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GSH (glutathione) response based diagnosis and treatment integrated organic molecular probe and production method thereof

A technology of organic molecules and probes, which is applied in the field of organic molecular probes for diagnosis and treatment based on GSH response and its preparation, can solve the problem of inability to avoid the mechanism of tumor drug resistance, large toxic and side effects of normal cells, and difficulty in controlling the free diffusion process of drugs and other problems, to achieve the effect of targeted therapy for tumors, simple and fast synthesis process, novel and feasible ideas

Inactive Publication Date: 2016-12-07
XIDIAN UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] The purpose of the present invention is to provide a GSH response-based integrated organic molecular probe for diagnosis and treatment and its preparation method, aiming to solve the problem that it is difficult to control the free diffusion process of drugs in tumor tissues due to the existence of current tumor drug carriers. The potential drug resistance mechanism of tumors, the problem of relatively large toxic and side effects on normal cells

Method used

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  • GSH (glutathione) response based diagnosis and treatment integrated organic molecular probe and production method thereof
  • GSH (glutathione) response based diagnosis and treatment integrated organic molecular probe and production method thereof
  • GSH (glutathione) response based diagnosis and treatment integrated organic molecular probe and production method thereof

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preparation example Construction

[0071] Such as figure 1 As shown, the preparation method of the integrated organic molecular probe for diagnosis and treatment based on the GSH response of the embodiment of the present invention includes the following steps:

[0072] S101: react mercapto compound A and mercapto compound B under the oxidation of iodine to prepare disulfide C, spin off the solvent under reduced pressure, and separate by high performance liquid chromatography; wherein the molar feed ratio of A and B is 1:5 , the reaction temperature is 25°C, the reaction time is 15 hours, and the reaction solvent is dichloromethane and methanol;

[0073]

[0074] S102: Reaction of symmetrical pentamethylcyanine dye CyIC and N-hydroxysuccinimide NHS under the catalytic conditions of N,N'-diisopropylcarbodiimide DIC in the dark to prepare mid-band active succinimide CyIC-NHS, a symmetrical pentamethylcyanine dye, was washed with anhydrous ether and dry ethyl acetate for 3 to 5 times to obtain a precipitate, an...

Embodiment 1

[0084] Preparation of Compound C1 and Compound C2:

[0085] (1) Synthesis of 2-((2-aminoethyl)dithio)-1-ethanol (compound C1), the reaction equation is:

[0086]

[0087] Add 1.5g (19.48mmol) β-mercaptoethanol, 30mL methanol, and 30mL dichloromethane to a 100mL eggplant-shaped flask, then add 7.5g (97.5mmol) 2-aminoethylmercaptan in batches, stir at room temperature for 3h, and then add Dissolve 0.75 g (2.95 mmol) of iodine in methanol, stir at room temperature for 12 hours, remove the solvent under reduced pressure, and separate by high performance liquid chromatography to obtain a yellow oily substance with a yield of 37.2%. Mass spectrometry for product structure identification as image 3 As shown, the data analysis is as follows:

[0088] Compound C1: Calculated Mr=153for C 4 h 11 NOS 2 , found m / z=154([Mr+H + ]).

[0089] (2) The synthetic reaction equation of 2-((2-aminoethyl) dithio)-1-acetic acid (compound C2) is:

[0090]

[0091] Add 0.5g (6.50mmol) 2-...

Embodiment 2

[0094] Preparation of symmetrical pentamethine dye CyIC-NHS with active succinimide in the middle:

[0095]

[0096] Add 2.0mg (2.28μmol) CyIC, 11.5mg (91.2μmol) N, N'-diisopropylcarbodiimide, 10.5mg (91.2μmol) N-hydroxysuccinimide into a 2mL cryovial, Ultra-dry dimethyl sulfoxide and dichloromethane were selected as the solvent, the total volume of the solution was 600 μL, and the mixture was stirred at room temperature in the dark for 4 hours. After the reaction, add anhydrous diethyl ether to the solution to precipitate out, centrifuge, pour off the supernatant, wash the precipitate with ethyl acetate dried over anhydrous magnesium sulfate for 3 to 5 times, and dry in vacuum to obtain CyIC-NHS , the yield was 95%.

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Abstract

The invention discloses a GSH (glutathione) response based diagnosis and treatment integrated organic molecular probe and a production method thereof. The diagnosis and treatment integrated molecular imaging probe of the class is structured on the basis of near-infrared fluorescent dyes and tumor microenviroment, disulfide bonds in the probe can be cut off through oxidation reduction of the GSH, active drugs are released, and the purpose of monitoring transferring and releasing of the drugs is achieved. The synthetic process is relatively simple and rapid, the active drugs are released rapidly, action period is short, side effect on normal cells is small, tremendous utilization potential is achieved, reaction step is simple, operation process is clear, the molecular imaging probe and anticancer prodrugs are integrated, target detection on cancers can be realized while effect of targeted cancer treatment can be achieved through the reasonably designed structure, meanwhile biological distribution of the prodrugs in biological bodies and releasing and enriching process of the active drugs can be monitored, and great significance in studying of action mechanism of the drugs, resistance mechanisms of the cancers and the like is achieved.

Description

technical field [0001] The invention belongs to the technical field of organic compounds, and in particular relates to a GSH response-based integrated organic molecular probe for diagnosis and treatment and a preparation method thereof. Background technique [0002] At present, many drug carriers are established based on the EPR effect, such as polymer nanoparticles, liposomes, silica mesoporous materials, etc.; this passive targeting method can make the drug more concentrated in the tumor tissue, Improving drug efficacy and reducing side effects, but it is difficult to control the free diffusion process of drugs in tumor tissue, and it is impossible to avoid the potential drug resistance mechanism of tumors. In addition, targeting ligands (antibodies, nucleic acid aptamers, polypeptides, etc.) , many tumor markers are expressed in both tumor cells and normal cells, and due to the heterogeneity of tumors, there are differences in the expression of biomarkers among different...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/073C07H1/00A61K31/7068A61P35/00A61K47/48
CPCC07H19/073A61K31/7068C07H1/00
Inventor 张象涵王忠良王博赵娜徐雨停左昕
Owner XIDIAN UNIV
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