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Chlorin e6 ferrocene conjugate with photo- and acoustic-sensitive activity as well as preparation method and application

A technology of chlorin and ferrocene, which is applied in the field of chemical medicine and can solve the problems of large required dose, low generation of active oxygen, slow removal rate and the like

Active Publication Date: 2020-07-28
DALIAN UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Aiming at the disadvantages of light and sound sensitizers such as chlorin e6, such as low generation of active oxygen, large dosage and slow clearance rate in the body, etc.

Method used

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  • Chlorin e6 ferrocene conjugate with photo- and acoustic-sensitive activity as well as preparation method and application
  • Chlorin e6 ferrocene conjugate with photo- and acoustic-sensitive activity as well as preparation method and application
  • Chlorin e6 ferrocene conjugate with photo- and acoustic-sensitive activity as well as preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Synthesis of Intermediate N-Succinimidyl Ferrocenecarboxylate

[0041] Dissolve Ferrocenecarboxylic acid (1.003g) in CH 2 Cl 2 (15mL), at 0 ℃, add EDCI (1.303g), N-Hydroxy succinimide (1.001g), at room temperature under N 2 React in the environment for 10h, after the reaction is completed in CH 2 Cl 2 :H 2 Extraction and removal of excess reactants and by-products in O solution system, anhydrous NaSO 4 dry. The target compound was purified in a 200-300-mesh silica gel column using a dichloromethane elution system to obtain 1.228 g, with a yield of 86%. 1 H-NMR (CDCl 3 ,400MHz,ppm)δ:4.94(t, J=4.0Hz,2H),4.57(t,J=4.0Hz,2H),5.00(s,5H),4.29(d,J=8.0Hz,4H). HR-MS found: m / z: 350.0079[M+Na] + , calcd for C 15 h 13 FeNO 4 ,327.0194.

[0042] Synthesis of compound 1

[0043] Pheophorbide a (3017.2 mg) with a purity of 51% was dissolved in DMF (35 mL), and N-Boc-ethylenediamine (980.5 mg) and EDCI (1165.0 mg) were added to the reaction system at 0° C. to room temper...

Embodiment 2

[0051] Synthesis of Chlorin e6

[0052] Pheophorbide a (300 mg) with a purity of 51% was dissolved in THF (7.5 mL), and an aqueous potassium hydroxide solution (4 mL, 5%) was added to the reaction system at 0° C., and then slowly rose to room temperature, and N 2 Protected and stirred overnight. TLC detects the progress of the reaction. After the reaction was complete, THF was evaporated under reduced pressure, diluted with water, and the pH of the diluted solution was adjusted to 3 with hydrochloric acid (2 mol / L), and the substance was precipitated in the aqueous solution. The precipitate was filtered, washed, and dried in vacuum. Not purified by column chromatography. 1 H-NMR (DMSO-d 6 ,400MHz,ppm)δ:9.73 (s,1H,10-H),9.59(s,1H,5-H),9.11(s,1H,20-H),8.12(dd,1H,J=16.0, 16.0Hz, 3 1 -H),6.35(d,1H,J=16.0Hz,3 2a -H),6.11(d,1H,J=12.0Hz,3 2b -H),5.40~5.48(m,2H,15 1 -H), 4.65(d, 1H, J=8.0Hz), 4.48(d, 1H, J=8.0Hz), 3.69~3.71(m, 2H, 8 1 -H),3.60(s,3H,12 1 -CH 3 ),3.64(s,3H,1...

Embodiment 3

[0062] Synthesis of compound 9

[0063] Pheophorbide a (42.3 mg) with a purity of 51% was dissolved in sulfuric acid methanol solution (0.1 g of sulfuric acid + 1.9 g of methanol) at 0°C. Then slowly warmed up to room temperature, N 2 Protected and stirred overnight. TLC detects the progress of the reaction. After the reaction is completed in CH 2 Cl 2 : saturated NaHCO 3 Extraction and removal of excess reactants and by-products in aqueous solution system, anhydrous NaSO 4 dry. The target compound was purified in a 200-300 mesh silica gel column using dichloromethane: methanol (60:1) + 1% formic acid elution system to obtain 18.4 mg, with a yield of 83.3%.

[0064] Synthesis of Compound 10

[0065] Compound 9 (163.8 mg) was dissolved in CH 2 Cl 2 (10mL), added ethylenediamine (1mL) to the reaction system at 0°C, then slowly warmed up to room temperature, N 2 Protected and stirred overnight. TLC detects the progress of the reaction. Ethylenediamine was removed by ...

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Abstract

The invention provides a chlorin e6 ferrocene conjugate with photo- and acoustic-sensitive activity as well as a preparation method and application thereof, and belongs to the technical field of chemical medicines. The chlorin e6 ferrocene conjugate disclosed by the invention has different degrees of inhibition effects on Hela cells in in-vitro anti-tumor activity evaluation. The introduction of the ferrocene group significantly improves the proliferation inhibition activity of the compound on tumor cells, and the proliferation inhibition activity of the chlorin e6 ferrocene conjugate on tumorcells is much higher than that of chlorin e6 used as a control group. The method can be used for preparing photosensitizers and sonosensitizers in photodynamic therapy and sonodynamic therapy methodsfor tumor therapy.

Description

technical field [0001] The invention relates to a preparation method and application of a class of chlorphine e6 ferrocene conjugates with photosensitive and acoustically sensitive activities, and belongs to the technical field of chemistry and medicine. Background technique [0002] Photodynamic therapy (PDT) and sonodynamic therapy (SDT) are new tumor treatment methods developed recently. Photodynamic therapy (Photodynamic therapy, PDT) is the use of photosensitizers and visible light in the presence of oxygen in the environment, through the light reaction to generate reactive oxygen species, to promote tumor cell death or apoptosis. Compared with traditional treatment methods such as surgery, chemotherapy, and radiotherapy, PDT has the advantages of high selectivity to target tissues, less side effects, and no damage to internal organs; Sonodynamic therapy (SDT) is used in Photodynamic therapy (Photodynamic therapy, PDT) is a new method that can be used in the clinical t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F17/02A61K33/26A61K41/00A61P35/00
CPCC07F17/02A61K41/0071A61K41/0033A61K33/26A61P35/00A61K2300/00
Inventor 郭修晗刘传鑫蔡蕊邵亚楠王世盛赵伟杰李广哲李悦青
Owner DALIAN UNIV OF TECH
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