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Chlorins glucoside compound, and preparation method and application thereof

A technology of glucoside and chlorin, which is applied in the field of chemical medicine, can solve the problems of complex method, small absorption coefficient, poor tumor cell selectivity, etc., and achieves the effects of simple synthesis method, easy control of conditions and favorable production.

Inactive Publication Date: 2018-02-23
DALIAN UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the first-generation and second-generation photosensitizers have been used, there are still many defects: the absorption coefficient at the maximum absorption wavelength of the red light treatment area is small, so that the 630nm laser does not kill the tumor deeply enough; the selectivity to tumor cells is poor, Moreover, it has disadvantages such as limited enrichment capacity and residence time.
Chen Gaojian et al. (a complex porphyrin sugar-containing photosensitizer and its preparation method, 2013, announcement number: CN103285403B) reported that a sugar-containing polymer complexed porphyrin can be used as a photosensitizer, but since the product is a polymer, It is not a single product, which brings great difficulties to further drug development, and the maximum absorption wavelength of artificially synthesized porphyrins is relatively short; Mikhail A.Grin et al. Grin, et al, Journal of Porphyrins and Phthalocyanines, 2009, 13:336–345) used click chemistry to glycosylate the porphine backbone, but this method is more complicated and requires the protection of the coordination center in advance

Method used

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  • Chlorins glucoside compound, and preparation method and application thereof
  • Chlorins glucoside compound, and preparation method and application thereof
  • Chlorins glucoside compound, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Synthesis of compound 3b

[0049] Compound 1 (CHC) (100.0 mg) was dissolved in DMF (1.7 ml). N 2 Protected and stirred in an ice bath. EDCI (38.5 mg) was added, stirring continued in the ice bath, and the ice bath was removed. Stir at room temperature for 2.5 h, dissolve 1,3,4,6-tetra-O-acetyl-beta-D-glucosamine hydrochloride (83.7 mg) in DMF (1 ml), add 40 μl of triethylamine, Mix well. Add it into the reaction solution, stir at room temperature, and monitor the termination of the reaction by TLC. The reaction solution was diluted with 50 ml of dichloromethane, and extracted with aqueous citric acid (25 mL×3). The organic phase was dried, filtered and the filtrate was concentrated. Separation by column chromatography, the elution condition was (dichloromethane / methanol=9:1), and intermediate product 2b (58.1 mg) was obtained;

[0050] Dissolve compound 2b in DMF (0.6ml), add iodomethane (31μl), potassium carbonate (150mg), and react the mixed solution at room te...

Embodiment 2

[0055] Synthesis of compound 6b

[0056] Dissolve methylated chlorophyllin a (100.0 mg) in CHCl 3 (1.8ml), N 2 Protected and stirred in an ice bath. EDCI (38.5 mg) was added, stirring continued in the ice bath, and the ice bath was removed. Stir at room temperature for 2.5 h, dissolve 1,3,4,6-tetra-O-acetyl-beta-D-glucosamine hydrochloride (83.7 mg) in DMF (1 ml), add 40 μl of triethylamine, Mix well. Add it into the reaction solution, stir at room temperature, and monitor the termination of the reaction by TLC. The reaction solution was diluted with 50 ml of dichloromethane, and extracted with aqueous citric acid (25 mL×3). The organic phase was dried, filtered and the filtrate was concentrated. Separation by column chromatography, the elution condition is (dichloromethane / methanol=9:1), to obtain the intermediate product 5b (55.1mg); the compound 5b was dissolved in methanol (0.6ml), and 1 times the amount (molar ratio) of methanol was added Sodium, the mixed solution...

Embodiment 3

[0061] Synthesis of compound 11

[0062]

[0063] Compound 1 (100 mg) was dissolved in 5% H 2 SO4 / MeOH solution (2ml), N 2 Protected, stirred at room temperature, and monitored by TLC to terminate the reaction. Rotary evaporator concentrated to remove methanol. Dilute the reaction solution with dichloromethane (25ml), wash with deionized water, aqueous sodium bicarbonate solution, and saturated NaCl water once each (25ml). The organic phase was dried, filtered and the filtrate was concentrated. After separation by column chromatography, the elution condition was (dichloromethane / methanol=19:1), and 97 mg was obtained, with a yield of 97%. Compound 8: 1 H NMR (400MHz, CDCl3) δ9.64 (1H, s, 10-H), 9.50 (1H, s, 5-H), 8.72 (1H, s, 20-H), 8.01 (1H, dd, J= 17.6, 11.6Hz, 3 1 -H),6.32(1H,dd,J=17.6Hz,1.2Hz,3 2a -H),6.12(1H,dd,J=11.6,1.2Hz,3 2b -H),5.51(1H,d,J=18Hz,15 1a -H),5.26(1H,d,J=18Hz,15 1b -H),4.46(1H,q,J=7.6Hz,18-H),4.12(1H,d,J=7.2Hz,17-H),3.82(3H,s,12 1 -H),3.74(...

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Abstract

The invention discloses a chlorins glucoside compound, and a preparation method and application thereof, and belongs to the technical field of chemical medicines. According to the chlorins glucoside compound disclosed by the invention, through the selective combination of the glucose transport protein which is highly expressed on the surface of the tumor cells, the targeting effect of a photosensitizer and a sound-sensitive agent on tumor cells is improved. The in-vitro anti-tumor activity evaluation shows that compared with chlorins e6 which is used as a control, the chlorins glucoside compound provided by the invention has relatively high light activity and sound activity on humanhepatoma carcinoma cells Hep G2. The chlorins glucoside compound disclosed by the invention can be used for preparation of a photosensitizer and a sound-sensitive agent in photodynamic therapy and sonodynamics therapy methods for tumor therapy. According to the invention, the preparation process is simple, the reaction conditions are easy to control, and the production is facilitated.

Description

technical field [0001] The invention belongs to the technical field of chemistry and medicine, and relates to a class of chlorin glucoside compounds and a preparation method and application thereof. Background technique [0002] Photodynamic therapy (Photodynamic therapy, PDT) is a kind of photochemical reaction of photosensitizer by visible light irradiation in the presence of oxygen, generating cytotoxic reactive oxygen species, killing tumor cells, so as to achieve the purpose of treatment. medical technology [1] . Its outstanding features are mainly characterized by good tissue selectivity, low toxicity and side effects, wide application range, short treatment time, and the ability to protect important organ functions, etc. [2] . Photosensitizer, visible light and oxygen are the three main elements of photodynamic therapy. Sonodynamic therapy (SDT) is a new method developed on the basis of photodynamic therapy (PDT) that can be used in the clinical treatment of malig...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H13/04C07H13/06C07H5/06C07H1/00A61K41/00A61P35/00
CPCA61K41/0033A61K41/0071C07H1/00C07H5/06C07H13/04C07H13/06
Inventor 郭修晗赵伟杰蔡蕊王世盛李广哲李悦青田诗德
Owner DALIAN UNIV OF TECH
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