Phosphoglyceromutase 1 inhibitor and application in related diseases thereof

A technology of phosphoglycerate and mutase, applied in organic chemistry, drug combination, antineoplastic drugs, etc., can solve the problems of poor cell activity, unclear structure-activity relationship, toxic and side effects of anthraquinone skeleton structure, etc.

Inactive Publication Date: 2018-12-21
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, there are relatively few reports on PGAM1 small molecule inhibitors. Among them, anthraquinone PGAM1 inhibitors have good enzymatic activity, but their cell activity is poor. The anthraquinone skeleton structure may have certain toxic and side effects, and the structure-activity relationship has not yet been clarified.

Method used

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  • Phosphoglyceromutase 1 inhibitor and application in related diseases thereof
  • Phosphoglyceromutase 1 inhibitor and application in related diseases thereof
  • Phosphoglyceromutase 1 inhibitor and application in related diseases thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Embodiment 1 Synthesis of some compounds of the present invention

[0027] Preparation of 1,3,6,7-tetrahydroxy-2,8-di(3-methylbut-2-en-1-yl)-xanthone (Ib)

[0028]

[0029] Dissolve 1,3,6-trihydroxy-7-methoxy-2,8-bis(3-methyl-2-butenyl)-xanthone (Ia) (410 mg, 1.0 mmol) in 10 mL of DMF , added NaH (480mg, 10.0mmol), stirred at room temperature under nitrogen protection for 20min, added ethanethiol (1.4mL, 20.0mmol), heated to reflux for 5h, TLC detection, the raw materials were completely reacted, cooled to room temperature, added 20mL of water and 60mL of acetic acid Ethyl ester, extraction, the organic phase was washed three times with saturated ammonium chloride, and the organic phase was dried over anhydrous sodium sulfate. Purified by column chromatography (dichloromethane:methanol=30:1→15:1) to obtain 214 mg of light yellow solid, yield: 54%. 1 H-NMR (300MHz, CDCl 3 ): δ13.90(s, 1H), 11.16(s, 1H), 10.72(s, 1H), 8.63(s, 1H), 6.76(s, 1H), 6.33(s, 1H), 5.20-5.18...

Embodiment 2

[0059] Example 2 Compounds Ia-Ii inhibit PGAM1 activity experiment.

[0060] The invention measures the inhibitory activity of the small molecule inhibitor on PGAM1 based on an enzyme-linked method. Using 3PG as a substrate, it is finally converted into lactic acid through the joint action of four enzymes, PGAM1, enolase, pyruvate kinase (PK) and lactate dehydrogenase (LDH). In the last step of the reaction, a molecule of NADH is oxidized to generate NAD+, and the inhibitory activity of the small molecule on PGAM1 is determined by detecting the signal change of NADH (λ=340nm). The enzyme-linked reaction involves 4 enzymes. In order to verify the specificity and specificity of small molecule compounds, 2PG is used as a substrate, and enolase, PK and LDH are used as catalyzed enzymes to determine the reaction rate as a negative control. Possibility of false-positive small molecule compounds that inhibit the latter three target enzymes.

[0061] experimental method

[0062] Ad...

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PUM

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Abstract

The invention belongs to the field of medicinal chemistry, and particularly relates to phosphoglyceromutase 1. The invention provides an inhibitor of the phosphoglyceromutase 1; a specific structure is as shown in the formula I as shown in the description. The invention further provides a synthesis method of the structure as shown in the formula I as shown in the description and application in diseases related to cell apoptosis and tumors thereof; the diseases include various kinds of cancer of stomach cancer, liver cancer, myelomas, bladder cancer, prostatic cancer, breast cancer, rectal cancer, head and neck cancer, lung cancer, melanomas, ovarian cancer, cervical cancer, esophagus cancer and the like.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to a preparation method of a phosphoglycerate mutase 1 inhibitor represented by formula I and its application in cell apoptosis and tumor-related diseases. [0002] Background technique [0003] Tumor is one of the most harmful diseases to human health, seriously affecting people's quality of life. In recent years, chemical drugs, as one of the important means of treating tumors, have made great progress and development. At present, a variety of antitumor drugs with different mechanisms of action have been developed, but these drugs show many defects in clinical use, such as poor selectivity, large toxic and side effects, and drug resistance. Therefore, the research and development of new antitumor drugs is particularly important (Journal of Experimental Medicine, 2012, 209, 211-215). [0004] Phosphoglycerate mutase 1 (PGAM1) is an important enzyme in the biologic...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D311/86C07D405/06A61P35/00
CPCC07D311/86A61P35/00C07D405/06
Inventor 王进欣周璐高彪
Owner CHINA PHARM UNIV
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