Chlorin p6 amino acid derivative, preparation method therefor and use of chlorin p6 amino acid derivative

A chlorin and amino acid technology, applied in the field of medicine, can solve the problems of short tumor killing depth, low photosensitivity activity, slow clearance, etc., and achieve the effect of excellent PDT killing effect.

Inactive Publication Date: 2016-10-26
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 (porfimer sodium) 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 Phototoxic
[0006] At present, there is no literature report using chlorin p6 as a leading structure, introducing amino acid residues into its 7-propanoxy group or introducing amino acid residues and 2-vinyl groups into its 7-position propanyl carboxyl group for etherification structure design

Method used

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  • Chlorin p6 amino acid derivative, preparation method therefor and use of chlorin p6 amino acid derivative
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  • Chlorin p6 amino acid derivative, preparation method therefor and use of chlorin p6 amino acid derivative

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Experimental program
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Effect test

Embodiment 1

[0054] Embodiment 1: Preparation of pheophorbide a (VII)

[0055] Chlorophyll a (Ⅷ) crude extract from silkworm excrement (paste chlorophyll) was purchased from Fengming Chlorophyll Co., Ltd., Haining City, Zhejiang Province.

[0056] Dissolve 100g of silkworm excrement chlorophyll a (Ⅷ) crude extract in 500mL ether, add an equal volume of concentrated hydrochloric acid at 0-5°C and stir for 1 hour, take the lower layer of acid solution, add 2 times the amount of water to dilute, and use it under cooling 10mol / L NaOH neutralized to pH 5-6, suction filtered, P 2 o 5 After drying, 15 g of crude black powder VII was obtained, which was directly used in the next reaction without further purification.

Embodiment 2

[0057] Embodiment 2: Preparation of purpurin-18 (Ⅵ)

[0058] VII Crude product 15g, dissolved in 50mL tetrahydrofuran, added 300mL diethyl ether to dilute, then added 25% (w / v) potassium hydroxide n-propanol solution 20mL, passed through O at 0-5°C 2 Reacted for 2h, extracted with water (300mL×2), 10%H 2 SO 4 Neutralize, filter, P 2 o 5 It was dried and separated by silica gel H column chromatography to obtain 2.7 g of black powder VI.

Embodiment 3

[0059] Example 3: Chlorin p 6 Preparation of Trimethyl Ester (Ⅴ)

[0060] Compound VI (2.0g, 3.55mmol), dissolved in 50mL of tetrahydrofuran, added 200mL of methanol, and 250mL of 0.5mol L-1 sodium hydroxide aqueous solution, stirred at room temperature until the absorption peak at 698nm disappeared, added 500ml of water, and dissolved in dilute hydrochloric acid and to pH 5-6, extracted with ether (3×200mL), dried over anhydrous sodium sulfate, filtered, added freshly prepared 2.8% (w / v) CH 2 N 2 Diethyl ether solution 20mL, reacted for 5min, washed with water, recovered solvent, dried and separated by silica gel H column chromatography to obtain 1.85g black powder Ⅴ, yield 83.6%, purity (HPLC): 99.8%.

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Abstract

The invention relates to the technical field of medicines and particularly relates to a novel chlorin photosensitizer, i.e., a chlorin p6 amino acid derivative, a preparation method therefor and use of the chlorin p6 amino acid derivative in preparation of antitumor drugs. The chlorin p6 amino acid derivative disclosed by the invention has a chemical structure represented by a general formula (I) shown in the description. The chlorin p6 amino acid derivative disclosed by the invention has the advantages of high efficiency, low toxicity and the like and can be used for preparing novel photodynamic cancer therapy drugs, drugs for photodynamic therapy on benign vascular diseases such as senile macular degeneration and nevus flammeus and drugs for photodynamic therapy on verruca acuminata.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a novel chlorin photosensitizer—a chlorin p6 amino acid derivative, a preparation method thereof, and an application in the preparation of antitumor drugs. Background technique [0002] Photodynamic therapy (PDT) is a new technology for tumor targeting therapy gradually developed in the 1980s, that is, the wavelength after administration (photosensitizer) matches the maximum absorption wavelength in the red light region of the photosensitizer. Laser irradiates the focus (tumor) tissue in a targeted manner, and the photosensitizer induces 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 or no damage to normal tissue...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/22A61K41/00A61P35/00A61P9/10A61P27/02A61P9/14A61P17/00A61P17/12A61P31/20
CPCC07D487/22A61K41/0071
Inventor 姚建忠孟志张万年盛春泉缪震元董国强贾宁阳韩贵焱刘明辉刘娜
Owner SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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