CN103435639A - Axial nucleoside asymmetrically-modified silicon phthalocyanine and preparation method and application thereof - Google Patents

Abstract

The invention discloses a silicon phthalocyanine asymmetrically modified by axial nucleosides, a preparation method and application thereof, and belongs to the field of preparation of photodynamic drugs or photosensitizers. The axial nucleoside asymmetrically modified silicon phthalocyanine provided by the present invention can be used as a photosensitizer for photodynamic therapy, photodynamic diagnosis or photodynamic disinfection. It has the structural characteristics of axial asymmetric substitution and shows good amphiphile and high photodynamic activity.

Description

A kind of axial nucleoside asymmetrically modified silicon phthalocyanine and its preparation method and application

technical field

The invention belongs to the field of preparation of photodynamic drugs or photosensitizers, and in particular relates to a silicon phthalocyanine asymmetrically modified by axial nucleosides and a preparation method and application thereof.

Background technique

Phthalocyanine compounds are an important class of functional materials, which can be developed into functional materials for different purposes through different structural modifications. By introducing suitable substituents and central ions on the phthalocyanine ring, it is possible to develop oxidation catalysts, desulfurization catalysts, nonlinear optical materials, photosensitive drugs, liquid crystal materials, optical recording materials or photoconductive materials, but how to regulate substituents and central ions To obtain the target functional compound, it requires creative work.

The application prospect of phthalocyanine compounds as photosensitizers in photodynamic therapy (Photodynamic Therapy) is attracting attention. The so-called photodynamic therapy (or photodynamic therapy), in essence, is the application of the photosensitization reaction of photosensitizers (or photosensitizers) in the medical field. The process of action is to first inject the photosensitizer into the body, and after a period of time (this waiting time is to allow the drug to be relatively enriched in the target body), the target body is irradiated with light of a specific wavelength (for the target in the body cavity, optical fiber can be used to Under the light excitation, the photosensitizer enriched in the target body inspires a series of photophysical and photochemical reactions to generate reactive oxygen species, thereby destroying the target body (such as cancer cells and cancer tissues).

In some developed countries, photodynamic therapy has become the fourth conventional method of treating cancer. Compared with traditional therapies, such as surgery, chemotherapy, and radiation therapy, the biggest advantage of photodynamic therapy is that it can selectively destroy cancer tissue without surgery, and the side effects are small, so it has attracted much attention.

At the same time, research in recent years has also shown that photodynamic therapy can also effectively treat non-cancer diseases such as bacterial infection, oral disease, macular degeneration eye disease, arteriosclerosis, trauma infection and skin disease. Photosensitizers can also be used for photodynamic disinfection, most importantly for water, blood and blood derivatives. At the same time, using the fluorescence properties of photosensitizers for photodynamic diagnosis is also an important application of photosensitizers.

The key to photodynamic therapy is the photosensitizer, and the photodynamic efficacy depends on the quality of the photosensitizer. Based on the potential of photodynamic therapy in the treatment of tumors and other diseases, the scientific community generally believes that photodynamic therapy will become an important medical method in the 21st century. Then, the photosensitizer as the core of photodynamic therapy will become an important and attractive new technology. technology industry.

So far, the photosensitizers approved for clinical use are mainly hematoporphyrin derivatives. In the United States, Canada, Germany, Japan and other countries, Photofrin is used (U.S. FDA officially approved Photofrin for clinical treatment of cancer in 1995), which is extracted from cow blood and chemically modified with low blood porphyrin. Polymer mixture. Hematoporphyrin derivatives have shown certain curative effects, but also exposed serious disadvantages: the maximum absorption wavelength (380-420nm) is not in the red light region (650-800nm) with better transmittance to human tissue, and the skin has high phototoxicity. It is a mixture and its composition is unstable, so its clinical application is limited, so the development of a new generation of photodynamic drugs (photosensitizers) is an international research hotspot.

Due to the characteristics that the maximum absorption wavelength is located in the red light region that is easy to pass through human tissues and the photosensitization ability is strong, the application of phthalocyanine compounds as photosensitizers has attracted attention. Among various phthalocyanine compounds, the application of silicon phthalocyanine as a new photosensitizer has been highly valued for the following reasons: (1) Silicon phthalocyanine can introduce two substituents in the axial direction, which can more effectively prevent the aggregation of phthalocyanine rings , to ensure the photosensitization ability of phthalocyanine; (2) Silicon has high biocompatibility and no dark toxicity. The axially substituted phthalocyanine silicon (Pc4) developed by Case Western Reserve University in the United States has shown high photodynamic activity and has entered phase I clinical trials. However, the synthesis route of Pc4 is complicated, the preparation cost is high, and the stability is poor. Therefore, it is urgent to screen new axially modified silicon phthalocyanine photosensitizers with high photosensitizing activity, easy preparation and low cost. In addition, the current photosensitizers (including phthalocyanine photosensitizers) in clinical trials still lack selectivity to tumor tissues and cancer cells, which is also a problem that needs to be overcome at present.

Chinese invention patents with patent numbers ZL200410013289.7 and ZL200610200598.4 introduce a series of axially substituted silicon phthalocyanine compounds, their preparation and their application in photodynamic therapy (this invention is the same inventor as this application). However, due to the potential huge economic and social value of photosensitizers and photodynamic therapy, the huge range of applications, and the refinement of treatment lesions, it is necessary to prepare more axially substituted silicon phthalocyanine compounds with photosensitizing activity as drug candidates.

It is particularly worth mentioning that Europe, America, Japan and other countries have increased their investment in new photosensitizers and the penetration of intellectual property rights. Under such circumstances, only by attaching great importance to the development of drugs with independent intellectual property rights and accelerating the pace of patent protection, In order to ensure my country's autonomy and commanding heights in the important medical field of photodynamic therapy. the

Contents of the invention

The object of the present invention is to provide a silicon phthalocyanine asymmetrically modified by axial nucleoside and its preparation method and application. The silicon phthalocyanine of the present invention has structural characteristics of axial asymmetric substitution, shows good amphiphilicity and high photodynamic activity, and has significant advantages in being used as a photosensitizer.

To achieve the above object, the present invention adopts the following technical solutions:

A silicon phthalocyanine asymmetrically modified by axial nucleosides, its structural formula is as follows:

，

,

Wherein the axial substituents R ₁ and R ₂ are respectively selected from the following groups:

、

、

中的一种； _R1 is ,

,

,

one of

、

、

、

、中的一种。 _R2 is

,

,

,

, One of.

The silicon phthalocyanine asymmetrically modified by the axial nucleoside is an axially asymmetric disubstituted silicon phthalocyanine, and the axial substituent is connected to silicon through an oxygen atom; silicon phthalocyanine, or silicon phthalocyanine, is a central ion of Phthalocyanine compounds of silicon. Phthalocyanine, the English name phthalocyanine, is the abbreviation of tetrabenzotetraazeporphyrin. The structural characteristics of the silicon phthalocyanine asymmetrically modified by the axial nucleoside are: one side of the axial substituent is uridine, cytidine or adenosine derivative, and the other side is aminoethylphenoxy or triethylene glycol or tetraethylene glycol derivatives.

The preparation method of the described axial nucleoside asymmetrically modified silicon phthalocyanine comprises the following steps:

(1) Bis[4-(2-aminoethyl)phenoxy]phthalocyanine silicon and 2',3'-O-isopropyl-uridine, 2',3'-O-isopropyl- One of cytidine, 2',3'-O-isopropyl-adenosine, and 2',3'-O-isopropyl-2-chloroadenosine is the reactant, and the molar ratio of the two is 1:1~10, use toluene, xylene or dioxane as solvent, under the protection of nitrogen, react at 100~130°C for 1~20 hours, remove excess raw materials and impurities by solvent cleaning and column chromatography, Obtain axial nucleoside and aminoethylphenoxy asymmetrically modified silicon phthalocyanine;

(2) Asymmetrically modify silicon phthalocyanine and one of triethylene glycol, triethylene glycol monomethyl ether, tetraethylene glycol, and tetraethylene glycol monomethyl ether with axial nucleosides and aminoethylphenoxy The first is the reactant, the molar ratio of the two is 1:1~10, with toluene, xylene or dioxane as the solvent, under the protection of nitrogen, react at 100~130°C for 1~20 hours, and wash with the solvent and column chromatography to remove excess raw materials and impurities to obtain axial nucleoside and oligoethylene glycol asymmetrically modified silicon phthalocyanine.

The silicon phthalocyanine asymmetrically modified by axial nucleosides as described above is applied to the preparation of photodynamic drugs or photosensitizers. The photosensitizer may be called a photosensitizer in the field of biomedicine, or a photosensitizer pharmaceutical preparation, also called a photodynamic drug. The prepared photodynamic drug or photosensitizer can be used for photodynamic therapy, photodynamic diagnosis or photodynamic disinfection. The photodynamic therapy may be the photodynamic therapy of malignant tumors, or the photodynamic therapy of benign tumors, or the extracorporeal photodynamic purification therapy of leukemia, or the photodynamic therapy of non-cancer diseases. The non-cancer diseases may be bacterial infections, oral diseases, macular degeneration eye diseases, arteriosclerosis, wound infections, skin diseases, or viral infections. The photodynamic disinfection can be photodynamic sterilization and purification of blood or blood derivatives, or photodynamic sterilization of water, or photodynamic disinfection of medical or domestic appliances.

The method for preparing photodynamic drugs or photosensitizers is as follows: water, or a mixed solution of water and other substances, wherein the mass fraction of other substances is not higher than 10%, is used as a solvent to dissolve the silicon phthalocyanine asymmetrically modified by axial nucleosides, It is formulated to contain a certain concentration of photosensitizer, and the concentration of silicon phthalocyanine asymmetrically modified by axial nucleosides is not higher than its saturation concentration; antioxidants, buffers and isotonic agents are added to the prepared solution as additives to maintain photosensitivity The chemical stability and biocompatibility of the agent; the other substances mentioned are castor oil derivatives (Cremophor EL), dimethyl sulfoxide, ethanol, glycerin, N,N-dimethylformamide, polyethylene glycol 300 - One or more mixtures of 3000, cyclodextrin, glucose, Tween, and polyethylene glycol monostearate.

Beneficial effect and outstanding advantage of the present invention are:

(1) The axial nucleoside asymmetrically modified silicon phthalocyanine provided by the present invention is an axially asymmetrically substituted silicon phthalocyanine, and the axial groups are respectively nucleoside and aminoethylphenoxy (or oligoethylene glycol) , with excellent amphiphilicity and unique asymmetric substitution characteristics.

(2) The axial group of the axial nucleoside asymmetrically modified silicon phthalocyanine provided by the present invention contains nucleoside derivatives, and nucleosides are biomolecules in vivo, so the biocompatibility and biological selection of the silicon phthalocyanine provided Sex is higher.

(3) The maximum absorption wavelength of the axial nucleoside asymmetrically modified silicon phthalocyanine provided by the present invention is located at 686-688 nm in aqueous solution, and the molar absorption coefficient is large (up to 10 ⁵ orders of magnitude), and its spectral properties are not only much better than those of the first A first-generation photosensitizer that outperforms other phthalocyanines currently in clinical trials. For example, the maximum absorption wavelength of silicon phthalocyanine provided by the present invention is red-shifted by nearly 10nm compared with Pc4 in the United States, and the tissue penetration ability of therapeutic light is further improved, which is very beneficial for photodynamic therapy and photodynamic diagnosis.

(4) The silicon phthalocyanine provided by the present invention has a clear structure and no positional isomers. The chemical modification of the parent structure of the phthalocyanine in the present invention is realized by introducing substituent groups in the axial direction of the phthalocyanine ring instead of the periphery of the phthalocyanine ring, so the structure of the target compound is clear and there is no isomer. If substituents are introduced around the phthalocyanine ring, since there are 16 possible substitution positions around the phthalocyanine ring, multiple isomers may be produced, resulting in products containing isomers or increased separation costs.

(5) The present invention selects silicon as the central ion of the phthalocyanine compound, the biological safety and biocompatibility of silicon are better than other common ions (zinc, aluminum, magnesium and gallium), and silicon phthalocyanine produces active oxygen High quantum yield.

(6) The silicon phthalocyanine provided by the present invention has high photostability, which is higher than other similar photosensitizers, such as Pc4 in the United States.

(7) The axial nucleoside asymmetrically modified silicon phthalocyanine provided by the present invention is obtained through a large number of screening tests and has extremely high photodynamic activity. For example, only 15nM [5'-( 2',3'-O-isopropyl)-uridineoxy][4-(2-aminoethyl)phenoxy]silicone phthalocyanine can 100% inhibit the growth of human gastric cancer cell BGC823 with IC ₅₀ value (the concentration of drug required to kill 50% of cancer cells) can be as low as 4nM.

(8) A large number of comparative experiments show that the photodynamic activity of the silicon phthalocyanine provided by the present invention with asymmetrically modified axial nucleosides is significantly higher than that of the corresponding symmetrically modified silicon phthalocyanine with axial nucleosides. The photodynamic anticancer activity of most axial nucleoside asymmetrically modified silicon phthalocyanines provided by the present invention is higher than that of axial aminoethylphenoxy symmetrically modified silicon phthalocyanines, that is, bis[4-(2-aminoethyl) Phenoxy]phthalocyanine silicon. The photodynamic anticancer activity of most axial nucleoside asymmetrically modified silicon phthalocyanines provided by the present invention is also higher than that of axial oligoethylene glycol symmetrically substituted silicon phthalocyanines, such as bis[(2-ethoxy)ethoxy Base] silicon phthalocyanine, bis [2-(2-methoxyethoxy) ethoxy] silicon phthalocyanine, bis {2- [2- (2-methoxyethoxy) ethoxy] ethyl Oxy}silyl phthalocyanine, bis{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}silyl phthalocyanine, bis{2-{2-[2-(2-methyl oxyethoxy)ethoxy]ethoxy}ethoxy}silylphthalocyanine, di{2-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy} Ethoxy}silicone phthalocyanine, etc. At the same time, the photodynamic anticancer activity of the axial nucleoside asymmetrically modified silicon phthalocyanine provided by the present invention is also significantly higher than that of other phthalocyanine compounds, such as axial bis(4-acetamidophenoxy) silicon phthalocyanine, di[ 4-(4-acetylpiperazine)phenoxy]silicon phthalocyanine, bis[4-(3-carboxypropyl)phenoxy]silicon phthalocyanine, bis(4-formylphenoxy)silicon phthalocyanine, Bis(3-phenoxyformyl)silyl phthalocyanine, bis(3,5-phenoxydicarboxylate)silyl phthalocyanine, bis(1-adamantane-methoxy)silyl phthalocyanine, bis(2-adamantane -ethoxy) silicon phthalocyanine, etc.; substituted zinc phthalocyanine, such as tetra-a-[4-(4-acetylpiperazine)phenoxy]zinc phthalocyanine, tetra-a-(4-formyl phenoxy ) Zinc phthalocyanine, etc.

(9) The synthesis and separation of asymmetrically substituted silicon phthalocyanines is difficult, and not all expected axially asymmetrically substituted silicon phthalocyanines can be obtained effectively. A large number of experimental studies have shown that the axially asymmetrically substituted silicon phthalocyanines described in the present invention can be effectively obtained, and their synthesis routes are relatively simple and have industrialization prospects.

Detailed ways

The preparation method of silicon phthalocyanine asymmetrically modified by axial nucleoside of the present invention is: (1) with bis[4-(2-aminoethyl)phenoxy]phthalocyanine silicon and 2', 3'-O-iso Propyl-uridine (or 2', 3'-O-isopropyl-cytidine, or 2', 3'-O-isopropyl-adenosine, or 2', 3'-O-isopropyl -2-chloroadenosine) as the reactant, the molar ratio of the two is 1:1~10, with toluene, xylene or dioxane as the solvent, under the protection of nitrogen, react at 100~130°C for 1 After ~20 hours, excess raw materials and impurities were removed by solvent washing and column chromatography to obtain axial nucleosides and aminoethylphenoxy asymmetrically modified silicon phthalocyanines. (2) Asymmetric modification of silicon phthalocyanine and triethylene glycol (or triethylene glycol monomethyl ether, or tetraethylene glycol, or tetraethylene glycol monomethyl ether) with axial nucleosides and aminoethylphenoxy ) as the reactant, the molar ratio of the two is 1:1~10, with toluene, xylene or dioxane as the solvent, under the protection of nitrogen, react at 100~130°C for 1~20 hours, pass through the solvent Excess raw materials and impurities are removed by washing and column chromatography to obtain axial nucleoside and oligoethylene glycol asymmetrically modified silicon phthalocyanine.

The axial nucleoside asymmetrically modified silicon phthalocyanine provided by the present invention can be used to prepare photodynamic drugs or photosensitizers (drugs), and can be used in photodynamic therapy or photodynamic diagnosis. The photodynamic therapy described in the present invention can be malignant Photodynamic therapy of tumors, or photodynamic therapy of benign tumors, or extracorporeal photodynamic purification therapy of leukemia bone marrow, or photodynamic therapy of non-cancer diseases. The non-cancer diseases mentioned in the present invention can be bacterial infection, or oral cavity disease, or macular degeneration eye disease, or arteriosclerosis, or wound infection, or skin disease, or virus infection.

The silicon phthalocyanine with axial nucleoside asymmetric modification provided by the present invention can be used to prepare photosensitizer (drug) agent for photodynamic disinfection. The photodynamic disinfection can be photodynamic sterilization and purification of blood or blood derivatives, Or photodynamic sterilization of water, or photodynamic disinfection of medical or domestic appliances.

The application of silicon phthalocyanine with axial nucleoside asymmetric modification provided by the present invention in photodynamic therapy, photodynamic diagnosis and photodynamic disinfection needs to be equipped with a suitable light source, and the suitable light source can be connected with a suitable filter by a common light source. Provided by a light sheet or by a laser with a specific wavelength, the wavelength range of the light source is 600-800nm, preferably 686-688nm.

The basic method for preparing photodynamic drugs (or photosensitizers) using the silicon phthalocyanine asymmetrically modified by axial nucleosides provided by the present invention is: use water, or a mixed solution of water and other substances (the content of other substances is not higher than 10 % (wt%)) as a solvent to dissolve the silicon phthalocyanine of the present invention, and prepare it to contain a certain concentration of photosensitizer, and the concentration of silicon phthalocyanine is not higher than its saturation concentration. The other substances mentioned can be one or a combination of the following: castor oil derivatives (Cremophor EL), dimethyl sulfoxide, ethanol, glycerin, N,N-dimethylformamide, polyethylene glycol 300- 3000, Cyclodextrin, Dextrose, Tween, Macrogol Monostearate. It is also possible to convert the silicon phthalocyanine described in the present invention into a salt form with hydrochloric acid or sulfuric acid or other acidic substances, and then dissolve it with the above-mentioned solvent. In the prepared solution, antioxidants, buffers and isotonic agents can be added as additives to maintain the chemical stability and biocompatibility of the photosensitizer.

For topical formulations, the silicon phthalocyanines of the present invention can be dissolved in penetrating solvents, or injected into ointments, lotions or gels. The penetrating solvent is preferably an aqueous solution of 5-35% (wt%) dimethyl sulfoxide.

The following non-limiting examples are used to further illustrate the present invention.

Example 1

Synthesis of Bis[5'-(2', 3'-O-isopropyl)-uridineoxy]silicone phthalocyanine

(1) Synthesis of 2’, 3’-O-isopropyl-uridine

Dissolve 245 mg (1 mmol) of uridine in 10-30 ml (preferably 20 ml) of acetone, and dissolve 8-12 mmol (preferably 10 mmol) of p-toluenesulfonic acid in 10-30 ml (preferably 20 ml) of acetone. Slowly add p-toluenesulfonic acid acetone solution to uridine acetone solution dropwise under ice-water bath, and stir at room temperature for 2-10 h (preferably 6 h). The reaction mixture was added to 4% sodium bicarbonate ice solution, extracted several times with dichloromethane (or trichloromethane), the organic layer was collected, dried over magnesium sulfate, filtered, concentrated, and dried to obtain a yellow powder product. Yield 85%.

The characterization data of the product are as follows: MS (EI-60) m/z: 283.4 [MH] ⁻ .

IR (KBr, cm ^-1 ): 1467, 2935 (CH ₃ ); 1703 (C=O); 1671 (C=C); 1467, 2935 (CH ₂ ); 3245 (NH,OH); -).

¹ H NMR (DMSO-d6, 400MHz, ppm): δ11.39 (s, 1H, pyrimidine-NH), 7.80 (d, J =8.0Hz, 1H, pyrimidine-NCH), 5.84 (s, 1H, 1′ -H), 5.64(d, J =8.0Hz, 1H, pyrimidine-COCH), 5.09(s, 1H, OH), 4.90(t, J =5.6Hz, 1H, 2′-H), 4.75(s, 1H, 3′-H), 4.07(s, 1H, 4′-H), 3.56-3.59(m, 2H, 5′-H), 1.49(s, 3H, Me), 1.29(s, 3H, Me ).

(2) Synthesis of bis[5'-(2', 3'-O-isopropyl)-uridineoxy]silicone phthalocyanine

Under nitrogen protection, dichlorosilicon phthalocyanine (40 mg, 0.065mmol), the above-mentioned isopropylidene protection product of uridine (0.260~0.650mmol, preferably 0.52mmol) and NaH (0.48~0.60mmol, preferably 0.42mmol ) into 10-40ml (preferably 20ml) of toluene, and reflux for 12-48 hours (preferably 24 hours). The solvent was removed by vacuum rotary evaporation, and washed with water to obtain a blue crude product. The crude product was purified by silica gel column, using ethyl acetate as the eluent, the second fraction was collected and concentrated, and then further purified by gel chromatography (S-X3 type) (tetrahydrofuran as the eluent), the target fraction was collected, concentrated and dried Afterwards, a blue product was obtained with a yield of 66%. The maximum absorption peak of the product in DMF is located at 678 nm, and the maximum absorption wavelength in 1% castor oil derivative (Cremophor EL, wt%) aqueous solution is located at 681 nm.

The structure of the product is shown in the following formula, and the characterization data are as follows:

。

.

HRMS (ESI) m/z: 1129.2948 [M+Na] ⁺ .

IR (KBr, cm ^-1 ): 734, 760, 911, 1081, 1291, 1336, 1429, 1522 (Pc ring); 1695, 1718 (C=O); 1374 (CH3); 3444 (NH); 1081 ( Si-O).

¹ H NMR (CDCl ₃ , 400MHz, ppm): δ9.66-9.68(m, 8H, Pc-H _α ), 8.44-8.46(m, 8H, Pc-H _β ), 7.44(s, 2H, pyrimidine- NH), 4.86 (d, J = 8.0 Hz, 2H, pyrimidine-NCH), 4.43 (d, J = 4.0 Hz, 2H, pyrimidine-COCH), 4.06 (d, J = 8.0 Hz, 2H, 1′-H ), 1.89-1.91(m, 2H, 2′-H), 1.36-1.39(m, 2H, 3′-H), 0.88(s, 6H, Me), 0.65(s, 6H, Me), 0.41 ( d, J =5.6Hz, 2H, 4'-H), -1.24(d, J =11.6Hz, 2H, 5'-H), -2.41(d, J =9.6Hz, 2H, 5'-H) .

Example 2

Synthesis of Bis[5'-(2', 3'-O-isopropyl)-cytidineoxy]silyl phthalocyanine

(1) Synthesis of 2’, 3’-O-isopropyl-cytidine

Dissolve 250 mg (1 mmol) of cytidine in 10-30 ml (preferably 20 ml) of acetone, and dissolve 8-12 mmol (preferably 10 mmol) of p-toluenesulfonic acid in 10-30 ml (preferably 20 ml) of acetone. Add p-toluenesulfonic acid acetone solution slowly dropwise to cytidine acetone solution under ice-water bath, stir at room temperature for 4~10 hours (preferably 6 hours), centrifuge, collect white precipitate, wash the precipitate with acetone three to four times, and dissolve with a small amount of DMF , add ethyl acetate to precipitate, membrane filtration, vacuum drying to obtain a white powder product with a yield of 95%.

The characterization data of the product are as follows: IR (KBr, cm ^-1 ): 1383 (CH ₃ ); 1123 (-O-); 1727 (C=O); 3067, 1204, 1650 (NH ₂ ); 1693 (C=C ); 3067, 1204(-OH).

¹ H NMR (DMSO-d6, 400MHz, ppm): δ9.49 (s, 1H, pyrimidine-H), 8.41 (s, 1H, NH ₂ ), 8.09 (d, J =7.6Hz, 1H, NH ₂ ) , 6.05(d, J =7.6Hz, 1H, pyrimidine-H), 5.76(d, J =1.2Hz, 1H, 1′-H), 4.86(t, J =3.0Hz, 1H, 2′-H) , 4.70-4.72(m, 1H, 3′-H), 4.21(d, J =2.8Hz, 1H, 4′-H), 3.51-3.61(m, 2H, 5′-H), 1.45(s, 3H, Me), 1.25(s, 3H, Me).

(2) Synthesis of bis[5'-(2', 3'-O-isopropyl)-cytidineoxy]silicone phthalocyanine

Under nitrogen protection, dichlorosilicon phthalocyanine (40 mg, 0.065mmol), the above-mentioned isopropylidene protection product of cytidine (0.260~0.650mmol, preferably 0.52mmol) and NaH (0.48~0.60mmol, preferably 0.42mmol ) into 10-40ml (preferably 20ml) of toluene, and reflux for 12-48 hours (preferably 24 hours). The solvent was removed by vacuum rotary evaporation, and washed with water to obtain a blue crude product. The crude product was purified by silica gel column, using ethyl acetate/DMF (volume ratio 20:1) mixed solvent as the eluent to remove the light green impurities, and then using DMF as the eluent to collect the target product. After concentration, it was further purified by gel chromatography (S-X3 type), and the blue product was obtained after vacuum drying with a yield of 52%. The maximum absorption peak of the product in DMF is located at 677 nm, and the maximum absorption wavelength in 1% castor oil derivative (Cremophor EL, wt%) aqueous solution is located at 681 nm.

The structure of the product is shown in the following formula, and the characterization data are as follows:

HRMS (ESI) m/z: 1127.3377 [M+Na] ⁺ . IR (KBr, cm ^-1 ): 742, 760, 910, 1081, 1123, 1291, 1335, 1428, 1519 (Pc ring); 3370 (NH ₂ ); 1081 (Si-O).

¹ H NMR (DMSO-d6, 400MHz, ppm): δ9.70-9.76(m, 8H, Pc-H _α ), 8.53-8.58(m, 8H, Pc-H _β ), 7.25(s(br), 2H, NH ₂ ), 7.06 (s(br), 2H, NH ₂ ), 5.38 (d, J = 6.8 Hz, 2H, pyrimidine-H), 4.51 (d, J = 3.6 Hz, 2H, pyrimidine-H) , 4.33(d, J =7.6Hz, 2H, 1′-H), 1.85-1.88(m, 2H, 2′-H), 1.24-1.31(m, 2H, 3′-H), 0.76(s, 6H, Me), 0.68(d, J =6.0Hz, 2H, 4'-H), 0.57(s, 6H, Me), -1.45(d, J =9.2Hz, 2H, 5'-H), - 2.31 (d, J = 10.4 Hz, 2H, 5'-H).

Example 3

Synthesis of Bis[5'-(2', 3'-O-isopropyl)-adenosyloxy]silyl phthalocyanine

(1) Synthesis of 2’, 3’-O-isopropyl-adenosine

Dissolve adenosine (1 mmol) in 10-30 ml (preferably 20 ml) of acetone, and 8-12 mmol (preferably 10 mmol) of p-toluenesulfonic acid in 10-30 ml (preferably 20 ml) of acetone. Add p-toluenesulfonic acid acetone solution slowly dropwise to 2-aminoadenosine acetone solution under ice-water bath, stir at room temperature for 24~72 h (preferably 6 h), pour into 4% sodium bicarbonate ice water solution, and precipitate white precipitate, Suction filter and dry. Purified by Soxhlet extraction with chloroform, and dried to obtain a white powder product. Yield 85%.

(2) Synthesis of bis[5'-(2',3'-O-isopropyl)-adenosyloxy]silicone phthalocyanine

Under nitrogen protection, dichlorosilicon phthalocyanine (40 mg, 0.065mmol), 2', 3'-O-isopropyl-adenosine (0.260~0.650mmol, preferably 0.52mmol) and NaH (0.48~0.60mmol , preferably 0.42mmol) into toluene 10 ~ 40ml (preferably 20ml), reflux for 12 ~ 48 hours (preferably 36 hours). The solvent was removed by vacuum rotary evaporation, and washed with water to obtain a blue crude product. The crude product was purified by a silica gel column, using acetone as the eluent, the target component was concentrated, and the blue product was obtained after drying, with a yield of 60%. The maximum absorption peak of the product in DMF is located at 677 nm, and the maximum absorption wavelength in 1% castor oil derivative (Cremophor EL, wt%) aqueous solution is located at 681 nm.

The structure of the product is shown in the following formula, and the characterization data are as follows:

.

MS (EI) m/z: 1152.7 [M] ⁺ .

IR (KBr, cm ^-1 ): 1618, 1426, 1256, 802, 692 (Pc ring); 1715, 1250 (C=O, O-C-O); 2922, 2862, 1435, (CH ₃ ) ; 2996 , 1445 (CH ₂ ) ; 1324 (CN); 1010 (Si—O).

¹ H NMR (CDCl ₃ , 400MHz, ppm): δ9.53-9.58 (m, 8H, Pc-H _α ), 8.34-8.40 (m, 8H, Pc-H _β ), 8.02 (s, 2H, pyrimidine- H), 5.65(s, 4H, NH ₂ ), 5.36 (s, 2H, imidazole-H), 4.51(d, J =5.4Hz, 2H, 1′-H), 2.11-2.14(m, 2H, 2 ′-H), 1.10(s, 6H, Me), 0.91(s, 6H, Me), 0.70(d, J =6.0Hz, 2H, 3′-H), -1.38 to -1.33 (m, 2H, 4'-H), -2.38 to -2.33 (m, 2H, 5'-H).

Elemental Analysis: Calculated C (60.41%), N (21.86%), H (4.20%) (calculated as C ₅₈ H ₄₈ N ₁₈ O ₈ Si); found C (60.16%), N (21.25%), H (4.90%).

Example 4

Synthesis of Bis[5'-(2', 3'-O-isopropyl)-2-chloroadenosyloxy]silyl phthalocyanine

(1) Synthesis of 2’, 3’-O-isopropyl-2-chloroadenosine

Dissolve 309 mg (1 mmol) of 2-chloroadenosine in 10-30 ml (preferably 20 ml) of acetone, and dissolve 8-12 mmol (preferably 10 mmol) of p-toluenesulfonic acid in 10-30 ml (preferably 20 ml) of acetone. Slowly add the acetone solution of p-toluenesulfonate into the acetone solution of 2-chloroadenosine in an ice-water bath, and stir at room temperature for 12-36 h (preferably 22 h). The reaction mixture was poured into 4% sodium bicarbonate ice solution, extracted with dichloromethane, the organic layer was collected, dried over magnesium sulfate, filtered, concentrated, and dried to obtain a white powdery product with a yield of 83%.

The characterization data of the product are as follows: The characterization data of the product are as follows: HRMS (ESI): 342.0968 [M+H] ⁺ .

IR (KBr, cm ^-1 ): 3475, 3409, 3154 (-OH, -NH ₂ ); 1656 (NC); 1598 (-NH ₂ ); 1472 (-CH ₂ -), 1313 (-CCH ₃ -) ;1098(COC).

¹ H NMR (DMSO-d6, 400MHz, ppm): δ8.37 (s, 1H, imidazole-H), 7.89 (s (br), 2H, NH ₂ ), 6.06 (d, J =2.4Hz, 1H, 1′-H), 5.28-5.30 (m, 1H, 2′-H), 5.10-5.12 (m, 1H, OH), 4.93-4.95 (m, 1H, 3′-H), 4.21-4.23 (m , 1H, 4′-H), 3.54-3.57 (m, 2H, 5′-H), 1.55 (s, 3H, Me), 1.33 (s, 3H, Me).

(2) Synthesis of bis[5'-(2', 3'-O-isopropyl)-2-chloroadenosyloxy]silicone phthalocyanine

Under nitrogen protection, dichlorosilicon phthalocyanine (40 mg, 0.065 mmol), the above-mentioned isopropylidene protection product of 2-chloroadenosine (0.260~0.650 mmol, preferably 0.52 mmol) and NaH (0.48~0.60 mmol, Preferably 0.42mmol) is added to toluene 10~40ml (preferably 20ml), and refluxed for 12~48 hours (preferably 24 hours). The solvent was removed by rotary evaporation in vacuo, dissolved in dichloromethane, washed with water, the organic layer was collected, dried over MgSO ₄ , filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified through a silica gel column, using ethyl acetate as the eluent to remove the light blue component, and then using tetrahydrofuran as the eluent to collect the target product, concentrated and further purified through a gel column, concentrated and dried in vacuo to obtain A blue product was obtained with a yield of 60%.

The maximum absorption peak of the product in DMF is located at 677 nm, and the maximum absorption wavelength in 1% castor oil derivative (Cremophor EL, wt%) aqueous solution is located at 680 nm.

The structure of the product is shown in the following formula, and the characterization data are as follows:

。

.

HRMS (ESI): m/z 1243.2866 [M+Na] ⁺ .

¹ H NMR (CDCl ₃ , 400MHz, ppm): δ9.62-9.63 (m, 8H, Pc-H _α ), 8.39-8.41 (m, 8H, Pc-H _β ), 6.43 (s, 4H, NH ₂ ), 5.39 (s, 2H, imidazole-H), 4.58 (d, J =3.0Hz, 2H, 1′-H), 2.19 (d, J =9.0Hz, 2H, 2′-H), 1.79-1.81 (m, 2H, 3′-H), 0.92(s, 6H, Me), 0.89-0.91(m, 2H, 4′-H), 0.76(s, 6H, Me), -1.28 (d, J = 14.0 Hz, 2H, 5'-H), -2.29 (d, J =15.5Hz, 2H, 5'-H).

Example 5

Synthesis and physical and chemical properties of bis[4-(2-aminoethyl)phenoxy]phthalocyanine silicon (structure shown in the following formula):

Under nitrogen protection, add dichlorosilyl phthalocyanine (244.7mg, 0.4mmol), 4-(2-aminoethyl)phenol 1.2~2 mmol (preferably 1.6mmol) and NaH to toluene or xylene or dioxane In 20~50ml (preferably toluene, 30ml), reflux for 12~24 hours (preferably 18 hours). Remove the solvent by rotary evaporation in vacuo, dissolve in 100ml of dichloromethane, centrifuge to remove insoluble matter, extract the dichloromethane solution with water (3×100ml), collect the organic layer, then extract with dilute hydrochloric acid (0.1~0.5 mmol), and collect the aqueous layer. The aqueous layer was neutralized with 1M sodium hydroxide, and a blue precipitate was precipitated, centrifuged, washed with water, and dried in vacuum to obtain a blue product with a yield of 45%. The maximum absorption peak of the product in DMSO is at 684 nm, and the maximum absorption wavelength in aqueous solution is at 689 nm.

The structural characterization data of the product are as follows: MS (ESI) m/z: 813.0 [M] ^- ; ¹ H NMR (DMSO-d6, ppm): δ 9.68 (m, 8H, Pc-Hα), 8.54 (m, 8H, Pc-Hβ), 5.40 (d, J = 8.4 Hz, 4H, CHAr), 2.21 (d, J = 8.3 Hz, 4H, CHAr), 1.97 (t, J = 7.0 Hz, 4H, CH2), 1.70 (t , J = 6.8 Hz, 4H, CH; IR (KBr, cm ^-1 ): 1607.9, 1524, 1429.3, 1335.8, 1290.8, 1166.1, 1122.9, 1080.9, 912.2, 760.5, 735.6, 3054, 3020, 1505, 2921.8, 285 , 1472, 3434, 3358.6, 1252.3.

Example 6

Synthesis and physicochemical properties of axial uridine/aminoethylphenoxy asymmetrically modified silicon phthalocyanine with the structure shown in the following formula:

The compound can be named as: [5'-(2',3'-O-isopropyl)-uridineoxy][4-(2-aminoethyl)phenoxy]silicone phthalocyanine.

Add 1 ~ 10mmol (preferably 2.5 mmol) 2', 3'-O-isopropyl-uridine, after adding a catalytic amount of NaH, continue the reaction at 110~130°C for 1~20 hours, monitor the reaction end point by TLC, and rotate the reaction mixture to a small amount, A small amount of DMF was added to dissolve, and then a large amount of water was added to precipitate a precipitate. The solvent, reaction raw materials and by-products were removed by membrane filtration, and dried. Purify the crude product through a silica gel column. First, use tetrahydrofuran as the elution solvent. After the first band is completely eluted, use DMF as the elution solvent to collect the target elution components. After rotary evaporation to a small amount of solvent, filter through a microporous membrane. Rotary evaporation and drying gave a blue-green product with a yield of about 20%. The maximum absorption peak of the product is located at 679nm in DMF and 688nm in water.

The maximum absorption peak of the product is located at 679nm in DMF and 688nm in water. HR-MS (ESI) of the product: m/z 906.3038[M+H] ⁺ . IR (KBr, cm-1): 3427.3, 3223.4, 3054.2, 2932.8, 1686.5, 1610.8, 1524.3, 1502.7, 1336.3, 1124.3, 1083.2, 737.3. 1H-NMR (DMSO-d5m, ppm): 55~9.9 , 8H, Pc~Hα), 8.40~8.70 (m, 8H, Pc~Hβ), 7.92~8.01 (s, 1H), 5.42~5.49 (d, 2H), 4.56~4.62 (d, 1H), 4.31~ 4.38 (t, 2H), 2.89~2.90 (s, 1H), 2.73~2.74 (s, 2H), 2.17~2.24 (d, 2H), 2.03~2.12 (t, 2H), 1.82~1.92 (t, 2H ), 1.69~1.74 (t, 1H), 1.52~1.59 (t, 1H), 0.70~0.82 (s, 3H), 0.55~0.66 (s, 3H), -1.35~ -1.25(m, 1H), - 2.35~ -2.25(m, 1H).

Example 7

Substituting 2', 3'-O-isopropyl-cytidine for 2', 3'-O-isopropyl-uridine in Example 6, the axial cytidine/aminoethyl Asymmetrically modified silicon phthalocyanines (ie [5'-(2',3'-O-isopropyl)-cytidineoxy][4-(2-aminoethyl)phenoxy]silicon Phthalocyanine). The maximum absorption peak of this compound is located at 678nm in DMF and 688nm in water, mass spectrum (ESI): m/z 959.2[M+H] ⁺ .

Example 8

Synthesis and physicochemical properties of the axial 2-chloroadenosine/aminoethylphenoxy asymmetrically modified silicon phthalocyanine whose structure is shown in the following formula:

The compound can be named as: [5'-(2',3'-O-isopropyl)-2-chloroadenosyloxy][4-(2-aminoethyl)phenoxy]silicone phthalocyanine

Add 1 ~ 10mmol (preferably 3 mmol) 2', 3'-O-isopropyl-2-chloroadenosine, after adding a catalytic amount of NaH, continue the reaction at 110~130°C for 1~10 hours, monitor the reaction end point by TLC, and rotate the reaction mixture Add a small amount of DMF to dissolve, and then add a large amount of water to precipitate a precipitate. Remove the solvent, reaction raw materials and by-products by membrane filtration, and dry. Purify the crude product through a silica gel column, using tetrahydrofuran as the elution solvent, after the first band is completely eluted, use DMF as the elution solvent, collect the target elution components, spin evaporate to a small amount of solvent, and filter through a microporous membrane. Rotary evaporation, drying to obtain the blue product, the yield is about 21%.

The maximum absorption peak of the product is located at 677nm in DMF and 688nm in water. Other characterization data of the product: HR-MS (ESI): m/z 1016.2842[M] ⁻ . IR (KBr, cm ^-1 ): 3408.5, 3208.5, 2927.7, 1635.3, 1522.9, 1506.0, 1334.2, 1124.3, 1079.8, 914.4, 738.4. ¹ H-NMR (DMSO-d ₆ , ppm): δ 9.55~9.85 (m, 8H, Pc~H _α ), 8.40~8.70 (m, 8H, Pc~H _β ), 7.90~7.96 (s, 1H) （ t, 2H), 1.78~1.91 (t, 2H), 1.28~1.35 (t, 1H), 1.18~1.25 (t, 1H), 1.02~1.06 (t, 1H), 0. 63~0.85 (s, 3H ), 0.44~0.62 (s, 3H), -1.45~ -1.30(m,1H), -2.25~ -2.05 (m, 1H).

Example 9

Substituting 2', 3'-O-isopropyl-adenosine for 2', 3'-O-isopropyl-2-chloroadenosine in Example 8, the axial adenosine structure shown in the following formula can be obtained: Glycoside/aminoethylphenoxy asymmetrically modified silicon phthalocyanine (ie [5'-(2',3'-O-isopropyl)adenosyloxy][4-(2-aminoethyl)phenoxy base] silicon phthalocyanine). The maximum absorption peak of this compound is located at 677nm in DMF and 688nm in water, and its mass spectrum MS (ESI) : m/z 982.3[M] ^- .

Example 10

Synthesis and physicochemical properties of axial uridine/triethylene glycol asymmetrically modified silicon phthalocyanine with the following structure:

The compound can be named as: [5'-(2',3'-O-isopropyl)-uridineoxy][(2-(2-(2-methoxyethoxy)ethoxy) ethoxy)] silicon phthalocyanine.

In 1mmol of [5'-(2',3'-O-isopropyl)-uridine oxy][4-(2-aminoethyl)phenoxy]silyl phthalocyanine (the compound described in Example 6 ) in toluene (or xylene or dioxane) solution, add 1~10mmol (preferably 1.5 mmol) triethylene glycol monomethyl ether, add a catalytic amount of NaH and react at 110~130°C for 1~20 hours, The end point of the reaction was monitored by TLC, the reaction mixture was rotary evaporated to a small amount, a small amount of DMF was added to dissolve, and a large amount of water was added to precipitate a precipitate, and the solvent, reaction raw materials and by-products were removed by membrane filtration, and dried. Purify the crude product through a silica gel column, use ethyl acetate as the elution solvent, collect the target eluted fraction, spin evaporate to a small amount of solvent, filter, spin evaporate, and dry to obtain the blue product with a yield of about 15%. The maximum absorption peak of the product is located at 677nm in DMF and 688nm in water. Its HR-MS (ESI) : m/z 1009.3066 [M+Na] ⁺ .

Example 11

Substituting triethylene glycol, tetraethylene glycol, and tetraethylene glycol monomethyl ether for triethylene glycol monomethyl ether in Example 10, respectively, can obtain the axial uridine/ethylene glycol derivatized structure shown in the following formula: Asymmetrically modified silicon phthalocyanine with a yield of 10-20%. These compounds have maximum absorption peaks at 677-680 nm in DMF and 688-690 nm in water.

Example 12

Synthesis and physicochemical properties of axial cytidine/triethylene glycol asymmetrically modified silicon phthalocyanine with the following structure:

The compound can be named as: [5'-(2',3'-O-isopropyl)-cytidineoxy][(2-(2-(2-methoxyethoxy)ethoxy) ethoxy)] silicon phthalocyanine.

the

Replace with [5'-(2',3'-O-isopropyl)-cytidineoxy][4-(2-aminoethyl)phenoxy]silicone phthalocyanine (the compound described in Example 7) [5'-(2',3'-O-isopropyl)-uridine oxy][4-(2-aminoethyl)phenoxy]silicon phthalocyanine in Example 10 can obtain [5 '-(2',3'-O-isopropyl)-cytidineoxy][(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)]silicone phthalocyanine , the maximum absorption peak of this compound is located at 678nm in DMF and 689nm in water, its MS (ESI) : m/z 1002.4 [M] ⁺ .

Example 13

By substituting triethylene glycol, tetraethylene glycol, and tetraethylene glycol monomethyl ether for triethylene glycol monomethyl ether in Example 12, the axial cytidine/ethylene glycol derivatized structure shown in the following formula can be obtained: asymmetrically modified silicon phthalocyanine with a yield of 13-22%. These compounds have maximum absorption peaks at 678-680 nm in DMF and 688-690 nm in water.

Example 14

The synthesis and physicochemical properties of the axial 2-chloroadenosine/triethylene glycol asymmetrically modified silicon phthalocyanine shown in the following structure:

The compound can be named as: [5'-(2',3'-O-isopropyl)-2-chloroadenosyloxy][(2-(2-(2-methoxyethoxy)ethyl oxy)ethoxy)] silicon phthalocyanine.

[5'-(2',3'-O-isopropyl)-2-chloroadenosyloxy][4-(2-aminoethyl)phenoxy]silicone phthalocyanine (described in Example 8 Compound) to replace [5'-(2',3'-O-isopropyl)-uridine oxy][4-(2-aminoethyl)phenoxy]silicon phthalocyanine in Example 10, can [5'-(2',3'-O-isopropyl)-2-chloroadenosyloxy][(2-(2-(2-methoxyethoxy)ethoxy)ethoxy base)] silicon phthalocyanine, the maximum absorption peak of this compound is located at 679nm in DMF and 689nm in water, its MS (ESI): m/z 1058.3 [M] ⁺ .

Example 15

Substitute triethylene glycol monomethyl ether in Example 14 with triethylene glycol, tetraethylene glycol, and tetraethylene glycol monomethyl ether respectively to obtain axial 2-chloroadenosine/ethyl ether as shown in the following formula: Diol derivatives asymmetrically modify silicon phthalocyanine with a yield of 13-22%. These compounds have maximum absorption peaks at 679-681 nm in DMF and 688-690 nm in water.

the

Example 16

Synthesis and physicochemical properties of axial adenosine/triethylene glycol asymmetrically modified silicon phthalocyanine with the following structure:

The compound can be named as: [5'-(2',3'-O-isopropyl)-adenosyloxy][(2-(2-(2-methoxyethoxy)ethoxy) ethoxy)] silicon phthalocyanine.

Replace with [5'-(2',3'-O-isopropyl)-adenosyloxy][4-(2-aminoethyl)phenoxy]silicone phthalocyanine (the compound described in Example 9) [5'-(2',3'-O-isopropyl)-uridine oxy][4-(2-aminoethyl)phenoxy]silicon phthalocyanine in Example 10 can obtain [5 '-(2',3'-O-isopropyl)-adenosyloxy][(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)]silicone phthalocyanine , the maximum absorption peak of this compound is located at 679nm in DMF and 689nm in water, its MS (ESI) : m/z 1025.6 [M] ⁺ .

Example 17

By substituting triethylene glycol, tetraethylene glycol, and tetraethylene glycol monomethyl ether for triethylene glycol monomethyl ether in Example 16, the axial adenosine/ethylene glycol derivatized structure shown in the following formula can be obtained: asymmetrically modified silicon phthalocyanine with a yield of 15-25%. These compounds have maximum absorption peaks at 678-680 nm in DMF and 688-690 nm in water.

Example 18

The method for preparing photodynamic drugs (i.e. photosensitive (drug) agents) using the axial nucleoside asymmetrically modified silicon phthalocyanine described in the present invention is: water, or a mixed solution of water and other substances (wherein the mass fraction of other substances is not higher than 10%) as a solvent to dissolve the silicon phthalocyanine asymmetrically modified by the axial nucleoside, and prepare a photosensitizer containing a certain concentration. The concentration of the silicon phthalocyanine asymmetrically modified by the axial nucleoside is not higher than its saturation concentration ( Preferably 1~0.01 mM). The other substances mentioned can be one or a combination of the following: castor oil derivatives (Cremophor EL), dimethyl sulfoxide, ethanol, glycerin, N,N-dimethylformamide, polyethylene glycol 300- 3000, Cyclodextrin, Dextrose, Tween, Macrogol Monostearate. In the prepared solution, antioxidants, buffers and isotonic agents can be added as additives to maintain the chemical stability and biocompatibility of the photosensitizer.

Dissolving the nucleoside asymmetrically modified silicon phthalocyanine in the present invention in an aqueous solution of 5-35% (wt%) dimethyl sulfoxide can be used as a preparation for topical administration.

Example 19

The photodynamic drug and photosensitizer (drug) agent prepared by the present invention are used in photodynamic therapy, photodynamic diagnosis, or photodynamic disinfection, and the use of phthalocyanine or porphyrin not described in the present invention in the prior art The photosensitizer or photosensitizer prepared by the compound is used in the same way, but it needs to be equipped with a suitable light source. The suitable light source can be provided by a common light source connected with a suitable filter or provided by a laser with a specific wavelength. The wavelength of the light source is The range is 300-800 nm, preferably 675-690 nm.

Example 20

The axial nucleoside asymmetrically modified silicon phthalocyanine of the present invention is dissolved in 1% castor oil derivative (Cremophor EL, wt%) aqueous solution to prepare 0.08mM photosensitizer. Their dark toxicity and photodynamic activity were tested against human gastric cancer BGC823 cells.

Dilute 0.08mM photosensitizer into cell culture fluid to prepare cell culture fluid with different concentrations of photosensitizer. The test cells were cultured in the culture solution containing different concentrations of photosensitizer for 2 hours, then the culture solution was discarded, and after the cells were washed with PBS, new culture solution (without photosensitizer) was added. In the light experiment group, the cells were irradiated with red light (the excitation light source used was red light with a wavelength greater than 610nm, irradiated for 30 minutes, and the power of the irradiated light was 15mw×cm ^-2 ); in the no light group, the cells were placed in the dark for 20 minute. After light or no light, the survival rate of cells was examined by MTT method. For specific experimental procedures, see " Bioorganic & Medicinal Chemistry Letters" , 2006, 16, 2450-2453.

The above-mentioned red light with a wavelength greater than 610nm is provided through a 500W halogen lamp connected to an insulated water tank and a filter greater than 610nm.

The results show that the axial nucleoside asymmetrically modified silicon phthalocyanine of the present invention can kill cancer cells under red light irradiation. When the concentration of the axial nucleoside asymmetrically modified silicon phthalocyanine of the present invention is 0.003 At mM (ie 3×10 ^-6 mol/L), it can kill 100% of cancer cells. At the same concentration, if no light is applied, the axial nucleoside asymmetrically modified silicon phthalocyanine of the present invention has no killing and growth inhibiting effect on cancer cells, indicating that they have no dark toxicity. Through the dose-effect relationship between concentration and cell viability, it was found that the semi-lethal concentration (IC ₅₀ , which is required to kill 50% of cancer cells) of the axial nucleoside asymmetrically modified silicon phthalocyanine described in the present invention was irradiated by red light. drug concentration) are:

4 nM ([5'-(2',3'-O-isopropyl)-uridineoxy][4-(2-aminoethyl)phenoxy]silicone phthalocyanine as described in Example 6 compound);

150 nM ([5'-(2',3'-O-isopropyl)-cytidineoxy][4-(2-aminoethyl)phenoxy]silyl phthalocyanine, as described in Example 7 compound);

7 nM ([5'-(2',3'-O-isopropyl)-2-chloroadenosyloxy][4-(2-aminoethyl)phenoxy]silyl phthalocyanine, Example 8 said compound);

5 nM ([5'-(2',3'-O-isopropyl)-adenosyloxy][4-(2-aminoethyl)phenoxy]silyl phthalocyanine, as described in Example 9 compound);

6-20 nM (axial uridine/oligoethylene glycol asymmetrically modified silicon phthalocyanine, the compound described in Examples 10-11);

200-310 nM (axial cytidine/oligoethylene glycol asymmetrically modified silicon phthalocyanine, the compound described in Examples 12-13);

7-15 nM (axial 2-chloroadenosine/oligoethylene glycol asymmetrically modified silicon phthalocyanine, the compound described in Examples 14-15);

5-18 nM (axial adenosine/oligoethylene glycol asymmetrically modified silicon phthalocyanine, namely the compound described in Examples 16-17).

It can be seen that the axial nucleoside asymmetrically modified silicon phthalocyanine has a low IC ₅₀ value, and some compounds are even as low as 4-7nM (ie 4-7×10 ^-8 mol/L). The extremely low IC ₅₀ value indicates that the axial nucleoside asymmetrically modified silicon phthalocyanine provided by the present invention has extremely high photodynamic activity.

The same experimental results can also be obtained by replacing the above 1% castor oil derivative (Cremophor EL, wt%) aqueous solution with 1% castor oil derivative (Cremophor EL, wt%) phosphate buffered saline solution (PBS).

Example 21

According to the method described in Example 20, the effects of axial nucleoside symmetrically modified silicon phthalocyanine, axial aminoethylphenoxy symmetrically modified silicon phthalocyanine, and axial low polyethylene glycol symmetrically modified silicon phthalocyanine on human gastric cancer were determined. Photodynamic activity of BGC823 cells.

The results showed that axial nucleoside symmetrically modified silicon phthalocyanine, bis[5'-(2', 3'-O-isopropyl)-uridine oxy] silicon phthalocyanine, bis[5'-(2', 3'-O-isopropyl)-cytidineoxy]silyl phthalocyanine, bis[5'-(2', 3'-O-isopropyl)-2-chloroadenosyloxy]silyl phthalocyanine and The IC ₅₀ values of bis[5'-(2', 3'-O-isopropyl)-adenosyloxy]silicon phthalocyanine photodynamic inhibition of human gastric cancer BGC823 cells were 31nM, 410nM, 10nM and 9nM, respectively.

The IC ₅₀ value of axial aminoethylphenoxy symmetrically modified silicon phthalocyanine, that is, bis[4-(2-aminoethyl)phenoxy]phthalocyanine silicon photodynamic inhibition of human gastric cancer BGC823 cells was 20nM.

The IC ₅₀ values of axial triethylene glycol symmetrically substituted silicon phthalocyanine and axial tetraethylene glycol symmetrically substituted silicon phthalocyanine photodynamically inhibit human gastric cancer BGC823 cells are 50-30nM.

Comparing the results of Example 20 and Example 21, it can be found that the photodynamic anticancer activity of the axial nucleoside asymmetrically modified silicon phthalocyanine described in the present invention is significantly higher than that of the corresponding axial nucleoside symmetrically modified silicon phthalocyanine, and The photodynamic anticancer activity of most axial nucleoside asymmetrically modified silicon phthalocyanines was significantly higher than that of axial aminoethylphenoxy symmetrically modified silicon phthalocyanines and axial oligoethylene glycol symmetrically substituted silicon phthalocyanines.

Example 22

According to the method described in Example 18, the photodynamic activity of the axial nucleoside asymmetric modification described in the present invention and the following other phthalocyanine compounds on human gastric cancer BGC823 cells was compared.

The following other phthalocyanine compounds are one of the following complexes: axial bis(4-acetylaminophenoxy)silyl phthalocyanine, bis[4-(4-acetylpiperazine)phenoxy]silyl phthalocyanine , bis[4-(3-carboxypropyl)phenoxy]silicon phthalocyanine, bis(4-formylphenoxy)silicon phthalocyanine, bis(3-formylphenoxy)silicon phthalocyanine, bis(3, 5-dicarboxyphenoxy) silicon phthalocyanine, bis(1-adamantane-methoxy) silicon phthalocyanine, bis(2-adamantane-ethoxy) silicon phthalocyanine, tetra-a-[4-( 4-acetylpiperazine)phenoxy]zinc phthalocyanine, tetra-a-(4-carboxyphenoxy)zinc phthalocyanine.

The results show that the photodynamic activity of the axial nucleoside asymmetrically modified silicon phthalocyanine of the present invention is significantly higher than that of other similar compounds. At the same concentration (1.0×10 ^-6 mol/L), the silicon phthalocyanine with axial nucleoside asymmetric modification described in the present invention has at least 3 times the photodynamic inhibition effect on gastric cancer BGC823 cells than other phthalocyanine compounds mentioned above above.

Example 23

The axial nucleoside asymmetrically modified silicon phthalocyanine of the present invention was dissolved in 1% castor oil derivative (Cremophor EL, wt%) PBS buffer to make 0.3mM photosensitizer, and tested their photodynamic activity on fungi inhibitory activity. The fungus used is Candida albicans CMCC(F)C1a (Candida albicans, C. albicans), and the concentration of the bacterial suspension is 2×10 ⁶ cells/ml. Under the irradiation of red light (the excitation light source used is red light with a wavelength greater than 610nm, the irradiation is 30 minutes, and the power of the irradiation light is 15mw×cm ^-2 ), the silicon phthalocyanine with axial nucleoside asymmetric modification of the present invention can kill 60% of Candida albicans can be killed, while the solvent control group, the only administration without light group, and the light without administration group do not affect the growth of Candida albicans.

Example 24

The effect of the axial nucleoside asymmetrically modified silicon phthalocyanine of the present invention as a photosensitizer for photodynamic disinfection was tested.

First, the axial nucleoside asymmetrically modified silicon phthalocyanine was dissolved in 1% castor oil derivative (Cremophor EL, wt%) aqueous solution to prepare 0.3mM photosensitizer. Then it was added to the water containing Escherichia coli so that the content of silicon phthalocyanine was 0.03 mM, and after 2 hours, the water containing Escherichia coli was irradiated with red light. The survival of Escherichia coli before and after irradiation was checked, and the results showed that the axial nucleoside asymmetrically modified silicon phthalocyanine of the present invention could kill more than 70% of Escherichia coli under the irradiation of red light.

The above descriptions are only preferred embodiments of the present invention, and all equivalent changes and modifications made according to the scope of the patent application of the present invention shall fall within the scope of the present invention.

Claims (4)

1. the silicon phthalocyanine of the asymmetric modification of an axial nucleosides, it is characterized in that: its structural formula is as follows:

，

Axial substituent R wherein ₁, R ₂be selected from respectively following group:

R ₁for

,

,

,

in a kind of;

R ₂for

,

,

,

,

in a kind of.

2. a method for preparing the silicon phthalocyanine of the asymmetric modification of axial nucleosides as claimed in claim 1 is characterized in that: comprise the following steps:

(1) with two [4-(2-amino-ethyl) phenoxy group] silicon phthalocyanine and 2 ', 3 '-O-sec.-propyl-uridine, 2 ', 3 '-O-sec.-propyl-cytidine, 2 ', 3 '-O-sec.-propyl-adenosine, 2 ', a kind of in 3 '-O-sec.-propyl-2-chlorine adenosine is reactant, both molar ratios are 1:1 ~ 10, take toluene, dimethylbenzene or dioxane as solvent, under the protection of nitrogen, 100 ~ 130 ℃ are reacted 1 ~ 20 hour, remove excessive raw material and impurity by solvent cleaning and column chromatography for separation, obtain the asymmetric modification silicon phthalocyanine of axial nucleosides and amino-ethyl phenoxy group;

(2) take a kind of in the asymmetric modification silicon phthalocyanine of axial nucleosides and amino-ethyl phenoxy group and triethylene glycol, triethylene glycol monomethyl ether, TEG, TEG monomethyl ether is reactant; both molar ratios are 1:1 ~ 10; take toluene, dimethylbenzene or dioxane as solvent; under the protection of nitrogen; 100 ~ 130 ℃ are reacted 1 ~ 20 hour; remove excessive raw material and impurity by solvent cleaning and column chromatography for separation, obtain the asymmetric modification silicon phthalocyanine of axial nucleosides and low polyoxyethylene glycol.

3. the application of the silicon phthalocyanine of the asymmetric modification of an axial nucleosides as claimed in claim 1 is characterized in that: the silicon phthalocyanine of the asymmetric modification of described axial nucleosides is for the preparation of photo-dynamical medicine or photosensitizers.

4. the application of the silicon phthalocyanine of the asymmetric modification of axial nucleosides according to claim 3, it is characterized in that: the method for preparing photo-dynamical medicine or photosensitizers is: the mixed solution of water or water and other material, wherein the massfraction of other material is not higher than 10%, as solvent, dissolve the silicon phthalocyanine of the asymmetric modification of axial nucleosides, be mixed with containing certain density photosensitive medicament, axially the concentration of the silicon phthalocyanine of the asymmetric modification of nucleosides is not higher than its saturation concentration; In the solution of making, add antioxidant, buffer reagent and isotonic agent as additive chemical stability and the biocompatibility to keep photosensitive medicament;

Described other material is one or more the miscellany in castor oil derivative, methyl-sulphoxide, ethanol, glycerine, DMF, Liquid Macrogol-3000, cyclodextrin, glucose, tween, polyethylene glycol mono stearate.