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Hydroxamic acid histone deacetylase inhibitor containing tetrahydrocarboline structure as well as preparation method and application of hydroxamic acid histone deacetylase inhibitor

A technology of tetrahydrocarboline and hydroxime, applied in the field of biomedicine, can solve problems such as affecting enzyme activity, changing DNA replication fidelity, etc., and achieve the effect of good inhibition activity

Pending Publication Date: 2022-06-07
UNIV OF JINAN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Some β-carboline derivatives, including pilocarpine, have been reported to intercalate into DNA, leading to altered DNA replication fidelity and affecting enzymatic activity in DNA

Method used

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  • Hydroxamic acid histone deacetylase inhibitor containing tetrahydrocarboline structure as well as preparation method and application of hydroxamic acid histone deacetylase inhibitor
  • Hydroxamic acid histone deacetylase inhibitor containing tetrahydrocarboline structure as well as preparation method and application of hydroxamic acid histone deacetylase inhibitor
  • Hydroxamic acid histone deacetylase inhibitor containing tetrahydrocarboline structure as well as preparation method and application of hydroxamic acid histone deacetylase inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-1

[0028] Example 1-1, 8-(9-ethyl-1,3,4,9-tetrahydro-2h-pyridine[3,4-b]indol-2-yl)-N-hydroxy-8-oxo Preparation of octanamide (YH01)

[0029] Take tryptamine hydrochloride and paraformaldehyde, stir in water, add 3M sodium acetate aqueous solution and reflux for more than 4 hours, add sodium hydroxide aqueous solution to adjust to alkaline, extract, and evaporate to dryness to obtain compound 2 as a yellow solid.

[0030] Tetrahydro-β-carboline (compound 2) was dissolved in 1,4-dioxane, suberic anhydride was added, and the mixture was heated to reflux for about 5 hours, and intermediate 3 was isolated. Intermediate 3 is dissolved in methanol, 3-4 drops of thionyl chloride are added dropwise, and the reaction system is heated to reflux. After 5 hours, the excess solvent was removed under reduced pressure to obtain the crude product 4, which was passed through a silica gel column after conventional post-treatment and used for the next reaction.

[0031] The obtained compound 4 was...

Embodiment 1-2

[0035] Example 1-2, 8-(8-bromo-5-ethyl-1,3,4,5-tetrahydro-2hydro-pyridin[4,3-b]indol-2-yl)-N- Preparation of Hydroxy-8-oxooctamide (YH10)

[0036] The bromophenylhydrazine hydrochloride and 4-piperidone hydrochloride monohydrate were stirred in ethanol, the reaction was refluxed, sodium hydroxide aqueous solution was added to make it alkaline, and the yellow solid was obtained by suction filtration, that is, compound 7.

[0037] Tetrahydro-γ-carboline (compound 7) was dissolved in 1,4-dioxane, suberic anhydride was added, and the mixture was heated to reflux for about 5 hours, and intermediate 8 was isolated. Intermediate 8 was dissolved in methanol, 3-4 drops of thionyl chloride were added dropwise, and the reaction system was heated to reflux. After 5 hours, the excess solvent was removed under reduced pressure to obtain crude product 9, which was subjected to conventional post-treatment and passed through a silica gel column for the next reaction.

[0038] The obtained co...

Embodiment 1-3

[0042] Example 1-3, 5-(2-benzoyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol-9-yl)-N-hydroxypentanamide Preparation of (YH19)

[0043]Dissolve HATU and acetic acid in DMF, stir in ice bath for half an hour, add compound 2 (4H-β-carboline) to react overnight at room temperature, extract with EtOAc after the reaction, and pass through silica gel column after routine post-treatment to obtain compound 11.

[0044] Compound 11 was dissolved in DMF, and NaH was added under ice bath to remove hydrogen for half an hour, then methyl 4-bromobutyrate was added to react at room temperature for three hours, extracted with EtOAc after the reaction, and passed through a silica gel column after conventional post-treatment to obtain compound 12.

[0045] KOH was added to the methanol solution of hydroxylamine hydrochloride at 40°C and kept for 10min, then the reaction system was cooled to 0°C and filtered, the ester (compound 12) was added to the filtrate, and then KOH was added, and the reaction...

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Abstract

The invention belongs to the field of biological medicine, and relates to a hydroxamic acid histone deacetylase inhibitor containing a tetrahydrocarboline structure and a preparation method and application thereof. The invention discloses a hydroxamic acid type compound with a tetrahydro-beta-indole structure and a tetrahydro-gamma-indole structure, a derivative of the hydroxamic acid type compound, and application of the hydroxamic acid type compound as a novel histone deacetylase inhibitor. The invention also discloses application of the compound or the pharmaceutical composition thereof in preparation of drugs for treating growth, metastasis, recurrence and other diseases of various malignant tumors caused by histone acetylation disorder. The compound can inhibit the growth of various malignant tumors, and has a potential effect of relieving the malignant degree of tumor metastasis patients.

Description

technical field [0001] The invention belongs to the field of biomedicine, and relates to a class of hydroxamic acid-type histone deacetylase inhibitors containing a tetrahydrocarboline structure and a preparation method and application thereof. Background technique [0002] Epigenetic modification refers to the covalent modification of chromosomes, mainly including structural modification of specific nucleotides in DNA and post-translational modification of histones. Currently, several enzymes related to epigenetic modification have been discovered and named after their main functions, such as DNA methyltransferases, DNA demethylases, histone acetyltransferases, histone deacetylases, Histone methyltransferases, histone demethylases, and more. Histone deacetylases are a class of proteases that widely exist in eukaryotic organisms. Up to now, there are 18 subtypes of known human HDACs. According to their homology with yeast histone deacetylases It can be divided into 4 subgr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61P35/00
CPCC07D471/04A61P35/00
Inventor 杨飞飞曲玉花张华仇荟然路文霞
Owner UNIV OF JINAN
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