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Chlorin and artesunate compound with photosensitive and sound-sensitive activity as well as preparation method and application of compound

A technology of chlorin artemisia annua and its conjugates, which is applied in the field of chemical medicine and can solve the problems of low production of reactive oxygen species, low selectivity of tumor cells, and large doses required

Active Publication Date: 2017-12-01
DALIAN UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, such photosensitizers still have the disadvantages of low selectivity to tumor cells, low production of reactive oxygen species, large doses required, and slow clearance rates in the body.

Method used

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  • Chlorin and artesunate compound with photosensitive and sound-sensitive activity as well as preparation method and application of compound
  • Chlorin and artesunate compound with photosensitive and sound-sensitive activity as well as preparation method and application of compound
  • Chlorin and artesunate compound with photosensitive and sound-sensitive activity as well as preparation method and application of compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Synthesis of intermediate artesunate NHS ester

[0037] Dissolve Artesunate in CH 2 Cl 2 (5ml). At 0°C, add EDCI (129.0mg), react the mixed solution at room temperature under nitrogen protection for 10min, add N-Hydroxysuccinimide (NHS, 78.2mg) mixed solution and react at room temperature for 10h, after the reaction, add Ionized water (20mL) with CH 2 Cl 2 Extraction (50mL×3), the organic phase was dried with anhydrous sodium sulfate, concentrated under low pressure, the concentrate was subjected to silica gel column chromatography, and the elution condition was (petroleum ether / ethyl acetate=1:1) to obtain the intermediate Artesunate NHS (248.1 mg, 99%). 1 H-NMR (CDCl 3 ,400MHz,ppm)δ:5.71(d,J=8.0Hz,1H),5.35(s,1H),2.81~2.97(m,2H),2.71~2.79(m,6H),2.41~2.49(m, 1H), 2.27(td, J=12.0Hz, 4.0Hz, 1H), 1.95(dt, J=12.0Hz, 4.0Hz, 1H), 1.77~1.85(m, 1H), 1.61~1.73(m, 2H) ,1.54(dt,J=12.0Hz,4.0Hz,1H),1.33~1.45(m,1H),1.33(s,3H),1.24~1.33(m,2H),1.20(dd,1H,J=8.0 Hz, 4.0Hz), 0.90~...

Embodiment 2

[0045] Synthesis of Compound 4

[0046] Pheophytin a (100.0mg) was dissolved in DMF (1ml). Add EDCI (38.0mg) and N-Boc-ethylenediamine (30.0mg) in turn. The mixed solution was reacted at room temperature for 10 hours. After the reaction, 10ml of water was added to dissolve it, extracted with dichloromethane (50mL×3), the organic phase was dried with anhydrous sodium sulfate, concentrated under low pressure, and the concentrate was subjected to silica gel column chromatography. The elution condition was for (CH 2 Cl 2 / MeOH=50:1), the intermediate product 17-(N-Boc-ethylenediamide)pheophytina was obtained. At 0°C, the intermediate product was dissolved in Acetone / 5%KOH (2ml, 50:50, v / v). Mixed solution React at room temperature for 10 h, add 5% citric acid solution after the reaction, adjust the pH to 5, and filter with suction to obtain compound 4 (53.6 mg, 43%). 1 H-NMR (DMSO-d 6 ,400MHz,ppm)δ:9.77(s,1H,10-H),9.69(s,1H,5-H),9.12(s,1H,20-H),8.34(dd,1H,J=16.0, 8.0Hz,3 1 -...

Embodiment 3

[0052] Synthesis of compound 7

[0053] Methylated chlorophyllin a (102.0 mg) dissolved in CHCl 3 (2ml), after stirring for 10 minutes, 0.2ml ethylenediamine was added, and the mixed solution was reacted at room temperature for 10h. After the reaction was completed, the solvent was concentrated and removed under low pressure, and the concentrate was subjected to silica gel column chromatography, and the elution condition was (CH 2 Cl 2 / MeOH=3:1), to obtain compound 7 (92.2mg, 82%). 1 H-NMR (CDCl 3 ,400MHz,ppm)δ:9.56(s,1H,10-H),9.50(s,1H,5-H),8.78(s,1H,20-H),7.91(dd,1H,J=20.0, 12.0Hz,3 1 -H),7.05(t,1H,J=4Hz,N-H),6.20(d,1H,J=20.0Hz,3 2a -H),5.99(d,1H,J=12.0Hz,3 2b -H),5.47(d,1H,J=20.0Hz,15 1a -H),5.18(d,1H,J=20.0Hz,15 1b -H),4.42~4.46(m,1H),4.33(dd,1H,J=8.0,4.0Hz),3.64(s,3H,12 1 -CH 3 ),3.60~3.64(m,2H),3.57(s,3H,2 1 -CH 3 ),3.39(s,3H),3.37(s,3H),3.24~3.32(m,2H,-CH 2 -),3.15(s,3H,7 1 -CH 3 ),2.76(t,2H,J=8.0Hz,-CH 2 -),2.48~2.54(m,1H,172a -H),2.11~2.20(m,2H,17 2b...

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Abstract

The invention relates to a chlorin and artesunate compound with photosensitive and sound-sensitive activity as well as a preparation method and an application of the compound and belongs to the technical field of chemical medicines. The chlorin and artesunate compound with photosensitive and sound-sensitive activity has different degrees of inhibition effects on human hepatoma cells Hep G2 in in-vitro anti-tumor activity evaluation. The photoactivity and ultrasonic activity are both higher than that of chlorin e6 and artesunate which are used as positive controls. The compound can be used for preparing a photosensitizer and a sound-sensitive agent in photodynamic therapy and sonodynamic therapy methods for tumor therapy.

Description

technical field [0001] The invention relates to a class of chlorin artesunate conjugates with light and sound-sensitivity activities, a preparation method and application thereof, and belongs to the technical field of chemical medicine. Background technique [0002] Photodynamic therapy (PDT) and sonodynamic therapy (SDT) use photosensitizer or photosensitizer (Sonosensitizer) to kill tumor cells by chemical reaction under light or ultrasound excitation, respectively. A medical technique for therapeutic purposes. Among them, photodynamic therapy (Photodynamic therapy, PDT) is the use of photosensitizers and visible light in an environment with oxygen to generate reactive oxygen species through photoreaction to cause 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 (SD...

Claims

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Application Information

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IPC IPC(8): C07D519/00C07D487/22A61P35/00
CPCC07D487/22C07D519/00
Inventor 郭修晗王世盛赵伟杰王柳李广哲李悦青
Owner DALIAN UNIV OF TECH
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