A glycosylated photosensitizer and its preparation method and application

Abstract

The present invention relates to a glycosylated photosensitizer, a compound shown in the following chemical formula: Also disclosed is a preparation method of the compound and the use of the compound in preparing medicine. The photosensitizer has good water solubility, high singlet oxygen generation efficiency, and can be co-cultured with cells.

Description

Technical Field

[0001] The invention relates to a photosensitizer, in particular to a glycosylated photosensitizer and a preparation method and application thereof. Background Art

[0002] Photodynamic therapy is a clinical technique for treating tumors in a non-surgical way. Its action is based on the photodynamic effect. It uses lasers of a specific wavelength to irradiate photosensitizers absorbed by tumor tissues to make the photosensitizers excited. The excited photosensitizers transfer energy to oxygen molecules around tumor cells, producing cytotoxic singlet oxygen, which causes damage and death of tumor cells. Compared with traditional tumor treatments, photodynamic therapy has the advantages of low trauma, few side effects, low toxicity, and tumor cells will not develop resistance to photosensitizers.

[0003] Phthalocyanine is a common type of photosensitizer, which has the characteristics of strong absorption of visible light, low dark toxicity, strong chemical stability, and easy structural modification. However, phthalocyanine compounds lack selectivity for tumor cells, and the planar rigid structure of phthalocyanine compounds makes them easy to aggregate in water, inducing fluorescence quenching and greatly reducing the yield of singlet oxygen, thereby weakening their photodynamic therapy effect on tumors. Summary of the invention

[0004] In view of the existing deficiencies, the present invention provides a glycosylated photosensitizer and a preparation method and application thereof.

[0005] The technical solution adopted by the present invention to solve the technical problem is: a glycosylated photosensitizer, a compound shown in the following chemical formula:

[0006]

[0007] in:

[0008] R is a hydrogen atom, and the sugar group of the compound is galactose.

[0009] A method for preparing a glycosylated photosensitizer, characterized in that the steps are as follows:

[0010] S1, dispersing compound 1 and compound 2 in N,N-dimethylformamide solvent, adding potassium carbonate, stirring, and purifying to obtain compound 3 after the reaction is completed;

[0011] S2, dispersing compound 3 in 1-pentanol solvent, adding compound 4, heating to 120° C., adding lithium to react for a period of time, then adding zinc acetate to react, and purifying to obtain a phthalocyanine compound after the reaction is completed;

[0012] S3, dispersing the sugar derivative 1 in 1,4-dioxane solvent, adding the sugar derivative 2 and azobisisobutyronitrile, and purifying after the reaction to obtain the sugar derivative 3:

[0013] S4, dispersing the phthalocyanine compound and the sugar derivative 3 in tetrahydrofuran solvent, adding cuprous iodide, and purifying after the reaction to obtain a glycosylated photosensitizer;

[0014] Wherein: Compound 1 is

[0015] Compound 2 is

[0016] Compound 4 is

[0017] Sugar derivative 1 is The sugar base is galactose;

[0018] Sugar derivative 2 is The sugar moiety is galactose, and R is a hydrogen atom;

[0019] The compound 3 prepared in step S1 is a compound having the following structural formula:

[0020]

[0021] The phthalocyanine compound prepared in step S2 is a compound having the following structural formula:

[0022] The saccharide derivative prepared in step S3 is a compound having the following structural formula: R is a hydrogen atom;

[0023] The glycosylated photosensitizer prepared in step S4 is a compound having the following structural formula: R is a hydrogen atom.

[0024] Preferably, in step 1, the molar ratio of compound 1 to compound 2 is 1:2.4-1:3.0, the reaction temperature is 80° C., and the reaction time is 6 to 12 hours.

[0025] Preferably, in step S2, the molar ratio of compound 3 to compound 4 is 1:8.0-1:10.0; the molar ratio of compound 3 to lithium is 1:0.2-1:0.5; the molar ratio of compound 3 to zinc acetate is 1:2-1:3.0, the reaction temperature is 120° C., and the reaction time is 5 to 8 hours.

[0026] Preferably, after the compound 3 and the compound 4 are mixed, lithium is added and reacted for 3 hours, and then zinc acetate is added and reacted for 2 hours.

[0027] Preferably, in step S3, the molar ratio of the saccharide derivative 1 to the saccharide derivative 2 is 1:6.0-1:8.0; the reaction temperature is 60° C., and the reaction time is 12 to 24 hours.

[0028] Preferably, in step S4, the molar ratio of the phthalocyanine compound to the sugar derivative 3 is 1:2.2-1:3.0; the reaction temperature is room temperature, and the reaction time is 6-12 hours.

[0029] A use of the glycosylated photosensitizer as described in any of the above items in the preparation of a drug for photodynamic therapy of tumors.

[0030] The beneficial effects of the present invention are as follows: the compound of the present invention is based on phthalocyanine as a basic skeleton, and is prepared by connecting oligosaccharides to phthalocyanine to obtain a glycosylated phthalocyanine photosensitizer with high water solubility and high singlet oxygen generation efficiency. Compared with traditional phthalocyanine photosensitizers, its fluorescence quantum yield and singlet oxygen yield in the aqueous phase are significantly enhanced; secondly, the oligosaccharide can interact with the glycoproteins and receptors on the surface of tumor cells, and can effectively guide the photosensitizer to selectively enter the tumor cells. At the same time, it can also be directly added to the cell culture medium and co-cultured with the cells to improve the effect of photodynamic therapy on tumor cells, thereby solving the problems of poor tumor selectivity and poor water solubility of traditional phthalocyanine photosensitizers. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 This is a diagram showing the photodynamic activity of the glycosylated phthalocyanine photosensitizer (Pc-gal8) on HeLa cells in an embodiment of the present invention;

[0032] Figure 2 is a fluorescence spectrum of Pc-gal8 in water according to an embodiment of the present invention;

[0033] Figure 3 is a graph of cellular uptake of Pc-gal8;

[0034] Figure 4 is the HPLC chromatogram of Pc-gal8 of the embodiment of the present invention;

[0035] Figure 5 It is a mass spectrometry characterization diagram of Pc-gal8 in the embodiment of the present invention. DETAILED DESCRIPTION

[0036] In order to more clearly illustrate the purpose, technical solutions and advantages of the embodiments of the present invention, the present invention will be further described below in conjunction with the accompanying drawings and embodiments for a clear and complete description. Obviously, the embodiments described are partial embodiments of the present invention, rather than all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work belong to the protection scope of the present invention.

[0037] A glycosylated photosensitizer and a preparation method and application thereof, wherein the glycosylated photosensitizer has the following structural formula:

[0038]

[0039] in:

[0040] R is a hydrogen atom.

[0041] The reaction route of its preparation method is as follows:

[0042]

[0043]

[0044] S1, dispersing compound 1 and compound 2 in N,N-dimethylformamide solvent, adding potassium carbonate, stirring, and purifying after the reaction to obtain compound 3, compound 1, compound 2 and compound 3 are compounds as shown in 1, 2, and 3 in the reaction scheme, the molar ratio of compound 1 to compound 2 is 1:2.4-1:3.0, the reaction temperature is 80°C, and the reaction time is 6 to 12 hours. If the molar ratio of compound 1 to compound 2 is selected to be 1:2.8, the reaction time is 10 hours;

[0045] S2, dispersing compound 3 in 1-pentanol solvent, adding compound 4, heating to 120°C, adding lithium to react for a period of time, and then adding zinc acetate to react. After the reaction, purifying to obtain a phthalocyanine compound. Similarly, compound 4 and the obtained phthalocyanine compound correspond to the compounds shown in 4 and 5 on the reaction route diagram. At this time, the molar ratio of compound 3 to compound 4 is 1:8.0-1:10.0; the molar ratio of compound 3 to lithium is 1:0.2-1:0.5; the molar ratio of compound 3 to zinc acetate is 1:2-1:3.0, the reaction temperature is 120°C, and the reaction time is 5 to 8 hours. For example, the molar ratio of compound 3 to compound 4 is 1:8.5, the molar ratio of compound 3 to lithium is 1:0.3, and the molar ratio of compound 3 to zinc acetate is 1:2.6; the corresponding compound 3 and compound 4 are mixed and heated, lithium is added to react for 3 hours, and then zinc acetate is added to react for 2 hours, and finally purified to obtain a phthalocyanine compound;

[0046] S3, dispersing the saccharide derivative 1 in a 1,4-dioxane solvent, adding the saccharide derivative 2 and azobisisobutyronitrile, purifying after the reaction, and obtaining the saccharide derivative 3, wherein the saccharide derivative 1, the saccharide derivative 2 and the obtained saccharide derivative 3 correspond to the compounds shown in 6, 7, and 8 on the reaction route diagram, and the molar ratio of the saccharide derivative 1 to the saccharide derivative 2 is 1:6.0-1:8.0; the reaction temperature is 60°C, and the reaction time is 12 to 24 hours. For example, the molar ratio of the saccharide derivative 1 to the saccharide derivative 2 is 1:7.5, and the reaction time is 20 hours. Meanwhile, the saccharide groups of the saccharide derivative 1 and the saccharide derivative 2 are galactose, respectively, and the R of the saccharide derivative 2 is a hydrogen atom. In the embodiment, the saccharide groups of the saccharide derivative 1 and the saccharide derivative 2 are preferably the same saccharide groups;

[0047] S4, dispersing the phthalocyanine compound and the sugar derivative 3 in tetrahydrofuran solvent, adding cuprous iodide, purifying after the reaction to obtain a glycosylated photosensitizer, at which the molar ratio of the phthalocyanine compound to the sugar derivative 3 is 1:2.2-1:3.0; the reaction temperature is room temperature, and the reaction time is 6-12 hours. For example, the molar ratio of the phthalocyanine compound to the sugar derivative 3 is 1:2.7, and the reaction time is 10 hours.

[0048] A use of a glycosylated photosensitizer as described above in the preparation of a drug for photodynamic therapy of tumors, that is, the glycosylated photosensitizer is made into a drug for photodynamic therapy of tumors, which has good water solubility, and its fluorescence quantum yield and singlet oxygen yield in the aqueous phase are significantly enhanced. The oligosaccharides on it interact with glycoproteins and receptors on the surface of tumor cells to guide the photosensitizer to selectively enter tumor cells, and it can also be directly added to the cell culture medium and co-cultured with the cells to improve the photodynamic therapy effect on tumor cells.

[0049] It should be understood that those skilled in the art can make improvements or changes based on the above description, and all these improvements and changes should fall within the scope of protection of the appended claims of the present invention.

Claims

1. A glycosylated photosensitizer, characterized in that: The compound shown in the following chemical formula: in: R is a hydrogen atom, and the sugar group of the compound is galactose.

2. A method for preparing a glycosylated photosensitizer, characterized in that: Here are the steps: S1, dispersing compound 1 and compound 2 in N,N-dimethylformamide solvent, adding potassium carbonate, stirring, and purifying to obtain compound 3 after the reaction is completed; S2, dispersing compound 3 in 1-pentanol solvent, adding compound 4, heating to 120° C., adding lithium to react for a period of time, then adding zinc acetate to react, and purifying to obtain a phthalocyanine compound after the reaction is completed; S3, dispersing the sugar derivative 1 in 1,4-dioxane solvent, adding the sugar derivative 2 and azobisisobutyronitrile, and purifying after the reaction to obtain the sugar derivative 3: S4, dispersing the phthalocyanine compound and the sugar derivative 3 in tetrahydrofuran solvent, adding cuprous iodide, and purifying after the reaction to obtain a glycosylated photosensitizer; Wherein: Compound 1 is Compound 2 is Compound 4 is Sugar derivative 1 is The sugar base is galactose; Sugar derivative 2 is The sugar moiety is galactose, and R is a hydrogen atom; The compound 3 prepared in step S1 is a compound having the following structural formula: The phthalocyanine compound prepared in step S2 is a compound having the following structural formula: The saccharide derivative prepared in step S3 is a compound having the following structural formula: R is a hydrogen atom; The glycosylated photosensitizer prepared in step S4 is a compound having the following structural formula: R is a hydrogen atom.

3. The method for preparing a glycosylated photosensitizer according to claim 2, characterized in that: In step S1, the molar ratio of compound 1 to compound 2 is 1:2.4-1:3.0, the reaction temperature is 80° C., and the reaction time is 6 to 12 hours.

4. The method for preparing a glycosylated photosensitizer according to claim 2, characterized in that: In step S2, the molar ratio of compound 3 to compound 4 is 1:8.0-1:10.0; the molar ratio of compound 3 to lithium is 1:0.2-1:0.5; the molar ratio of compound 3 to zinc acetate is 1:2-1:3.0, the reaction temperature is 120° C., and the reaction time is 5 to 8 hours.

5. The method for preparing a glycosylated photosensitizer according to claim 4, characterized in that: After the compound 3 and the compound 4 were mixed, lithium was added and reacted for 3 hours, and then zinc acetate was added and reacted for 2 hours.

6. The method for preparing a glycosylated photosensitizer according to claim 2, characterized in that: In step S3, the molar ratio of the saccharide derivative 1 to the saccharide derivative 2 is 1:6.0-1:8.0; the reaction temperature is 60° C., and the reaction time is 12 to 24 hours.

7. The method for preparing a glycosylated photosensitizer according to claim 2, characterized in that: In step S4, the molar ratio of the phthalocyanine compound to the sugar derivative 3 is 1:2.2-1:3.0; the reaction temperature is room temperature, and the reaction time is 6-12 hours.

8. Use of the glycosylated photosensitizer according to claim 1 in the preparation of a drug for photodynamic therapy of tumors.

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