Zinc phthalocyanine-doxorubicin conjugate with synergistic anticancer effects of photodynamic therapy and chemotherapy

A technology of zinc phthalocyanine and conjugates, applied in the field of drug preparation, can solve the problems of limited clinical application, high skin phototoxicity, lack of efficient combination drugs, etc., and achieve excellent amphiphilicity and high cancer cell uptake rate. Effect

Active Publication Date: 2019-02-01
FUZHOU UNIV
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  • Abstract
  • Description
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Problems solved by technology

Hematoporphyrin derivatives have shown certain curative effects, but also exposed serious disadvantages: the maximum absorption wavelength (380-420nm) is not in the red light region (650-800nm) with better transmittance to human tissue, and the skin has high phototoxicity. It is a mixture and its composition is unstable, so its clinical application is limited, so the development of a new generation of photodynamic drugs (photosensitizers) is an international research hotspot
However, there is still a lack of highly effective combination drugs, especially those with targeted functions

Method used

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  • Zinc phthalocyanine-doxorubicin conjugate with synergistic anticancer effects of photodynamic therapy and chemotherapy

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preparation example Construction

[0045] 1. The preparation method of terminal dipeptide-phthalocyanine zinc compound (I), comprising the following steps:

[0046] (1) With 1-[4-(2-carboxyethyl)phenoxy]zinc phthalocyanine and N-hydroxysuccinimide as reactants, the ratio of the two is 1:1.5-3, with N,N - Dimethylformamide as solvent, 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride as dehydrating agent, under nitrogen protection, stirring reaction at -5-5°C After 1-2 hours, move to 20-35°C and continue to stir the reaction for 12-36 hours, then separate by column chromatography to obtain the carboxyl activated product of zinc phthalocyanine: ; Wherein, the consumption of 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride needs 1.5-4mmol for every mmol of zinc phthalocyanine reactant;

[0047] (2) The carboxyl activated product of zinc phthalocyanine and glycine-proline dipeptide prepared in step (1) are used as reactants, and the feeding ratio of the two is 1:1.5-2, and N,N-dimethyl formazan...

Embodiment 1

[0082] Compound (Ⅱ) The preparation method is:

[0083] (1) First prepare the carboxyl activated product of zinc phthalocyanine whose structure is shown in the following formula:

[0084] ;

[0085] With 1-[4-(2-carboxyethyl)phenoxy]zinc phthalocyanine (60 μmol) and N-hydroxysuccinimide (120 μmol) as reactant, DMF as solvent (5ml), in 1-ethyl In the presence of 3-(3-dimethylaminopropyl)carbodiimide hydrochloride (180 μmol) and nitrogen protection, the reaction was stirred at 5°C for 1.5 hours, moved to room temperature and continued to stir for 20 hours, and the reaction was carried out by thin-layer chromatography. Monitor the endpoint of the reaction. After the reaction is complete, the reaction solution is concentrated by rotary evaporation, passed through a silica gel column, and the first blue band is collected with a mixed solvent of dichloromethane / tetrahydrofuran (volume ratio: 15:1) as the eluent, and then rotary evaporated to dryness after collection, and dried...

Embodiment 2

[0090] Preparation of compound (Ⅲ): ;

[0091] (1) to (Ⅶ) (60μmol) and N-hydroxysuccinimide (120μmol) as reactant, with DMF as solvent (5ml), in 1-ethyl-(3-dimethylaminopropyl) carbodiimide In the presence of hydrochloride (180 μmol) and under the protection of nitrogen, the reaction was stirred at 5°C for 1.5 hours, moved to room temperature and continued to stir for 20 hours, and the end of the reaction was monitored by thin-layer chromatography. After the reaction is complete, the reaction solution is concentrated by rotary evaporation, passed through a silica gel column, and the first blue band is collected with a mixed solvent of dichloromethane / tetrahydrofuran (15:1 by volume) as the eluent, and then rotary evaporated to dryness after collection, and dried in vacuum Finally, a blue powder is obtained with a yield of 70-80%.

[0092] (2) Using the carboxyl activated product of zinc phthalocyanine (40 μmol) and threonine-serine-glycine-proline tetrapeptide (60 μmol) co...

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Abstract

The invention discloses novel substituted zinc phthalocyanine and their conjugates with doxorubicin, discloses their preparation methods and applications, and belongs to the field of preparation of photosensitizers and drugs. The compound is a novel high-efficiency photosensitizing drug. The zinc phthalocyanine-doxorubicin conjugate is an anticancer drug with the dual effects of photodynamic therapy and chemotherapy. The zinc phthalocyanine-doxorubicin conjugate is linked through a substrate peptide which can be specifically recognized and hydrolyzed by a tumor-associated fibroblast activationprotein, and can be used as an enzyme-targeting activated anticancer prodrug.

Description

[0001] This application is a divisional application based on the original application with application number 2016101335853. technical field [0002] The invention belongs to the field of medicine preparation, and in particular relates to a class of phthalocyanine zinc doxorubicin conjugates with synergistic anticancer effects of phototherapy and chemotherapy. Background technique [0003] Photodynamic therapy (or photodynamic therapy), in essence, is the application of the photosensitization reaction of photosensitizers (or photosensitizers) in the medical field. The process of action is to first inject the photosensitizer into the body, and after a period of time (this waiting time is to allow the drug to be relatively enriched in the target body), the target body is irradiated with light of a specific wavelength (for the target in the body cavity, optical fiber can be used to Under the light excitation, the photosensitizer enriched in the target body inspires a series of ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/103C07K1/107A61K41/00A61K47/55A61P35/00A61K31/704
CPCA61K31/704A61K41/0071A61K47/552A61P35/00C07K5/06026C07K5/1013A61K2300/00
Inventor 黄剑东柯美荣陈少芳郑碧远
Owner FUZHOU UNIV
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