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LSD1 inhibitors and application thereof

A technology of inhibitors and compounds, applied in the field of medicine, can solve problems such as few and no drugs on the market

Inactive Publication Date: 2014-08-06
南通中国科学院海洋研究所海洋科学与技术研究发展中心 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are not many LSD1 inhibitors currently reported, mainly including cyclopropylamines, polyamines, guanidines, ureas, thioureas, cyclic peptides, triazole-dithiocarbamates, etc. These compounds are used as LSD inhibitors have shown good application potential in anti-tumor, anti-virus and treatment of leukemia, but there is no marketed drug yet

Method used

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  • LSD1 inhibitors and application thereof
  • LSD1 inhibitors and application thereof
  • LSD1 inhibitors and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] (3′,4′-Dihydroxy-phenyl)-(2-bromo-4,5-dihydroxy-phenyl)-methanone (I) and (2′-bromo-4′,5′-dihydroxy Preparation of phenyl)-(2-bromo-4,5-dihydroxyphenyl)-methanone (II).

[0021] The synthetic route of the compound is shown in the figure below:

[0022]

[0023] (1) After adding 22.08g (120mmol) of veratrolic acid, 16.92g (120mmol) of veratrole and 100g of polyphosphoric acid into a 500ml three-necked flask, the mixture was reacted under electric stirring at 80°C for 1 hour. The reaction mixture was cooled to 60° C. and 250 ml of ice water was added dropwise to the reactant within 30 min. At this time, a large amount of water-insoluble pink solid appeared in the reactant. After removing water by filtration, the obtained solid was dissolved in 100 ml of dichloromethane, and then the dichloromethane phase was washed 3 times with an equal volume of 3% sodium hydroxide solution and distilled water, respectively. After drying over anhydrous magnesium sulfate, it was conc...

Embodiment 2

[0029] Lysine-specific histone methylase 1 (LSD1) inhibitory activity assay

[0030] Human recombinant LSD1 / CoREST was expressed in Escherichia coli as an independent protein and co-purified using the method reported in the literature (Forneris F et al. Trends Biochem Sci, 2008, 33(4):181-189). Enzyme activity and inhibition experiments refer to methods reported in literature (Forneris F, et al. J. Biol. Chem. 282, 20070-20074), and a screening system was established. Compounds I and II were dissolved in a small amount of DMSO (the weight-to-volume ratio of compound to DMSO: 100mg: 1ml), diluted with buffer solution (50mM Hepes / NaOH with a pH of 7.5), and 2 μL was added to a 30 μL reaction system. Make the final concentrations of 100 μM, 10 μM, 1.0 μM, 0.1 μM, and 0.01 μM respectively, use Lys4 monomethylated histone H3 peptide as a substrate, and measure the fluorescence at 665 nm and 615 nm wavelengths with Lance detection reagent from Perkin Elmer Company The signal intens...

Embodiment 3

[0033] Preparation of compound (I) and (II) injection

[0034] Compounds (3′,4′-dihydroxy-phenyl)-(2-bromo-4,5-dihydroxy-phenyl)-methanone (I) and (2′-bromo-4′,5′-di Hydroxyphenyl)-(2-bromo-4,5-dihydroxyphenyl)-methanone (II) with a small amount of DMSO (weight ratio: 1:0.1-1:0.5, here is 1:0.4) After dissolving, add water for injection as usual (weight ratio is 1:20-1:200, here is 1:200), fine filter, potting and sterilizing to make injection solution.

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Abstract

The invention relates to novel LSD1 inhibitors and application of the LSD1 inhibitors in drugs, in particular to application of the LSD1 inhibitors in preparing LSD1-resistant inhibitor drugs, drugs for treating tumor, virus infectious diseases, hematological diseases and the like. The chemical structural formula of the LSD1 inhibitors is shown in the description. For the compound I (one LSD1 inhibitor), the No. 2 carbons of benzene rings are connected with bromine atoms; the No. 4 carbons, No. 5 carbons, No. 3' carbons and No. 4' carbons are connected with hydroxyl groups; the English name of the compound I is (3',4'-dihydroxyphenyl)-(2-bromo-4,5-dihydroxyphenyl)methanone. For the compound II (the other LSD1 inhibitor), the No. 2 carbons and No. 2' carbons of benzene rings are connected with bromine atoms; the No. 4 carbons, the No. 5 carbons, the No. 4' carbons and No. 5' carbons are connected with hydroxyl groups; the English name of the compound II is (2'-bromo-4',5'-dihydroxyphenyl)-(2-bromo-4,5-dihydroxyphenyl)methanone.

Description

technical field [0001] The present invention relates to the technical field of medicines, specifically two novel LSD1 inhibitors (3', 4'-dihydroxy-phenyl)-(2-bromo-4,5-dihydroxy-phenyl)-methanone ( I) and (2'-bromo-4',5'-dihydroxyphenyl)-(2-bromo-4,5-dihydroxyphenyl)-methanone (II) and its pharmacological activity and pharmaceutical use. The compound and its derivatives can be used as LSD1 inhibitors to prevent and / or treat diseases and symptoms related to the activity of histone demethylase LSD1, especially diseases related to abnormal gene transcription, cell differentiation and proliferation, etc. Such as tumors, viral infections and blood diseases. Background technique [0002] Malignant tumors seriously affect people's health and have become the second leading cause of human death, second only to cardiovascular and cerebrovascular diseases. According to the statistics of the World Health Organization, more than 10 million cancer patients are newly diagnosed every year...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/122A61P35/00A61P31/20A61P31/18A61P35/02C07C49/83C07C45/65
Inventor 史大永王立军江波吴宁王帅玉
Owner 南通中国科学院海洋研究所海洋科学与技术研究发展中心
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