CN112010880B - Mono-iodine substituted BODIPY compound and preparation method and application thereof - Google Patents

Abstract

The invention belongs to the field of drug synthesis, relates to a BODIPY compound with a general formula (I), and particularly relates to a monoiodo-substituted BODIPY compound, and a preparation method and application thereof in pharmacy. Tests prove that the compound plays a remarkable role in inhibiting the growth of tumors by generating photodynamic action; the result shows that the compound has good antitumor activity, can be further used for preparing photodynamic treatment medicines and novel malignant tumor treatment medicines, and is used for treating malignant tumors such as skin cancer, prostatic cancer, oral squamous carcinoma, cervical cancer, lung cancer, liver cancer, gastric cancer, breast cancer, colon cancer, bladder cancer, esophageal cancer and the like.

Description

Mono-iodine substituted BODIPY compound and preparation method and application thereof

Technical Field

The invention belongs to the field of drug synthesis, and relates to a novel monoiodo-substituted BODIPY compound, a preparation method and application thereof. In particular to a BODIPY compound containing monoiodo substitution, a preparation method and application thereof in pharmacy.

Background

Malignant tumors have been reported to be a common disease that seriously endangers the health of people. According to incomplete statistics, about 1810 ten thousand new cancer cases and 960 ten thousand cancer death cases exist around the world in 2018; the number of new cases is 160-200 ten thousand per year and 130 ten thousand deaths in China. Because of the early stage tumor metastasis ability, about 50% of patients clinically diagnosed with primary tumors have distal metastasis, tumor cells grow rapidly and are easy to mutate, and multidrug resistance is easy to generate, so that chemotherapy failure is caused, and according to relevant statistics, more than 90% of the patients are related to multidrug resistance of tumor cells. Clinical practice shows that the anti-tumor drugs clinically applied at present far cannot meet the requirements of treatment, and the search of an effective tumor treatment intervention scheme is always the key point of research in the field of medicine.

Photodynamic therapy is a novel tumor therapy intervention scheme which is more and more emphasized at present, and compared with the traditional tumor therapy mode, the photodynamic therapy has the following obvious advantages: can kill tumor with high selectivity; the photodynamic can be applied independently or combined with chemotherapy, operative treatment, radiotherapy or immunotherapy to carry out synergistic treatment on the tumor, the treatment effect is obvious, the wound is small, and the drug resistance is not generated after multiple treatments. Research shows that a plurality of photosensitizers are on the market or enter clinical research in the photodynamic antitumor drugs at present, and the photosensitizers are applied to treatment of skin cancer, prostatic cancer, oral squamous carcinoma, acne, cervical cancer, lung cancer, liver cancer, gastric cancer and esophageal cancer, and particularly have obvious curative effect in treatment of skin cancer.

The first generation of photosensitizers was developed in the early 70 and 80 th 20 th century, which typically represented a mixture of hematoporphyrins (HpD), which were first approved by the FDA by Dougherty et al, who isolated their active ingredients as porfimer sodium (Photofrin); however, practice has shown that these photosensitizers suffer from the following serious disadvantages: (1) The molar absorptivity (3000-5000) in the near infrared band is very low, so that a very large light dose and photosensitizer dose are required to achieve a therapeutic effect; (2) The metabolism is slow, and the photophobic time is up to 4-6 weeks after the injection of the photosensitizer, which brings serious inconvenience to patients; (3) The photosensitizer has complex components and no definite chemical structure; (4) poor tumor selectivity and bioavailability; these disadvantages severely limit their clinical applications.

In order to improve the disadvantages of the first generation of photosensitizers, the second generation of photosensitizers was gradually developed in the 80 s, and mainly classified into the following types: (1) Ela and Ela prodrugs, such as 5-aminolevulinic acid (ALA) and methyl 5-aminolevulinic acid (M-ALA); (2) porphyrins, such as hamporfin (Hemoporfin); (3) Chlorins, such as chlorin E6 (Ce 6), photocloro (Photochlor), talaporfi (Talaporfi)n), temoporfin (Temoporfin) and Verteporfin (Verteporfin); (4) Phthalocyanines, e.g. aluminium phthalocyanine sulfonate (AlPcS) ₄ ) And silicon phthalocyanine Pc4, the chemical structures of these typical photosensitizers are shown in the following formula. The photosensitizers on the market at present mainly focus on the second-generation photosensitizers, but the photosensitizers still have respective defects, such as too strong water solubility of the Ela and low molar absorptivity of the generated protoporphyrin IX (PpIX); the temoporfin can precipitate in the injection process due to strong hydrophobicity; verteporfin produces serious self-aggregation phenomenon in aqueous solution, so that the verteporfin is clinically used for the administration mode of liposome, but the administration mode severely limits the application range of the verteporfin in clinic, and the verteporfin is only applied to the treatment of macular degeneration retina at present; talaporfin and Ce 6-polyvinylpyrrolidone are photosensitizers based on porphyrin structures, but the high photobleaching disadvantage thereof seriously reduces the photodynamic effect thereof; in view of various unsatisfactory points of the existing second-generation photosensitizer, the development of a novel photosensitizer with excellent performance has important fundamental research significance and clinical requirements.

BODIPY (BODIPY) is a novel dye discovered in recent years, and becomes a hotspot of research due to the advantages of good light stability, high molar absorption coefficient, high fluorescence quantum yield, easy chemical modification of molecular structure and the like. It has been found that substitution of BODIPY-type dyes with heavy atoms results in novel photosensitizers for photodynamic therapy, typically represented by ADPM06. The BODIPY photosensitizer has the following advantages: the synthesis is convenient and fast, and different groups are conveniently introduced for derivatization; the phototoxicity is high, and the dark toxicity is low; the in vivo clearance and metabolism are faster in the existing photosensitizer; the molar absorptivity coefficient is high; the light stability is strong; the yield of singlet oxygen is high; the unique advantages described above make it one of the promising second-generation photosensitizers.

Based on the current situations that the BODIPY photosensitizer reported in the prior art contains two or more heavy atoms, and the like, the inventor of the application intends to provide monoiodo-substituted BODIPY compounds and a preparation method and application thereof.

The invention content is as follows:

the invention aims to provide monoiodo-substituted BODIPY compounds, a preparation method and application thereof based on the current situation of the prior art, and compared with the compounds in the prior art, the monoiodo-substituted BODIPY photosensitizer has the advantages of enhanced photostability, enhanced chemical stability, improved singlet oxygen yield, improved phototoxicity, good in-vivo antitumor activity and the like.

Specifically, the invention provides a novel BODIPY photosensitizer with good anti-tumor effect, and relates to a monoiodo-substituted BODIPY compound with a structure shown in a general formula (I):

wherein:

R ₁ 、R ₂ 、R ₃ ar is independently selected from phenyl and C _1-6 Alkyl-substituted phenyl, C _1-6 Alkoxy-substituted phenyl, halogen-substituted phenyl, hydroxy-substituted phenyl, thienyl, C _1-6 Alkyl-substituted thienyl, pyridyl, C _1-6 An alkyl-substituted pyridyl group; the dotted line is a C-C bond or absent.

Preferably, wherein the dotted line is a C-C bond.

Preferably wherein the dotted line is absent.

Preferably, wherein R ₁ 、R ₂ Selected from phenyl.

Preferably, wherein R ₃ Selected from phenyl, methylphenyl, methoxyphenyl, ethoxyphenyl, chlorophenyl, thienyl, methylthiophenyl or pyridyl; further preferably, wherein R ₃ Selected from p-methylphenyl, p-methoxyphenyl and 2-thienyl5-methyl-2-thienyl.

Preferably, ar is selected from phenyl, methylphenyl, methoxyphenyl, ethoxyphenyl, chlorophenyl, thienyl, methylthiophenyl or pyridyl; further preferably, ar is selected from p-methylphenyl, p-methoxyphenyl, 5-methyl-2-thienyl.

In the present invention, the compound has the following structure of compound 1,2, 3, 4,5, 6, 7:

the invention also aims to provide a preparation method of the BODIPY compound, and particularly relates to a method for preparing monoiodo-substituted BODIPY compound.

Taking compound 1 as an example, the preparation process of the compound of the present invention is as follows:

taking compound 5 as an example, the preparation process of the compound of the present invention is as follows:

furthermore, the monoiodo-substituted BODIPY compound can be used for preparing a photodynamic anti-tumor photosensitizer. The malignant tumor comprises skin cancer, prostatic cancer, oral squamous carcinoma, cervical cancer, hepatocarcinoma, gastric cancer, breast cancer, lung cancer, colon cancer, bladder cancer and esophageal cancer.

The compound of the invention is tested for tumor inhibition activity, and the result shows better tumor inhibition activity, wherein the compounds 1 and 5 show better tumor inhibition activity for three tumor strainsNanomolar cytostatic activity, wherein the inhibitory activity on HeLa tumor strains IC ₅₀ The value was less than 0.1. Mu.M. The compound of the invention can be further used for preparing photodynamic anti-tumor photosensitizer.

The pharmacodynamic test method employed in the present invention is a method well known to those skilled in the art.

In the present invention, heLa cells, MCF-7 cells and SW480 cells are commercially available to those skilled in the art.

Drawings

Figure 1, photosensitizer 1 and positive control ADPM06 in different solvents (a) N, N-dimethylformamide; (B) acetonitrile; (C) isopropyl alcohol; (D) Normalized absorbance in PBS buffer-irradiation time histogram.

FIG. 2, bar graph of normalized absorbance-time response of photosensitizer 1 and positive control ADPM06 in acetonitrile (A) and PBS (B, containing 0.01% emulsifier system); wherein the emulsifier system is polyoxyethylene castor oil/1,2 propylene glycol (10.

FIG. 3 phototoxicity of photosensitizer 1 and ADPM06 in HeLa cells (light dose 54J/cm) ² ，λ>590 nm) and dark toxicity.

FIG. 4, histogram of cell viability versus light dose for photosensitizer 1 in HeLa cells.

Figure 5, organelle localization assay for compound 1: wherein (a, E, I) cell morphology in bright field; (B) Images after incubation with mitochondrial green fluorescent probe (250 nM); (F) Images after incubation with endoplasmic reticulum green fluorescent probe (2 μ M); (J) Images after incubation with lysosomal green fluorescent probe (160 nM); (C, G, K) Red fluorescence image of Compound 1; (D, H, L) overlay of green fluorescence of the corresponding probe and red fluorescence of 1; scale bar: 5 μm.

FIG. 6 is a overlay of the green fluorescence of (A, B, C) mitochondrial, endoplasmic reticulum and lysosomal localization probes, respectively, and the red fluorescence of photosensitizer 1; (D, E, F) are the corresponding fluorescence intensity superposition graphs in the graphs A, B, C. Figure 7, compound 1 induces HeLa apoptosis: wherein, (A) a control group; (B) 1 concentration 200nM, light dose 54J/cm ² (ii) a (C) 1 concentration 200nM, light dose 27J/cm ² (ii) a (D) 1 concentration 40nM, light dose 54J/cm ² 。

FIG. 8, test of intracellular reactive oxygen species induced by Compound 1, in which HeLa cells were incubated with different concentrations of 1 (0.004,0.02, 0.10,0.5,2.5. Mu.M) for 3H, followed by H ₂ DCFDA (10. Mu.M) incubation for 20min at a light dose of 54J/cm ² (λ>590 nm), (a) cytofluorometric profiles at different times; (B) relative fluorescence intensity in Panel A; and (C) measuring the fluorescence intensity by using a microplate reader.

FIG. 9, the addition of sodium azide to verify the reactive oxygen species generation experiment, wherein (A) cells were incubated with 1; (B) 1/H for cells ₂ DCFDA incubation; (C) 1/H for cells ₂ DCFDA/NaN ₃ Incubation; (D) NaN for cell ₃ Incubation; (E-H): figures a-D correspond to the non-illuminated groups.

Fig. 10, wherein (a) nude mice were live imaged at different times; (B) fluorescence pictures of organs at different times; (C) fluorescence values corresponding to the organs at different times.

Fig. 11, evaluation of the tumor suppression effect of photosensitizer 1 in a nude mouse HeLa xenograft tumor model, wherein, (a) tumor ex vivo pictures; (B) tumor volume growth curve; (C) ex vivo tumor weight; and (D) a weight change curve of the nude mice.

The specific implementation mode is as follows:

example 1: synthesis of Compound 1

(1) Synthesis of 3-phenyl-2H-aziridine

The starting material (1,2-dibromoethyl) benzene (5.2 g,19.9 mmol) was dissolved in DMF (30 ml), and sodium azide (3.9 g, 60mmol) was slowly added to the above solution and reacted at room temperature for 10h. Then extracting with anhydrous ether and saturated sodium carbonate solution for three times, combining organic phases and concentrating to obtain (1-azido vinyl) benzene;

triethylene diamine (DABCO, 1.5g,13.4 mmol) is added into toluene (70 ml), the temperature is raised to 110 ℃, the (1-azidovinyl) benzene is dissolved in the toluene, the solution is dripped into the solution, the reflux is carried out for 2H, and the toluene is removed by rotary evaporation, thus obtaining a yellow oily crude product, namely the 3-phenyl-2H-aziridine. The product was used in the next reaction without isolation.

(2) Synthesis of 2- (4-methoxyphenyl) -4-phenyl-1H-pyrrole

P-methoxyacetophenone (1g, 6.7 mmol) was dissolved in dry THF (30 ml), cooled to-78 deg.C under nitrogen protection, LDA (13.4 mmol) was slowly added by injection, and reacted for 30min. 3-phenyl-2H-azacyclopropene (784 mg,6.7 mmol) is dissolved in tetrahydrofuran, and the mixture is slowly added into the reaction system to react for 2H and react for 1H at room temperature. After the reaction was completed, an aqueous ammonium chloride solution was added to quench the reaction, followed by extraction with dichloromethane and water, and the organic phases were combined, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and quenched with dichloromethane: petroleum ether =1:10 column chromatography gave the intermediate 2- (4-methoxyphenyl) -4-phenyl-1H-pyrrole as white crystals, 939mg, 56.3% yield. ¹ H NMR(400MHz,CDCl ₃ )δ8.27(s,1H),7.45(d,J＝7.1Hz,2H), 7.33(s,2H),7.24(s,2H),7.08(s,1H),7.00(s,1H),6.83(s,2H),6.59(s,1H),3.72(s, 3H).

(3) Synthesis of dye A

2- (4-methoxyphenyl) -4-phenyl-1H-pyrrole (49.8mg, 0.2mmol) was added to a mixed solution of glacial acetic acid/acetic anhydride (1 ml/0.4 ml) with stirring, and then the temperature was lowered to 5 ℃ and sodium nitrite (6.9mg, 0.1mmol) was slowly added. The reaction solution is continuously stirred for 30min, and then the temperature is adjusted to 80 ℃ for continuous reaction for 30min. The reaction solution was cooled to room temperature, crushed ice was added thereto to precipitate a blue dye, the reaction solution was filtered, and the filter cake was washed with water. Performing neutral alumina column chromatography on the filter cake, wherein an eluent is dichloromethane, then spin-drying the solvent, and then pumping to dry by using an oil pump;

the product was dissolved in 1,2-dichloroethane, triethylamine (0.24 ml) was added and stirred, thenAdding boron trifluoride ether solution (0.24 ml), reacting at room temperature for 30min, then adjusting the temperature to 80 ℃, and continuing the reaction for 30min. Cooling the reaction liquid to room temperature, adding crushed ice to quench, extracting by dichloromethane, combining organic phases, concentrating, carrying out neutral alumina column chromatography by using dichloromethane as an eluent, and spin-drying the solvent to obtain the product. The product was recrystallized from dichloromethane/petroleum ether to give the final product as a copper solid, 41.9mg, 75.3% yield. ¹ H NMR (400MHz,CDCl ₃ )δ8.09(ddd,J＝11.1,8.6,1.9Hz,8H),7.46(dt,J＝11.1,6.9Hz, 6H),7.07–6.99(m,6H),3.90(t,J＝1.4Hz,6H).

(4) Synthesis of Compound 1

Dissolving dye A (20mg, 0.036mmol) in dichloromethane (6 ml), adding glacial acetic acid (2 ml), then adding NIS (8.1mg, 0.036mmol), reacting at room temperature for 30min, extracting reaction liquid for three times by using a sodium thiosulfate solution and dichloromethane, combining organic phases, concentrating the organic phases, then carrying out column chromatography, eluting by dichloromethane, and concentrating to obtain the product. The product was recrystallized from dichloromethane/petroleum ether (1/1) to give the final product as a dark brown solid, 21.9mg, 89.2% yield. ¹ H NMR(400MHz,CDCl ₃ )δ8.09–7.99 (m,4H),7.86–7.80(m,2H),7.70(d,J＝8.6Hz,2H),7.54–7.42(m,3H),7.37(dd, J＝5.2,1.9Hz,3H),7.12(s,1H),7.04–6.99(m,2H),6.98–6.93(m,2H),3.88(s, 3H),3.85(s,3H). ¹³ C NMR(151MHz,CDCl ₃ )δ162.28,161.28,160.34,155.70, 146.19,144.80,143.95,142.83,132.08,131.81,131.67,131.63,131.60,130.99, 130.23,129.23,128.62,128.25,127.98,127.17,123.49,122.53,119.24,113.87, 112.69,80.03,54.87,54.63,29.07,28.70.。

Example 2: synthesis of Compound 2

(1) Synthesis of 4-phenyl-2- (p-tolyl) -1H-pyrrole

P-methylacetophenone (1g, 7.5 mmol) was dissolved in dry THF (20 ml), cooled to-78 ℃ under nitrogen protection, LDA (15.0 mmol) was slowly added by injection and reacted for 30min. 3-phenyl-2H-azacyclopropene (877mg, 7.5mmol) is dissolved in tetrahydrofuran, slowly added into the reaction system for reaction for 2H, and reacted for 1H at room temperature. After the reaction was completed, an aqueous ammonium chloride solution was added to quench the reaction, and the reaction solution was extracted three times with dichloromethane and water, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and quenched with dichloromethane: petroleum ether =1 column chromatography 10 gave the intermediate 4-phenyl-2- (p-tolyl) -1H-pyrrole as white crystals in 62.3% yield 1.09 g.

(2) Synthesis of dye B

4-phenyl-2- (p-tolyl) -1H-pyrrole (46.6 mg,0.2 mmol) was added to a mixed solution of glacial acetic acid/acetic anhydride (1 ml/0.4 ml) and stirred, then the temperature was lowered to 5 ℃ and sodium nitrite (6.9 mg, 0.1mmol) was slowly added. The reaction solution is continuously stirred for 30min, and then the temperature is adjusted to 80 ℃ for continuous reaction for 30min. The reaction solution was cooled to room temperature, crushed ice was added thereto to precipitate a blue dye, the reaction solution was filtered, and the filter cake was washed with water. Performing neutral alumina column chromatography on the filter cake, wherein an eluent is dichloromethane, then spin-drying the solvent, and then pumping the solvent by using an oil pump;

the product is dissolved in 1,2-dichloroethane, triethylamine (0.24 ml) is added and stirred, then boron trifluoride diethyl etherate solution (0.24 ml) is added and reacted for 30min at room temperature, and then the temperature is adjusted to 80 ℃ and the reaction is continued for 30min. Cooling the reaction liquid to room temperature, adding crushed ice to quench, extracting by dichloromethane, combining organic phases, concentrating, carrying out neutral alumina column chromatography by using dichloromethane as an eluent, and spin-drying the solvent to obtain the product. The product was recrystallized from dichloromethane/petroleum ether (1/1) to give the final product as a copper solid, 36.5mg, 69.6% yield. ¹ H NMR(400MHz,CDCl ₃ )δ8.09–8.02(m,4H),7.99–7.94(m,4H),7.49–7.39 (m,6H),7.31–7.26(m,4H),7.03(d,J＝1.3Hz,2H),2.41(s,6H).

(3) Synthesis of Compound 2

Dissolving dye B (20mg, 0.038mmol) in dichloromethane (6 ml), adding glacial acetic acid (2 ml), then adding NIS (8.6mg, 0.038mmol), reacting at room temperature for 30min, extracting reaction liquid for three times by using a sodium thiosulfate solution and dichloromethane, combining organic phases, concentrating column chromatography, eluting by dichloromethane, and concentrating to obtain the product. The product was recrystallized from dichloromethane/petroleum ether (1/1) to give the final product as a copper solid, 21.6mg, 87.5% yield. ¹ H NMR(400MHz,CDCl ₃ )δ8.05–7.97(m,2H),7.91(d,J ＝8.1Hz,2H),7.86–7.80(m,2H),7.60(d,J＝7.9Hz,2H),7.53–7.41(m,3H), 7.36(dd,J＝5.3,1.9Hz,3H),7.28(d,J＝7.9Hz,2H),7.24(d,J＝4.9Hz,2H),7.08 (s,1H),2.42(s,3H),2.37(s,3H). ¹³ CNMR(151MHz,CDCl ₃ )δ161.89,157.13, 146.04,145.06,144.75,143.17,142.07,139.73,131.91,131.01,130.23,129.90, 129.28,129.25,128.96,128.65,128.41,128.14,128.01,127.99,127.47,127.21, 119.29,80.37,21.08.。

Example 3: synthesis of Compound 3

(1) Synthesis of 2- (5-methylthiophen-2-yl) -4-phenyl-1H-pyrrole

Synthetic methods are consistent with the synthetic route for the compound 4-phenyl-2- (p-tolyl) -1H-pyrrole. 2- (5-methylthiophen-2-yl) -4-phenyl-1H-pyrrole as a white solid in 61.8% yield. ¹ H NMR(400MHz,CDCl ₃ ) δ8.24(s,1H),7.58–7.49(m,2H),7.35(t,J＝7.6Hz,2H),7.19(t,J＝7.4Hz,1H), 7.05(t,J＝2.1Hz,1H),6.85(d,J＝3.5Hz,1H),6.65(dt,J＝17.1,1.8Hz,2H),2.54 –2.43(m,3H). ¹³ CNMR(151MHz,CDCl ₃ )δ137.71,135.34,133.55,128.63, 127.95,126.42,125.76,125.72,125.18,120.99,114.79,104.12,15.28.

(2) Synthesis of dye C

The synthesis method is the same as the synthesis route of the dye A. Dye C, a copper colored solid, yield 79.2%. ¹ H NMR(400 MHz,CDCl ₃ )δ8.17(d,J＝3.9Hz,2H),8.07–8.01(m,4H),7.50–7.37(m,6H), 7.10(d,J＝1.1Hz,2H),6.94(dd,J＝3.9,1.2Hz,2H),2.60(s,6H). ¹³ CNMR(151 MHz,CDCl ₃ )δ149.20,147.91,145.47,142.07,133.66,132.34,132.01,129.17, 129.13,128.72,128.50,118.26,29.71,15.91,0.00.

(3) Synthesis of Compound 3

Synthetic methods are consistent with the synthetic route for compound 2. Compound 3, a copper colored solid, yield 83.1%. ¹ H NMR (400MHz,CDCl ₃ )δ8.22(d,J＝4.0Hz,1H),8.04–7.98(m,2H),7.78(dt,J＝6.1, 1.5Hz,2H),7.73(d,J＝3.7Hz,1H),7.53–7.42(m,3H),7.37(dt,J＝5.6,3.3Hz, 3H),7.18(s,1H),6.97–6.91(m,2H),2.62(s,3H),2.60(s,3H). ¹³ C NMR(151MHz, CDCl ₃ )δ153.42,151.56,147.90,147.15,145.71,144.75,144.05,143.51,136.58, 133.88,132.91,131.29,131.12,130.96,129.90,129.81,129.57,129.14,128.70, 128.59,127.70,126.17,119.92,16.15,15.66.。

Example 4: synthesis of Compound 4

(1) Synthesis of dye D

4-phenyl-2- (p-tolyl) -1H-pyrrole (23.3mg, 0.1mmol) was added to glacial acetic acid (1 ml) and stirred, the temperature was reduced to 5 ℃ then sodium nitrite (6.9mg, 0.1mmol) was added and stirring was continued for 15 min. The color of the solution changed from colorless to brown, then to green, and finally to brown. Then 7-methoxy-3-phenyl-4,5-dihydro-1H-benzo [ g ] indole (27.5mg, 0.1mmol) was added followed by acetic anhydride (0.4 ml) and the reaction turned green immediately, stirring was continued for 30min at room temperature, then warmed to 80 ℃ and stirred for 30min, TLC spot plates indicated complete reaction. And cooling the reaction liquid to room temperature, adding ice water to quench the reaction, filtering the precipitated blue dye, washing a filter cake with water, and drying. Performing chromatography on the filter cake by using a neutral alumina column, taking dichloromethane as an eluent, spin-drying the solvent, and pumping by using an oil pump to obtain a product;

the above product was dissolved in dry 1,2-dichloroethane (10 ml), triethylamine (0.24 ml) was added, then boron trifluoride diethyl etherate (0.24 ml) was added dropwise, stirred at room temperature for 30min, then warmed to 80 ℃ and stirred for 30min. The reaction solution was cooled to room temperature, ice water was added to quench the reaction, dichloromethane was used for extraction three times, the organic phases were combined, dried over anhydrous sodium sulfate, and column chromatography was performed using dichloromethane/petroleum ether (1/8), and the product obtained was recrystallized using dichloromethane/n-hexane (1/1) to give a product as a copper solid, 40.0mg, yield 70.7%. ¹ H NMR(400MHz, CDCl ₃ )δ8.71(d,J＝9.0Hz,1H),8.10–8.02(m,2H),7.96(d,J＝8.1Hz,2H),7.77 –7.69(m,2H),7.53–7.46(m,2H),7.46–7.28(m,6H),6.99–6.91(m,2H),6.82(d, J＝2.6Hz,1H),3.89(s,3H),2.95(t,J＝3.1Hz,4H),2.43(s,3H). ¹³ C NMR(151 MHz,CDCl ₃ )δ162.34,155.50,153.95,146.33,144.59,143.54,139.49,139.38, 138.19,132.42,132.11,131.87,131.17,129.81,129.17,128.65,128.26,127.99, 127.86,127.79,127.54,119.20,116.39,113.93,112.71,54.89,29.86,29.07,28.69, 26.59,21.23,20.95.

(2) Synthesis of Compound 4

Dissolving dye D (20mg, 0.035mmol) in dichloromethane (6 ml), adding glacial acetic acid (2 ml), then adding NIS (7.9mg, 0.035mmol), reacting at room temperature for 30min, extracting the reaction liquid with dichloromethane for three times, combining organic phases, concentrating, performing column chromatography separation, and concentrating to obtain the product, wherein the eluent is dichloromethane/petroleum ether (1/7). For productsDichloromethane/petroleum ether (1/1) was recrystallized to give the final product as a copper solid, 21.6mg, 89.0% yield. ¹ H NMR(400MHz,CDCl ₃ )δ8.59(d,J＝9.1Hz,1H),7.84– 7.78(m,2H),7.68–7.63(m,2H),7.61(d,J＝7.9Hz,2H),7.47–7.35(m,6H),7.32 (d,J＝7.9Hz,2H),6.88(dd,J＝9.0,2.7Hz,1H),6.80(d,J＝2.6Hz,1H),3.86(s, 3H),2.94(td,J＝7.4,4.7Hz,4H),2.46(s,3H). ¹³ C NMR(151MHz,CDCl ₃ )δ 163.27,158.42,152.35,147.33,145.49,141.73,140.75,139.41,138.82,133.42, 132.84,132.76,132.38,130.53,130.13,129.66,129.00,128.32,127.89,127.68, 127.58,127.03,118.48,114.02,113.01,77.75,54.97,29.71,28.70,21.42,21.08.。

Example 5: synthesis of Compound 5

(1) Synthesis of dye E

Synthetic methods refer to the synthetic route for dye D. Product E, a copper colored solid, yield 74.2%. ¹ H NMR (400MHz,CDCl ₃ )δ8.70(d,J＝9.0Hz,1H),8.09–8.03(m,4H),7.72(d,J＝7.6Hz, 2H),7.41(ddt,J＝38.1,13.8,7.1Hz,6H),7.02(d,J＝8.8Hz,2H),6.95(d,J＝8.2 Hz,2H),6.82(d,J＝2.7Hz,1H),3.89(d,J＝2.4Hz,6H),2.94(s,4H).

(2) Synthesis of Compound 5

Synthetic methods refer to the synthetic route for compound 4. Compound 5, a copper colored solid, yield 85.4%. ¹ H NMR (400MHz,CDCl ₃ )δ8.61(d,J＝9.0Hz,1H),7.86–7.78(m,2H),7.75–7.63(m, 4H),7.53–7.34(m,6H),7.09–7.01(m,2H),6.91(dd,J＝9.0,2.6Hz,1H),6.82(d, J＝2.6Hz,1H),3.91(s,3H),3.88(s,3H),2.94(q,J＝4.4,3.8Hz,4H). ¹³ C NMR (151MHz,CDCl ₃ )δ163.18,159.89,158.06,152.32,147.20,145.41,141.87,141.02, 139.27,133.29,132.68,132.38,131.85,130.57,130.13,129.65,128.28,127.71, 127.57,127.03,124.14,118.54,114.02,112.97,112.59,78.08,54.96,54.60,29.72, 21.41.。

Example 6: synthesis of Compound 6

(1) Synthesis of dye F

A synthetic method of a synthetic homodye D. Compound F, a copper colored solid, yield 78.3%. ¹ H NMR(400 MHz,CDCl ₃ )δ8.80(d,J＝9.0Hz,1H),8.27(dd,J＝3.9,1.0Hz,1H),8.10–8.01 (m,2H),7.74–7.69(m,2H),7.54–7.30(m,7H),7.23(dd,J＝5.1,3.9Hz,1H),7.09 (s,1H),7.02(dd,J＝9.0,2.7Hz,1H),6.85(d,J＝2.7Hz,1H),3.91(s,3H),2.96(s, 4H). ¹³ CNMR(151MHz,CDCl ₃ )δ162.28,154.79,146.40,145.74,144.53,143.68, 139.40,137.80,134.08,132.02,131.96,131.57,131.20,130.64,129.79,128.95, 128.74,128.25,128.05,127.95,127.80,127.53,119.38,116.35,113.99,112.75,54.91, 29.91,29.08,21.21.

(2) Synthesis of Compound 6

A method for synthesizing compound 4. Compound 6, a copper colored solid, yield 83.4%. ¹ H NMR(400 MHz,CDCl ₃ )δ8.70(d,J＝9.1Hz,1H),7.78(dt,J＝6.4,1.4Hz,2H),7.71(dd,J＝ 3.8,1.2Hz,1H),7.66(dd,J＝7.6,2.1Hz,2H),7.61(dd,J＝5.1,1.2Hz,1H),7.48– 7.36(m,6H),7.23(dd,J＝5.1,3.7Hz,1H),6.95(dd,J＝9.0,2.7Hz,1H),6.83(d,J ＝2.6Hz,1H),3.90(s,3H),2.96(td,J＝6.8,4.5Hz,4H). ¹³ C NMR(151MHz, CDCl ₃ )δ164.21,159.72,148.52,146.49,144.95,142.36,141.43,140.12,134.50, 133.74,133.00,132.54,132.38,131.00,130.82,130.28,129.05,128.99,128.33, 128.23,127.64,127.05,119.02,114.73,113.79,55.66,30.33,22.09.。

Example 7: synthesis of Compound 7

(1) Synthesis of dye G

A synthetic method of a synthetic homodye D. Dye G, a copper colored solid, yield 67.3%. ¹ H NMR(400 MHz,CDCl ₃ )δ8.77(d,J＝9.0Hz,1H),8.10(d,J＝3.9Hz,1H),8.07–8.01(m,2H), 7.71(dt,J＝6.6,1.3Hz,2H),7.52–7.44(m,2H),7.44–7.29(m,4H),7.07–6.97 (m,2H),6.91(dd,J＝3.9,1.2Hz,1H),6.84(d,J＝2.6Hz,1H),3.90(s,3H),2.94(s, 4H),2.58(s,3H). ¹³ C NMR(151MHz,CDCl ₃ )δ162.50,154.04,147.22,146.54, 146.21,144.73,144.68,140.38,137.78,132.60,132.41,132.34,132.06,131.96, 131.74,130.41,128.89,128.71,128.41,128.33,128.12,120.28,117.08,114.56, 113.24,55.50,30.59,29.71,21.80,15.80.

(2) Synthesis of Compound 7

Synthetic route to compound 4. Compound 7, a copper colored solid, yield 87.2%. ¹ H NMR(400 MHz,CDCl ₃ )δ8.71(d,J＝9.1Hz,1H),7.79–7.73(m,2H),7.68–7.63(m,2H), 7.59(d,J＝3.7Hz,1H),7.47–7.36(m,6H),6.96(dd,J＝9.0,2.7Hz,1H),6.90(dd, J＝3.7,1.1Hz,1H),6.83(d,J＝2.6Hz,1H),3.90(s,3H),2.97–2.93(m,4H),2.61 (d,J＝1.1Hz,3H). ¹³ C NMR(151MHz,CDCl ₃ )δ163.92,158.80,148.17,146.18, 145.85,144.54,142.63,142.16,139.75,134.11,133.48,133.05,131.14,130.85, 130.27,130.07,129.89,128.93,128.35,128.20,127.62,125.88,55.63,30.37,22.07, 15.61.。

Example 8: optical parameter and photosensitization efficiency test of photosensitizer

The synthesized photosensitizer was tested for the maximum absorption wavelength (. Lamda.) in the corresponding solvent _abs ) Molar extinction coefficient (. Epsilon.), fluorescence emission wavelength (. Lamda.) _em ) Fluorescence quantum yield (phi) _f ) Relative velocity of singlet oxygen productionRate and singlet oxygen yield (. PHI.) _Δ ) The corresponding data are listed in table 1. The data in the table show that the synthesized photosensitizer has the maximum absorption in the near infrared band and higher molar absorption coefficient, and compared with positive control, the single-iodine substituted photosensitizer has lower fluorescence quantum yield; the relative photosensitizing efficiency of the photosensitizer in isopropanol was tested with Methylene Blue (MB) as a reference; the relative singlet oxygen yield of the photosensitizer in N, N dimethylformamide was tested by taking zinc phthalocyanine (ZnPc) as a reference, and the data shows that the photosensitization ability of the compounds 1 and 5 is relatively better under two test systems, and the compounds are likely to have better cell activity. The photosensitization efficiency test method comprises the following steps:

preparation of DPBF solution

Weighing 2.70mg of DPBF (M = 270.32), transferring to a 100ml brown volumetric flask, fixing the volume of an organic solvent, uniformly mixing, ultrasonically oscillating, standing for 30min in a dark place, and preparing an organic solution of 100 mu M of DPBF;

2. preparation of photosensitizer solution

Transferring 2ml (10 mu M photosensitizer solution) to a 10ml volumetric flask by a pipette, and preparing 2 mu M solution by organic solvent with constant volume;

3. preparation of the Mixed solution

Transferring 2ml of the prepared 100 mu M DPBF solution into a photophobic EP tube made of tinfoil paper by a pipette, taking 2ml of the prepared 2 mu M photosensitizer solution into the EP tube by the same method, uniformly mixing, immediately testing sample absorption, and recording as 0s;

4. illuminated operation

The light source adopts a halogen lamp (25W), the middle part of the halogen lamp contains a heat-insulating water layer and an optical filter (A), (B)>510 nm), the optical power is 6.0mW/cm ² . The light source was turned on, the light barrier was removed, the light barrier was inserted after an irradiation interval of 10s to 10s, and the absorption of the sample was immediately measured. According to the process, the absorption of 20s, 30s, 40s, 50s and 60s illumination samples is respectively measured;

5. the photosensitization efficiency of standard zinc phthalocyanine (ZnPc) or Methylene Blue (MB) was used as a reference.

TABLE 1 photophysical parameters of the photosensitizers

a: testing in chloroform; b, testing the relative singlet oxygen yield in isopropanol; c: singlet oxygen quantum yield value (reference ZnPc, phi) _Δ =0.56, solvent DMF).

Example 9: photostability test

Photostability is an important investigational indicator of photosensitizers. In the photodynamic illumination, the photosensitizer ensures certain stability, and the data obtained by the test can more truly reflect the photodynamic effect of the photosensitizer; in cell biology experiments and animal in vivo experiments, effective photodynamic reactions can be generated only by illumination under the condition that photosensitizer is not damaged or aggregated and separated out. Therefore, in order to more fully study the photostability behavior of the photosensitizer, the stability was studied in N, N-dimethylformamide, acetonitrile, isopropanol and PBS buffer systems, respectively. Preparing a solution of the photosensitizer with a certain concentration (10 mu M), placing the solution in a cuvette, respectively giving illumination for 0,1,2,4,6 and 10min, then testing the absorbance of the solution for corresponding time, and normalizing the data, wherein the obtained data are shown in a bar chart below;

as shown in FIG. 1, the stability of monosubstituted photosensitizer 1 is superior to the positive control in the DMF system; in an acetonitrile system, the degradation speed of the photosensitizer is obviously slowed down, and the stability of the photosensitizer 1 is still better than that of a positive control; in the isopropanol and PBS system, the decrease in absorbance of the photosensitizer was relatively slow and also showed that the stability of monosubstituted photosensitizer 1 was superior to the positive control.

Example 10: chemical stability test

After the light stability investigation is finished, continuing to research the chemical stability of the photosensitizer; acetonitrile and a PBS buffer solution system (containing 0.01 percent of emulsifier system) are respectively selected, the concentration of the photosensitizer is prepared to be 10 mu M, the solution is placed in a dark place, the absorbance of the solution is respectively tested at different time, and the change condition of the solution is observed. For an acetonitrile system, after the absorbance test is finished on the seventh day, volatilizing acetonitrile, adding Dichloromethane (DCM) with the same volume for redissolving, and testing the absorbance;

as shown in fig. 2, in the acetonitrile system, the absorbance of photosensitizer 1 was still greater than 95% at day seven, the absorbance of control ADPM06 decreased relatively quickly, and after addition of dichloromethane, the absorbance did not recover significantly, indicating that the photosensitizer may be destroyed. In a PBS buffer system, the absorbance change of the monosubstituted photosensitizer is small; the drop in disubstituted photosensitizer was large, indicating that damage could occur in this system, or aggregation occurred due to poor solubility resulting from low emulsifier content, so the chemical stability of 1 was superior to the positive control ADPM06 in both test systems.

Example 11: cell viability assay

(1) Cell culture

Cell culture conditions: three tumor cell lines, heLa (human cervical cancer cell), MCF-7 (human breast cancer cell) and SW480 (human intestinal cancer cell), were selected for the experiment. The medium was DMEM (HyClone) containing 10% Fetal Bovine Serum (FBS) and 1% penicillin (10,000units/mL) -streptomycin (10,000. Mu.g/mL) (HyClone). After cell recovery, 5% CO at 37 ℃ ₂ Culturing in an incubator. Cell and animal lighting conditions: the light source adopts a halogen lamp (75W), and the near infrared light (lambda) is obtained by filtering with a filter>590 nm), heat emitted by the halogen lamp is removed by adopting a heat-insulating water layer;

(2) Cytotoxicity test

The cytotoxicity was evaluated by MTT assay. The cultured cells are digested by pancreatin and then inoculated into a 96-well culture plate, the density is about 3000 cells/well, and the cells are cultured for 12 hours to grow adherently. Then removing the culture medium, adding photosensitizer with different concentrations, setting five multiple wells for 3 hr incubation, sucking out the culture medium containing photosensitizer, adding fresh culture medium, and irradiating with halogen lamp (lambda)>590nm, light dose 54J/cm ² ) After 24 hours of further incubation, the medium was aspirated, 100. Mu.l of a medium containing MTT (0.5 mg/ml) was added to a 96-well plate, the plate was left in an incubator for 4 hours, then the medium was carefully aspirated, 100. Mu.l of DMSO was added to each well, the incubator was incubated for 15 minutes to sufficiently dissolve formazan produced, and then the solution was measured with a microplate reader at 490nmAbsorbance (OD value). Cell viability was calculated by the following formula: cell viability = [ (experimental OD value-zero adjustment hole OD value)/(control OD value-zero adjustment hole OD value)]×100％；

The dark toxicity test of the cells does not need illumination, and the rest adopts the test method which is the same as the phototoxicity;

(3) The results are shown in table 2, and show that the inhibitory activity of chemicals 1 and 5 is relatively better than that of the positive control ADPM06 in the three tumor cell models tested;

the result shows that the compound of the invention can be further used for preparing a novel photodynamic anti-tumor photosensitizer;

TABLE 2 phototoxicity and dark toxicity of photosensitizers in three tumor cell lines HeLa, MCF-7 and SW480

(4) To more intuitively compare phototoxicity and dark toxicity of 1 and ADPM06, they were IC's on HeLa cells ₅₀ Specific data for the curves and dark toxicity are shown in FIG. 3, as shown in FIG. 3A, at a light dose of 54J/cm ² 1 shows phototoxicity superior to ADPM06 at a photosensitizer concentration of 30-250 nM; as shown in fig. 3B, in the dark toxicity test, both photosensitizer 1 and ADPM06 showed some dark toxicity with increasing concentration, and exhibited concentration dependence; the dark toxicity of the two was greatly different at a concentration of 50. Mu.M, and the dark toxicity of 1 was lower than that of ADPM06.

Example 12: light dose toxicity test

The dose given in the photodynamic research is an important experimental parameter, different doses of light have great influence on the activity of the photosensitizer, and the appropriate dose is usually searched and fixed in the research to perform other studies on the photodynamic effect; in this example, for more complete research on photosensitizer 1, a HeLa cell line was selected and subjected to a light dose test experiment, as shown in fig. 4, in which cells were incubated with 1 at a concentration of 100nM, and cell survival rates were tested by administering different light doses, and the results showed that, in a certain concentration range, the cell survival rates were dose-positively dependent on light dose.

Example 13: organelle localization experiments

The localization properties of photosensitizers determine the site of photodynamic action, affecting the cell death mechanism. In photodynamic reactions, it is generally believed that singlet oxygen generated by type II reactions plays a major role, and since singlet oxygen has a very short half-life (0.03 to 0.18ms) and a limited diffusion distance (< 0.04 μm), the location of distribution of the photosensitizer in the tumor cell is the site at which the photosensitizer acts; in this example, in order to investigate the organelle localization ability of photosensitizer 1, an organelle co-localization experiment was performed; in the experiment, a laser confocal living cell workstation is used, heLa cells are respectively incubated with a photosensitizer and a commercially available organelle dye, and the positioning effect of the HeLa cells is judged according to the positioning and overlapping capacity of the photosensitizer and the commercially available organelle dye;

HeLa cells were seeded in a culture dish and then were allowed to reach a content of 5% CO ₂ The culture box is incubated for 12 hours at the temperature of 37 ℃, the culture medium is sucked off, fresh culture medium containing photosensitizer 1 (5 mu M) is added, the culture box is incubated for 2 hours, then the cells are rinsed three times by PBS, then the cells are respectively incubated for 20 minutes by Mito-Tracker Green (250 nM), lyso-Tracker Green (160 nM) or ER-Tracker Green (1 mu M), then the cells are rinsed three times by PBS, fresh culture medium is added, then confocal localization imaging is carried out (Carl Zeiss LSM710 living cell imaging workstation),

as shown in fig. 5, fig. 5A, 5E, 5I are the morphology of the cells in the bright field, 5B, 5F, 5G are the green fluorescence images of the cells after incubation with the mitochondrial, endoplasmic reticulum, and lysosome localization probes, respectively, 5C, 5G, 5K are the red fluorescence images of the cells after incubation with photosensitizer 1, 5D, 5H, 5L are the superimposed images of the green fluorescence of the corresponding probes and the red fluorescence of the photosensitizer, the localization effect is shown from the three panels 5D, 5H, 5L, and the fluorescence co-localization curve of fig. 6 shows: FIG. 5D shows better coincidence, FIGS. 5H, 5L are less coincident, indicating that 1 is predominantly localized to mitochondria, and only marginally distributed to the endoplasmic reticulum and lysosomes; mitochondria are the main energy supply unit of cells, and the photosensitizer is positioned in the mitochondria to realize the in-situ damage to the mitochondria, so that the killing effect of the photosensitizer is exerted to the maximum extent, the energy supply system of the cells is damaged, and the cells are dead; photosensitizer 1 is mainly localized to mitochondria, suggesting that 1 has a better photodynamic effect, which is consistent with its excellent cell activity results.

Example 14: apoptosis assay

Experiments were carried out using HeLa cells, seeded in six-well plates and then assayed at 5% CO ₂ Was incubated at 37 ℃ for 12 hours. Then, the original culture medium was aspirated, and photosensitizer 1 was added to each of the culture media at different concentrations, incubated for 3 hours, and a light dose of 54J/cm was administered ² Then washed three times with PBS, fresh medium was added, and incubation was continued for 24h. Cell necrosis and apoptosis were assessed by Annexin V-FITC and PI (Beyotime, china) double staining with a Cytoflexs flow cytometer (Beckman, USA). The results of the experiment are shown in FIG. 7: the concentration is 200nM, and the light dose is 54J/cm ² In time, the apoptosis rate of the B group reaches 89.64 percent; the concentration is 200nM, and the light dose is 27J/cm ² In time, the apoptosis rate of group C reached 35.44%; the concentration was 40nM and the light dose was 54J/cm ² When the cell is in the normal state, the apoptosis rate of the group D is 20.99%; the apoptosis rate of the control group A is only 6.46%; the data indicate that the effect of photosensitizer 1 on apoptosis appears concentration-dependent and light dose-dependent.

Example 15: intracellular reactive oxygen species level testing

In the photodynamic reaction, the photosensitizer kills tumor cells by reactive oxygen species generated by type I and type II reactions. In order to further more intuitively study the level of active oxygen generated in the photodynamic reaction, a commercially available active oxygen probe H was used in this example ₂ DCFDA carries out 1 intracellular reactive oxygen level test, and carries out forward and reverse verification experiments;

forward validation experiment: heLa cells were incubated with different concentrations (0.004,0.02,0.10,0.5,2.5. Mu.M) of photosensitizer before addition of active oxygen probe H ₂ DCFDA (10. Mu.M) incubation with 54J/cm light dose ² Then, using a confocal laser microscope to image the cells incubated with the photosensitizer at different concentrations, as shown in FIG. 8A, a-e represent the illumination group, a1-e1 represent the non-illumination group, and FIG. 8B represents the corresponding fluorescence intensity values of the cells at different concentrations in FIG. 8A; the two figures areThe data show that the photosensitizer generates active oxygen levels in a concentration positive dependence relationship within the tested concentration range (0.004-2.5 mu M); in order to verify the accuracy of the result, the corresponding fluorescence intensity of the cells is further tested by an enzyme-labeling instrument method, as shown in fig. 8C, the fluorescence intensity value of the group without illumination is very low, after illumination is added, the generated fluorescence value is obviously different from that of the control group, and the data is matched with the confocal result;

further, a reverse verification method is adopted to probe whether active oxygen generated by the reaction is a main mechanism of photodynamic, and the following experiment is carried out; sodium azide is a common quenching agent of active oxygen, and the influence of the sodium azide on the fluorescence of cells is researched by adding the sodium azide in a contrast manner; as shown in FIG. 9, panel A is a control group, and panel B is incubated with photosensitizer and then with H ₂ DCFDA incubation, panel C photosensitizer incubation followed by H ₂ DCFDA incubation followed by sodium azide incubation, panel D sodium azide incubation followed by 54J/cm light dose administration to group A-D cells ² And FIGS. E-H are corresponding non-illuminated groups; the group without light shows no fluorescence; panel A/D shows no fluorescence, indicating that the cells themselves and sodium azide have no effect on fluorescence; the fluorescence intensity of panel C is significantly lower than that of panel B, indicating that some degree of photodynamic-generated reactive oxygen species is quenched after the addition of sodium azide.

Example 16: small animal living body imaging and in vitro organ imaging experiment

Nude mice with the weight of 18-22g are selected for the experiment and inoculated with HeLa tumor cell strains, the cell density of which is 5 multiplied by 10 ⁶ When the tumor volume reaches 80-100mm ³ The test is carried out; the concentration of the photosensitizer 1 is 250 mu M, the tail vein injection volume is 0.1ml, and the nude mouse living body fluorescence images are tested at different time after the injection; then, the nude mice corresponding to the time are dissected and tested for the isolated fluorescence intensity of different organs (heart, liver, spleen, lung, kidney and tumor);

as shown in fig. 10, the blank mice were not fluorescent themselves, and at the selected time point after the injection of the photosensitizer, the fluorescence intensity reached a maximum at 1h, after which the fluorescence intensity rapidly dropped, and at 10h the fluorescence intensity was already close to the background intensity; in organ fluorescence intensity testing, photosensitizers present a differential distribution in different organs: the distribution is the most in the lung, the second in the liver, spleen and kidney, and the distribution of tumor and heart is relatively less; in the metabolic rate, the heart has the highest fluorescence intensity within 1-3h, and the liver, the spleen, the kidney and the heart have peak values within 20min-3 h; the fluorescence of the tumor part shows a peak value in about 3h and then begins to decline, and a certain fluorescence intensity is still maintained in 10h, which indicates that the photosensitizer is accumulated in the tumor part to a certain extent.

Example 17: experiment on HeLa xenograft tumor in nude mouse

In the experiment, ADPM06 and a commercially available photosensitizer Ce6 are selected as references to perform an anti-tumor activity experiment of the compound 1 in a nude mouse body; inoculating HeLa tumor cell strain on the right back of nude mouse, wherein the cell density of each tumor inoculation is 5 × 10 ⁶ And selecting the weight of 18-22g and the tumor volume of 80-100mm on the seventh day after inoculation ³ The nude mice of (2) were used for the experiment; nude mice were randomly divided into four groups: control, ADPM06, 1 and Ce6, six per group; the control group is administered with normal saline solution of the same amount, the experimental group is injected with photosensitizer solution (2 mg/kg) by tail vein injection, the tumor part is illuminated 15min after injection, and the light source is halogen lamp (emitting power 90 mW/cm) ² ) A water layer heat insulation and optical filter system is adopted between the halogen lamp and the nude mice, the irradiation time of each nude mouse is 10min, and the total light dose is 54J/cm ² (ii) a After the light irradiation, all the nude mice were kept in an animal room, and the long diameter (L) and the short diameter (W) of the tumor were recorded with a vernier caliper every other day, and the nude mice were weighed with a balance. Tumor volume calculation formula: v =0.5 × (L × W) ² )；

The experimental results are shown in FIG. 11, in which panel A shows the ex vivo images of tumors of each group after 24 days, panel B shows the growth curve of tumors of each group, panel C shows the weight of tumors of each group, and panel D shows the weight change of mice of each group during growth; the tumor volume and weight of the ADPM06 group and the ADPM06 group were significantly lower than those of the control group and the Ce6 group, tumors of the 1 group and the ADPM06 group began to rebound starting at 14 days after the light irradiation, and then the growth rate of the tumors of the ADPM06 group was gradually higher than that of the 1 group with the time; the body weights of the mice in the group 1 and the ADPM06 group have no obvious difference and increase along with the increase of time, and finally the body weight tends to be constant; the body weights of the mice in the control group and the Ce6 group start to obviously decrease at the 12 th day, wherein the body weight decrease speed of the mice in the control group is greater than that of the mice in the Ce6 group; the overall anti-tumor effect of the photosensitizer 1 is superior to that of the ADPM06 group and the commercially available photosensitizer Ce6 group.

Claims (16)

1. Monoiodo substituted BODIPY compounds having the structure of formula (I):

wherein:

R ₁ 、R ₂ 、R ₃ ar is independently selected from phenyl and C _1-6 Alkyl-substituted phenyl, C _1-6 Alkoxy-substituted phenyl, thienyl, C _1-6 Alkyl-substituted thienyl;

the dotted line is a C-C bond or absent.

2. The monoiodo substituted BODIPY compound of claim 1, wherein the dashed line is a C-C bond.

3. The monoiodo substituted BODIPY compound of claim 1, wherein the dashed line is absent.

4. The monoiodo substituted BODIPY compound of any of claims 1-3, wherein R is ₁ 、R ₂ Selected from phenyl.

5. The monoiodo substituted BODIPY compound of claim 1, wherein R is ₃ Selected from p-methylphenyl, p-methoxyphenyl, 2-thienyl, 5-methyl-2-thienyl.

6. The monoiodo-substituted BODIPY compound of claim 1, ar is selected from the group consisting of p-methylphenyl, p-methoxyphenyl, 5-methyl-2-thienyl.

7. The monoiodo-substituted BODIPY compound of claim 1, wherein the compound is Compound 1 having the following structure,

8. the monoiodo-substituted BODIPY compound of claim 1, wherein the compound is Compound 2 having the following structure,

9. the monoiodo-substituted BODIPY compound of claim 1, wherein the compound is Compound 3 having the following structure,

10. the monoiodo-substituted BODIPY compound of claim 1, wherein the compound is Compound 4 having the structure,

11. the monoiodo-substituted BODIPY compound of claim 1, wherein the compound is Compound 5 having the structure,

12. the monoiodo substituted BODIPY compound of claim 1, wherein the compound is Compound 6 having the structure,

13. the monoiodo-substituted BODIPY compound of claim 1, wherein the compound is Compound 7 having the structure,

14. use of a monoiodo substituted BODIPY compound according to any one of claims 1 to 13 for the preparation of a medicament for photodynamic therapy.

15. Use of a monoiodo-substituted BODIPY compound according to any one of claims 1 to 13 for the preparation of a medicament for the treatment of a malignant tumor.

16. The use of claim 15, wherein the malignant tumor is selected from the group consisting of skin cancer, prostate cancer, oral squamous carcinoma, cervical cancer, lung cancer, liver cancer, gastric cancer, breast cancer, colon cancer, bladder cancer, and esophageal cancer.

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