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Pyropheophorbide-a ether amino acid derivative as well as preparation method and application thereof

A technology of pyropheophorbide and amino acid, which is applied in the field of medicine, can solve the problems of short tumor killing depth, low photosensitivity activity, high retention phototoxicity, etc., and achieves the effect of excellent photodynamic killing effect.

Inactive Publication Date: 2016-03-09
SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The first generation of porphyrin photosensitizers such as porfimer sodium (porfimersodium) have been successfully used in the clinical treatment of tumors, and have achieved remarkable curative effects, but there are also obvious defects: (1) the maximum absorption wavelength in the red light region is short (630nm ) makes the laser with a matching wavelength penetrate and kill the tumor not deep enough; and the molar absorption coefficient (ε) is small, resulting in low photosensitivity; (2) is a multi-component porphyrin mixture; (3) slow clearance in the body leads to retention of light Toxic
[0006] At present, there is no literature report on the etherification structure design of pyropheophorbide a as the lead structure and the introduction of amino acid residues and 2-vinyl groups at the same time

Method used

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  • Pyropheophorbide-a ether amino acid derivative as well as preparation method and application thereof
  • Pyropheophorbide-a ether amino acid derivative as well as preparation method and application thereof
  • Pyropheophorbide-a ether amino acid derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] Embodiment 1: Preparation of pyropheophorbide a (V)

[0057] Silkworm excrement paste chlorophyll was purchased from Zhejiang Haining Fengming Chlorophyll Co., Ltd.

[0058] Method 1: Add 100g of silkworm excrement paste chlorophyll, add 500mL of ether and an equal volume of concentrated hydrochloric acid, pass N 2 After 2 days of airtight reaction, the reaction solution was poured into a separatory funnel and left to stand to separate the lower layer of acid water, diluted with 2 times the amount of water, neutralized with 10mol / L NaOH to a pH of 5-6 under cooling, suction filtered, P 2 o 5 After drying, it was separated by silica gel H column chromatography [the mobile phase was CH 2 Cl 2 :CH 3 COCH 3 :CH 3 OH: HCO 2 H=60:1:1:0.1 (v / v / v / v)] to obtain 2 g of pure compound V.

[0059] MS (ESI + ) m / z: 535.54 (M+H, 100%); 1068.98 (2M+1, 100%).

[0060] 1 HNMR (300MHz, CDCl 3 ,δ,ppm):9.36(1H,s,meso-H),9.26(1H,s,meso-H),8.50(1H,s,meso-H),7.91(1H,dd,J=18.0,9.0 ...

Embodiment 2

[0062] Example 2: 3 1 -Bromoethyl-3 1 - Preparation of devinylpyropheophorbide a(IV)

[0063] Compound V (1.0 g) was added with 100 mL of 33% HBr glacial acetic acid solution, sealed at room temperature for 24 hours, and the glacial acetic acid was evaporated under reduced pressure to obtain dark green solid compound IV, which was directly used in the next reaction without purification.

Embodiment 3

[0064] Example 3: 3 1 -Methoxy-3 1 - Devinylpyropheophorbide a(Ⅲ 1 ) preparation

[0065] The above dark green solid compound IV (0.5g), dissolved in 50mL of dry DCM, added 1gK 2 CO 3 and 10 mL of dry methanol in N 2 The reaction was carried out at room temperature under protection, and the progress of the reaction was monitored by TLC. After about 2 hours, the reaction was completed and the reaction was stopped. Add 5 times the volume of water to the reaction solution, extract with DCM (200mL×3), separate and combine the organic layers, wash 3 times with water, wash 1 time with saturated brine, anhydrous Na 2 SO 4 After drying for 2h, the organic solvent was recovered under reduced pressure and separated by silica gel H chromatography, mobile phase DCM:CH 3 COCH 3 :CH 3 OH:CH 3 CO 2 H=80:1:1:0.1(v / v / v / v), get 0.3g black powderⅢ 1 , melting point 230-231°C, yield 56.6%.

[0066] MS (ESI + ) m / z: 567.66 (M+H, 100%), 1133.93 (2M+1, 35%).

[0067] 1 HNMR (300MHz, ...

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Abstract

The invention relates to the technical field of medicines and in particular relates to a novel chlorine photosensitizer-pyropheophorbide-a ether amino acid derivative, a preparation method thereof and an application to preparation of antitumor medicines. A chemical structure of the pyropheophorbide-a ether amino acid derivative is shown in a general formula (I) in the specification. The pyropheophorbide-a ether amino acid derivative has the advantages of high efficiency, low toxicity and the like, and can be used for preparing new medicines for photodynamic therapy of cancers, medicines for photodynamic therapy of benign vascular diseases, such as age-related macular degeneration and nevus flammeus and medicines for photodynamic therapy of condyloma acuminate.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a novel chlorin-type photosensitizer—pyropheophorbide a-ether amino acid derivatives, a preparation method thereof, and an application in the preparation of antitumor drugs. Background technique [0002] Photodynamic therapy (photodynamic therapy, PDT) is a new technology of tumor targeting therapy gradually developed in the 1980s, that is, after administration (photosensitizer), the laser with a wavelength matching the maximum absorption wavelength in the red light region inherent to the photosensitizer is used. Targeted irradiation of lesion (tumor) tissue, induced matrix oxygen (O 2 ) excited to produce singlet oxygen ( 1 o 2 ) and other reactive oxygen species (ROS), lead to apoptosis or necrosis of tumor cells and play a role in tumor targeting therapy. Because PDT only implements targeted light on tumor tissue, it can selectively destroy tumor cells while causing little...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/22A61K41/00A61P35/00A61P27/02A61P17/00A61P17/12A61P31/20
CPCC07D487/22A61K41/0071
Inventor 姚建忠单彬张万年盛春泉缪震元贾宁阳孟志杜红丽韩贵焱刘明辉董国强
Owner SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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