PBS, the cells were collected and images were captured using a Nikon Eclipse microscope. Each experiment was performed independently at least three times. The results are shown in FIG. Figure 2 shown.

Claims

1. A BODIPY-based nickel porphyrin derivative (I), characterized in that: Its structural formula is shown in the following formula (I):

2. The method for preparing a BODIPY-based nickel porphyrin derivative (I) according to claim 1, wherein: The method is achieved by the following steps: using a porphyrin derivative 1 as a raw material, a metalation reaction of the porphyrin derivative 1 with nickel (II) acetate is performed to obtain compound 2; compound 2 is subjected to a Vilsmeier reaction to obtain compound 3, which is then subjected to a bromination reaction to obtain compound 4; compound 4 is subjected to a Suzuki coupling reaction with BDP to obtain compound 5; and finally, compound 5 is subjected to a Knoevenagel condensation reaction with 2-(3-oxo-2,3-dihydroindene-1-ylidene)malononitrile to obtain a BODIPY-based nickel porphyrin derivative (I). The reaction formula of the preparation process is as follows:

3. A method for preparing a BODIPY-based nickel porphyrin derivative (I) according to claim 2, characterized in that The steps are as follows: 1) Compound 1 was dissolved in a chloroform solution and a methanol solution of Ni(CH3CO2)2 was added dropwise thereto. The mixture was heated at 60°C for 18 h. After the reaction, the organic solvent was removed by distillation under reduced pressure and the product was purified by silica gel column chromatography using dichloromethane-petroleum ether as the eluent to obtain compound 2; 2) Under argon protection, a 1,2-dichloroethane solution of compound 2 was added dropwise to a solution of phosphorus oxychloride (POCl3) in N,N-dimethylformamide (DMF), and the mixed solution was heated to 50°C for 2 h. After the reaction, the mixture was cooled to 0°C and quenched with a saturated aqueous NaOAc solution. The mixture was extracted with CH2Cl2, and the organic layers were combined and dried over anhydrous Na2SO4. The solvent was removed by distillation under reduced pressure, and the mixture was purified by silica gel column chromatography using dichloromethane-petroleum ether as the eluent to obtain compound 3; 3) NBS was added to a dichloromethane solution of compound 3 at 0°C, stirred at room temperature for 2 h, diluted with CH2Cl2, washed with water, and the organic layer was dried over anhydrous Na2SO4. The solvent was removed under reduced pressure, and purified by silica gel column chromatography using dichloromethane-petroleum ether as eluent to obtain compound 4; 4) Under argon protection, Pd(PPh3)4 was added to a mixed solution of compound 4, BDP, Na2CO3, THF, and MeOH. The mixed solution was heated to 65°C and stirred for 18 h, washed with water and extracted with CH2Cl2, dried over anhydrous Na2SO4, and the solvent was removed by distillation under reduced pressure. The product was purified by silica gel column chromatography using dichloromethane-petroleum ether as eluent to obtain compound 5; 5) Under argon protection, a drop of pyridine was added to a chloroform solution of compound 5 and 2-(3-oxo-2,3-dihydroindan-1-ylidene)malononitrile. The mixed solution was heated to 65°C and stirred for 18 h. The solvent was distilled off under reduced pressure and purified by silica gel column chromatography using dichloromethane-petroleum ether as eluent to obtain a BODIPY-based nickel porphyrin derivative (I).

4. A method for preparing a BODIPY-based nickel porphyrin derivative (I) according to claim 3, characterized in that In the step 2), the molar ratio of compound 2 to POCl 3 and DMF is 0.1 mmol:9 mmol:9 mmol.

5. A method for preparing a BODIPY-based nickel porphyrin derivative (I) according to claim 3, characterized in that In the step 3), the molar ratio of compound 3 to NBS is 1 mmol:1 mmol.

6. A method for preparing a BODIPY-based nickel porphyrin derivative (I) according to claim 3, characterized in that In the step 4), the volume ratio of THF and MeOH and the amount of compound 4, BDP, Na2CO3, and Pd(PPh3)4 is 8 mL:1 mL:0.04 mmol:0.04 mmol:0.66 mmol:0.004 mmol.

7. A method for preparing a BODIPY-based nickel porphyrin derivative (I) according to claim 3, characterized in that In the step 5), the molar ratio of compound 5, 2-(3-oxo-2,3-dihydroindan-1-ylidene)malononitrile and pyridine is 0.04 mmol: 0.66 mmol: 0.004 mmol.

8. Use of the BODIPY-based nickel porphyrin derivative (I) as claimed in claim 1 in the preparation of a drug for inhibiting Jeko-1 and Rec-1 lymphoma cells.

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