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Glyoxalase I inhibitor, preparation method and medical application thereof

A technology of glyoxalase and inhibitor, applied in the field of medicine, can solve the problems of apoptosis and low activity of tumor cells

Inactive Publication Date: 2015-02-11
CHENGDU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0021] The present invention solves the defects in the prior art that anti-tumor drugs have adverse effects on the DNA and / or protein of normal cells, and the activity of the existing GlxI competitive inhibitors is not high, leading to high-dose administration, etc., and proposes a new synthetic The glyoxalase I competitive inhibitor, namely GlxI inhibitor, its mechanism of action is to cause the concentration of methylglyoxal in tumor cells to increase by competitively inhibiting the activity of glyoxalase I, resulting in tumor cell apoptosis , is an ideal drug for the treatment of cancer

Method used

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  • Glyoxalase I inhibitor, preparation method and medical application thereof
  • Glyoxalase I inhibitor, preparation method and medical application thereof
  • Glyoxalase I inhibitor, preparation method and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] Example 1: Synthesis of the compound mAH, namely N-((N'-acetoxy-2-(N"-hydroxylamine-N"-(3-ethynyl-phenyl))propionamido)-acetamido)- Synthesis of 4-amino-4-formyl-butanamide

[0057]

[0058] Step 1: Preparation of 3-nitro-(2-(trimethylsilyl)ethynyl)benzene (1)

[0059] Under nitrogen protection, 3-nitro-bromobenzene (3g, 15mmol), trimethylsilylacetylene (1.8g, 18mmol), dichlorotriphenylphosphopalladium (1.0g, 1.5mmol), cuprous iodide ( 0.5g, 3mmol) and triethylamine (50ml) were added into a 100ml round bottom flask to obtain a black suspension, which was stirred and reacted overnight at 40°C. After TLC detected that the reaction of the raw materials was complete, the reaction was stopped. The reaction solution was concentrated under reduced pressure at room temperature to dryness to obtain a black solid. The black solid was dissolved with dichloromethane, and the insoluble matter was filtered out, and the filtrate was concentrated under reduced pressure at room te...

Embodiment 2

[0068] Embodiment 2: The synthesis of compound mAHG, that is, the synthesis of S-(N-3-alkynylbenzene-N-hydroxyl 3-((N-hydroxyl-N-glutathione thiomethyl ester) amino)phenylacetylene

[0069]

[0070] Step 1: Preparation of 3-nitro-(2-(trimethylsilyl)ethynyl)benzene (1)

[0071] Under nitrogen protection, 3-bromonitrobenzene (3g, 15mmol), trimethylsilylacetylene (1.8g, 18mmol), dichlorotriphenylphosphopalladium (1.0g, 1.5mmol), cuprous iodide (0.5g , 3mmol) and triethylamine (50ml) were added into a round bottom flask to obtain a black suspension. The reaction was stirred overnight at 40° C., and the reaction was stopped after TLC detected that the reaction of the raw materials was complete. The reaction solution was concentrated to dryness under reduced pressure at room temperature to obtain a black solid. Dissolve the black solid with dichloromethane, filter, and concentrate the filtrate under reduced pressure at room temperature to distill off the solvent. The crude residu...

Embodiment 3

[0082] Example 3: Synthesis of pAH, namely N-((N'-acetoxy-2-(N"-hydroxylamine-N"-(4-ethynyl-phenyl))propionamido)-acetamido)-4 - Synthesis of amino-4-formyl-butyramide

[0083]

[0084] Step 1: Preparation of p-nitro-(2-(trimethylsilyl)ethynyl)benzene (1)

[0085] Under nitrogen protection, p-bromonitrobenzene (3g, 15mmol), trimethylsilylacetylene (1.8g, 18mmol), dichlorotriphenylphosphopalladium (1.0g, 1.5mmol), cuprous iodide (0.5g, 3mmol) and triethylamine (50ml) were added into a round bottom flask to obtain a black suspension. Stir at room temperature for 6 h, and stop the reaction after TLC detects that the reaction of the raw materials is complete. The reaction solution was concentrated to dryness at room temperature under reduced pressure to obtain a black solid. The black solid was dissolved in dichloromethane, filtered, and the filtrate was concentrated under reduced pressure at room temperature to evaporate the solvent. The residue was purified by silica gel ...

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PUM

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Abstract

The invention discloses a glyoxalase I inhibitor shown in formula I, wherein R1 and R2 are H, ethyl and cyclopentane; X is any one of methylene, sulphur and oxygen atom; R3 is alkynyl, cyano group, halogen atom, 1-3 halogen atoms substituted vinyl, 1-6 linear alkyl and any one or more simultaneously substituted benzene ring or pyridine ring of alkyl substituted by halogen atoms in different number. The invention further discloses a preparation method of the glyoxalase I inhibitor and application in preparation of drugs for treating and suppressing tumor growth and drugs for treating osteoporosis.

Description

technical field [0001] The invention relates to an inhibitor of glyoxalase system, in particular to a glyoxalase I inhibitor (GlxI inhibitor) and its preparation method and medical application. Background technique [0002] At present, many drugs used clinically or under development are aimed at attacking tumor cells by directly or indirectly inhibiting DNA and / or proteins. In this case, rapidly dividing normal cells, such as the intestinal epithelium and bone marrow, are also adversely affected with strong side effects. [0003] A toxic compound called methylglyoxal is inevitably produced in the process of glucose metabolism in the human body, which can cause programmed cell death. The human body has developed a glyoxalase system during the long-term evolution process, which is composed of glyoxalase I (glyoxalase I, GlxI for short) and glyoxalase II (glyoxalase II, GlxII for short), which can detoxify methylglyoxalase The role of aldehydes. GlxI is highly expressed in m...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K5/027C07K1/06A61K38/06A61P35/00A61P19/10
CPCY02P20/55
Inventor 郑哲彬姚中伟邓琪山石清李静曹胜华赵俊曾文王昉彤唐克慧褚以文姬海红肖忠行王宇驰杨晨李宗河王辂
Owner CHENGDU UNIV