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Pharmaceutical application of small-molecule inhibitor in preparation of drugs for inhibiting interaction between ornithine decarboxylase and ornithine decarboxylase antienzyme 1

A small-molecule inhibitor, ornithine decarboxylase technology, is used in anti-tumor drugs, medical preparations containing active ingredients, drug combinations, etc., and can solve problems such as large toxic and side effects, high concentration of action, and weak binding ability.

Inactive Publication Date: 2020-10-30
HUBEI UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, its binding ability to ODC is weak, and its concentration is very high, and because it is a suicide inhibitor that forms a covalent bond with ODC, its toxic and side effects are very large

Method used

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  • Pharmaceutical application of small-molecule inhibitor in preparation of drugs for inhibiting interaction between ornithine decarboxylase and ornithine decarboxylase antienzyme 1
  • Pharmaceutical application of small-molecule inhibitor in preparation of drugs for inhibiting interaction between ornithine decarboxylase and ornithine decarboxylase antienzyme 1
  • Pharmaceutical application of small-molecule inhibitor in preparation of drugs for inhibiting interaction between ornithine decarboxylase and ornithine decarboxylase antienzyme 1

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] Small Molecule Inhibitors: A Chemical Synthetic Route to 6-[N'-(4-Dimethylaminobenzylidene)-hydrazino-[1,3,5]triazole-2,4-diamine.

[0056]

[0057] In a 100ml one-mouth bottle, add D24-1-1 (purchased from Shanghai Aladdin Biochemical Technology Co., Ltd.) 5g, hydrazine hydrate (purchased from Shanghai Aladdin Biochemical Technology Co., Ltd.) (80%wt) 11g and water 50ml , protected by nitrogen, heated to 85°C, reacted for 7h, cooled to room temperature, filtered, and dried in vacuo (45°C, 24h) to obtain 3.85g of white solid D24-1-2 with a yield of 79.4%.

[0058] In a 100ml single-necked bottle, sequentially add 3.5g of D24-1-2, 3.8g of D24-1-3 (purchased from Shanghai Aladdin Biochemical Technology Co., Ltd.) and 40ml of methanol, under nitrogen protection, react at 30°C for 18h, and cool to After filtering at room temperature, the resulting solid was slurried with 20 ml of DMSO, protected by nitrogen, filtered, and dried in vacuo at 45°C for 12 hours to obtain 2.1 ...

Embodiment 2

[0072] The small molecule inhibitor 1,3-dimethyl-8-(2-thienyl)-3,7-dihydro-1H-purine-2,6-dione was purchased from SPECS (http: / / www.specs .net).

[0073] In order to verify whether the small molecule 1,3-dimethyl-8-(2-thienyl)-3,7-dihydro-1H-purine-2,6-dione can inhibit the enzymatic activity of ODC, the Chromatography (HPLC) detects putrescine, the enzyme-catalyzed product, to obtain a half-inhibitory concentration of C small molecules to ODC enzyme activity of about 31.8 μM ( Figure 16 ). Figure 16 In order to detect putrescine, the catalytic product of ODC, by high performance liquid chromatography, the inhibitory efficiency of small molecules on ODC enzyme activity was calculated by comparing with those without adding small molecules.

[0074] For the small molecule 1,3-dimethyl-8-(2-thienyl)-3,7-dihydro-1H-purine-2,6-dione, in order to verify its inhibition of ODC-OAZ1 interaction, A method based on fluorescence resonance energy transfer (FRET) was used. ODC protein...

Embodiment 3

[0080] Small molecule inhibitor: 1-Butyl-N-(4-chlorophenyl)-1H-benzo[d]imidazol-2-amine purchased from SPECS (http: / / www.specs.net).

[0081] In order to verify whether the small molecule 1-butyl-N-(4-chlorophenyl)-1H-benzo[d]imidazol-2-amine can inhibit the enzymatic activity of ODC, the enzyme catalysis was detected by high performance liquid chromatography (HPLC). Product putrescine, the half-inhibitory concentration of C small molecule to ODC enzyme activity is about 31.8 μ M ( Figure 21 ). Figure 21 In order to detect putrescine, the catalytic product of ODC, by high performance liquid chromatography, the inhibitory efficiency of small molecules on ODC enzyme activity was calculated by comparing with those without adding small molecules.

[0082] To verify the inhibition of ODC-OAZ1 interaction by 1-butyl-N-(4-chlorophenyl)-1H-benzo[d]imidazol-2-amine molecules, fluorescence resonance energy transfer (FRET)-based method. ODC protein tagged with YPET fluorescent prote...

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Abstract

The invention provides pharmaceutical application of a small-molecule inhibitor in preparation of drugs for inhibiting interaction between ornithine decarboxylase and ornithine decarboxylase antienzyme 1, and application of the small-molecule inhibitor in preparation of drugs for stabilizing ornithine decarboxylase inactive dimers. The small molecule inhibitor comprises any one selected from a group consisting of 6-[N'-(4-dimethylaminobenzyl)-hydrazino-[1,3,5]triazole-2,4-diamine, 1-butyl-N-(4-chlorphenyl)-1H-benzo[d]imidazol-2-amine, and 1,3-dimethyl-8-(2-thienyl)-3,7-dihydro-1H-purine-2,6-dione.

Description

technical field [0001] The invention relates to a small molecule inhibitor and its pharmaceutical use, specifically -[N'-(4-dimethylaminobenzyl)-hydrazine-[1,3,5]triazole-2,4 -diamine, or 1-butyl-N-(4-chlorophenyl)-1H-benzo[d]imidazol-2-amine, or 1,3-dimethyl-8-(2-thienyl) -Pharmaceutical use of 3,7-dihydro-1H-purine-2,6-dione and its analogues. Background technique [0002] Protein is one of the main components of organisms and the main substance to complete various life activities. Among various proteins, proteases are crucial to life activities, and almost all biochemical reactions in organisms are catalyzed by proteases. The activity of various proteases in organisms has a strict regulation mechanism. Once there is a problem with the regulation mechanism, the activity of proteases is too high, too low or completely inactivated, which will cause various diseases. Therefore, it has very important theoretical and practical significance to regulate the activity of proteas...

Claims

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Application Information

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IPC IPC(8): A61K31/53A61K31/522A61K31/4184A61P35/00
CPCA61K31/4184A61K31/522A61K31/53A61P35/00
Inventor 刘森何梦溪柴晓颖占景琼
Owner HUBEI UNIV OF TECH
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