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Protein tyrosine phosphatase selective inhibitor, application, preparation method and pharmaceutical composition

A tyrosine phosphatase, selective technology, applied in the field of protein tyrosine phosphatase selective inhibitors, can solve the problems of affecting the metabolic process, high similarity of enzyme active centers, adverse drug reactions, etc., to improve enzyme inhibition Activity, the effect of reducing the effective use concentration

Active Publication Date: 2021-12-17
PEKING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although there are many kinds of PTPs and their downstream target proteins are different, the similarity of their enzyme active centers is relatively high
At present, the PTP inhibitors designed based on the structure of the PTP active center generally need phosphate or phosphate analogs as active groups. These inhibitors will inevitably affect other phosphate-related metabolic processes in the cell at high concentrations, resulting in medical side effects

Method used

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  • Protein tyrosine phosphatase selective inhibitor, application, preparation method and pharmaceutical composition
  • Protein tyrosine phosphatase selective inhibitor, application, preparation method and pharmaceutical composition
  • Protein tyrosine phosphatase selective inhibitor, application, preparation method and pharmaceutical composition

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Embodiment 1, the preparation method of GQDs

[0036] Graphene (0.15 g) was added to a mixture of concentrated sulfuric acid (30 mL) and concentrated nitric acid (10 mL). After the mixed solution was sonicated for 2 h, the mixture was put into a polytetrafluoroethylene-lined reactor and reacted at 120° C. for 5 h. After the reaction, the reaction solution was cooled to room temperature and diluted to 300 mL with deionized water. The pH was adjusted to about 8 with solid anhydrous sodium carbonate. The reaction solution was placed at 4 ° C for 24 h. After the supernatant was filtered through a 0.22 μm water-based filter membrane, it was dialyzed with a 1000 Da dialysis bag at room temperature for 2 days (changing water 6 times a day) to remove inorganic salt ions to obtain a light brown clear solution, which was then freeze-dried to obtain a loose brown-yellow solid .

Embodiment 2

[0037] Embodiment 2, the preparation method of PTP1B selective ligand

[0038]

[0039] 500 mg of 2,6-dihydroxybenzoic acid was dissolved in 5 mL of methanol, and 5 mL of methanol solution containing 323.6 μL of thionyl chloride was slowly added dropwise under ice cooling. After the dropwise addition was completed, it was heated to 60° C. for 2 h. The reaction was detected by TLC. After the reaction was completed, the reaction liquid was removed by rotary evaporation to obtain the crude product, which was recrystallized in methanol to obtain the pure intermediate 1.

[0040]

[0041] 400mg of intermediate 1, 342.8mg of N-Boc-4-aminobutanol, and 652.7mg of triphenylphosphine were suspended in 20mL of tetrahydrofuran, and under nitrogen protection, diethyl azodicarboxylate (368 μL diluted in 2mL tetrahydrofuran), reacted for 1h, and after the reaction was completed, diluted the reaction solution with ethyl acetate, extracted the reaction solution with water three times, col...

Embodiment 3

[0046] Example 3. Preparation method of GQDs-based vanadium coordination complex with PTP1B selective inhibitory activity

[0047] Take equal volumes of 0.012M Ligand 1 and 0.024M NaVO 3 After mixing, the ligand 1-V complex was obtained, and then the GQDs aqueous solution was stirred overnight at a ratio of 0.6 mg of ligand 1 to 1 mg of GQDs, and the reaction solution was passed through a 0.02 μm filter membrane to obtain a GQD-ligand 1-V solution. Collect the prepared GQD-ligand 1-V solution, and finally use Sephadex TMG-25M (GE Healthcare, USA) to remove unbound ligands 1 and V.

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Abstract

The invention discloses a protein tyrosine phosphatase selective inhibitor and a preparation method thereof, and relates to the field of protein tyrosine phosphatase inhibition. The protein tyrosine phosphatase selective inhibitor is a functionalized carrier-protein tyrosine phosphatase selective ligand-vanadium coordination compound, can be used for preparing drugs for treating diabetes, tumors or obesity, can reduce the effective use concentration while improving the enzyme inhibition activity, and does not generate adverse reaction to the body. The preparation method comprises the following steps: mixing a vanadium compound with a protein tyrosine phosphatase selective ligand, and loading the obtained compound onto a functional carrier to form a functional carrier-protein tyrosine phosphatase selective ligand-vanadium coordination compound.

Description

technical field [0001] The invention relates to the field of protein tyrosine phosphatase inhibition, in particular to a protein tyrosine phosphatase selective inhibitor, application, preparation method and pharmaceutical composition. Background technique [0002] Protein tyrosine phosphatase (PTP) and protein tyrosine kinase (PTK) jointly regulate the process of protein phosphorylation in vivo. PTP plays an important role in cell metabolism, immunity and survival, and is a potential target for drug design of many diseases. Among them, tyrosine phosphatase 1B (PTP1B) is one of the important targets for diabetes treatment. Although there are many kinds of PTPs and their downstream target proteins are different, the similarity of their enzyme active centers is relatively high. At present, the PTP inhibitors designed based on the structure of the PTP active center generally need phosphate or phosphate analogs as active groups. These inhibitors will inevitably affect other phos...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/00A61K31/28A61P35/00A61P3/10A61P3/04
CPCC07F9/00A61P35/00A61P3/10A61P3/04
Inventor 杨晓达冯波董雅琼
Owner PEKING UNIV
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