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Dihydroporphine photosensitizer and sonosensitizer and preparation method and application thereof

A technology of chlorin and sound sensitizer, which is applied in the field of chemical medicine and can solve the problems of slow clearance rate, poor solubility, and large dose required

Active Publication Date: 2015-02-04
DALIAN UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, light and sound sensitizers still have disadvantages such as low selectivity to tumor cells, large dosage, poor solubility under physiological conditions, and slow clearance rate in the body.

Method used

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  • Dihydroporphine photosensitizer and sonosensitizer and preparation method and application thereof
  • Dihydroporphine photosensitizer and sonosensitizer and preparation method and application thereof
  • Dihydroporphine photosensitizer and sonosensitizer and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Synthesis of compound a

[0027] Dissolve 100mg of commercially available compound 1 in 10mL of dichloromethane and 2mL of DMF, add 25.1mg of HOBt, 59.6mg of TBTU, and 500μL of DIEA in sequence, stir at 0-50°C, protect with nitrogen balloon, TLC (monitoring, stop after 30min) Then add 49.2mg N-(2-aminoethyl)maleimide, 500μL DIEA, 1mL DMF, stir at 0-50℃, protect with nitrogen balloon, monitor by TLC, and stop the reaction after 6h. Dilute with methyl chloride, place in a 250mL separatory funnel, wash with deionized water (50mL×3), dry the dichloromethane layer with anhydrous sodium sulfate, and concentrate to obtain a crude product, which is subjected to silica gel column chromatography (developing solvent: Petroleum ether: ethyl acetate = 1:4) purification to obtain 57.7 mg of dark green solid, namely compound a. ESI-MS m / z: 715.3 [M+H] + . 1 H NMR (400MHz, CDCl 3 )δ9.32(1H,s),9.29(1H,s),8.54(1H,s),7.97(1H,dd,J=17.2,10.5Hz,),6.58(2H,s),6.27(1H, dd,J=17.2,1.2Hz),6.16...

Embodiment 2

[0033] Synthesis of compound d

[0034] Dissolve 40.1 mg of commercially available compound 2 in 10 mL of DMF, add 23.3 mg of N-(2-aminoethyl)maleimide, 1 mL of triethylamine, stir at 0-50°C, protect with nitrogen balloon, monitor by TLC, The reaction was stopped after 2h. Add 30.2 mg of anhydrous potassium carbonate and 230 μL of methyl iodide to the reaction solution, continue to stir at a temperature of 0 to 50 ° C, protect with a nitrogen balloon, and detect the reaction by TLC (developer: petroleum ether: ethyl acetate = 1:2), and the reaction proceeds. Stop after 2h. The reaction solution was diluted with 40mL of dichloromethane, transferred to a 250mL separatory funnel, washed with deionized water (50mL×3), washed with saturated brine (50mL×2), dried over anhydrous sodium sulfate, filtered with suction, and concentrated the organic layer to obtain The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:2) to obtain 36.4 m...

Embodiment 3

[0040] Synthesis of compound g

[0041] ① Dissolve 53.2 mg of commercially available compound 2 in 10 mL of methanol, add 200 μL of concentrated sulfuric acid dropwise, stir at 0-50 °C, protect with nitrogen balloon, monitor by TLC, stop the reaction after 4 hours, add 20 mL of deionized water to the reaction solution, and Transfer to a 125mL separatory funnel, extract with dichloromethane (30ml×3), combine the dichloromethane layers, add anhydrous sodium sulfate to dry, filter with suction, and concentrate to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:4) to obtain 44.2 mg of a dark green solid, compound 3, with a yield of 77%. ESI-MS m / z:625.4[M+H] + . 1 H NMR (400MHz, CDCl 3 )δ9.64(1H,s),9.50(1H,s),8.72(1H,s),8.01(1H,dd,J=17.8,11.5Hz),6.32(1H,dd,J=17.8,1.2Hz ),6.12(1H,dd,J=11.5,1.2Hz),5.51(1H,d,J=18.7Hz),5.26(1H,d,J=18.7Hz),4.46(1H,q,J=7.56Hz ),4.12(1H,d,J=7.1Hz),3.82(3H,s),3.74(2H,m),...

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PUM

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Abstract

The invention relates to a preparation method and application of a dihydroporphine photosensitizer and a dihydroporphine sonosensitizer belonging to the chemical medicine field. The compounds have the general formula as shown in the specification, and the dihydroporphine photosensitizer and sonosensitizer compounds have different degrees of inhibition effects on human hepatoma cell line Hep G2 in in-vitro antineoplastic activity assessment. The ratios of optical activity to dark activity and sound activity to dark activity are higher than that of hematoporphyrin monomethyl ether as a positive control, and the method can be used for preparation of the photosensitizer and the sonosensitizer for photodynamic therapy sonodynamic therapy method for cancer treatment.

Description

technical field [0001] The invention relates to a preparation method and application of a class of chlorin-based light and sound sensitizers, belonging to the field of chemical medicine. Background technique [0002] Photodynamic therapy (PDT) and sonodynamic therapy (SDT) kill tumor cells through a chemical reaction of a photosensitizer or a photosensitizer under light or ultrasound excitation, respectively. A medical technique to achieve the purpose of treatment. Among them, photodynamic therapy (Photodynamic therapy, PDT) is the use of photosensitizers and visible light in the presence of oxygen, through the reaction of singlet oxygen ( 1 o 2 ) and free radicals have great lethality to tumor cells. 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 A new method developed on the basis o...

Claims

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Application Information

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IPC IPC(8): C07K5/037C07K1/107C07D487/22A61K38/06A61K31/409A61K41/00A61P35/00
Inventor 郭修晗赵伟杰李悦青王世盛曹雷王柳
Owner DALIAN UNIV OF TECH
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