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Use of a gamma-carboline hydroxamic acid anti-tumor metastasis compound and its preparation method

An anti-tumor metastasis, carboline hydroxime technology, applied in the field of biomedicine, can solve the problems of poor effect and achieve good inhibitory activity and low cytotoxicity

Active Publication Date: 2022-05-24
UNIV OF JINAN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] In view of the poor effect of existing histone deacetylase inhibitors on solid tumors, the present invention combines the γ-carboline structure as the CAP region with the hydroxamic acid structure to synthesize a new type of anti-tumor metastasis histone sirtuin inhibitor

Method used

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  • Use of a gamma-carboline hydroxamic acid anti-tumor metastasis compound and its preparation method
  • Use of a gamma-carboline hydroxamic acid anti-tumor metastasis compound and its preparation method
  • Use of a gamma-carboline hydroxamic acid anti-tumor metastasis compound and its preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Example 1 Synthesis and characterization of γ-carboline hydroxamic acids.

[0031] In this embodiment, 1 H-NMR was measured by Bruker AVANCE Ⅲ HD 600 Mega NMR spectrometer; MS was measured by Agilent 6440 Triple Quad LC / MS, all of which were ESI unless otherwise noted; all solvents were redistilled before use, and the used The anhydrous solvents were obtained by drying treatment according to standard methods; except for the description, all reactions were carried out under the protection of argon and tracked by TLC, and were washed with saturated brine and dried with anhydrous magnesium sulfate during post-treatment; Column chromatography on silica gel (200-300 mesh) was used for purification unless stated; the silica gel used, including 200-300 mesh and GF254, was produced by Qingdao Hailang Silica Gel Desiccant Co., Ltd.

[0032] The specific synthesis steps are as follows:

[0033] (1) Phenylhydrazine hydrochloride (1000 mg, 6.92 mmol) and 4,4-piperidinediol hydroc...

Embodiment 2

[0071] Example 2 Inhibition of HDAC1 enzyme activity by compounds QY01-QY08

[0072] Using Ac-Lys-Tyr-Lys(Ac)-AMC as the substrate, the enzyme activity was detected in 96-well or 384-well flat-bottom microplates by fluorescence detection method: Substrate Ac-Lys-Tyr-Lys(Ac)- After AMC is deacetylated by HDAC1, the product AMC obtained by trypsin hydrolysis emits fluorescence at 460 nm under excitation at 355 nm by a fluorescence detector. The addition of the inhibitor will affect the intensity of the fluorescence. By detecting the change of the fluorescence signal with time, the initial speed of the reaction is calculated, and the IC is calculated. 50 , with SAHA as the positive control, the results are shown in Table 1:

[0073] Table 1 Inhibition of HDAC1 by compounds QY01-QY08

[0074]

[0075] It can be seen from Table 1 that the compounds QY03-QY08 have a certain inhibitory activity against HDAC1, and are significantly better than SAHA, especially the inhibitory acti...

Embodiment 3

[0076] Example 3 Effects of different compounds on tumor cell proliferation.

[0077] Compounds QY06-QY08 with better inhibitory activity on HDAC1 were selected, MDA-MB-231, H157, A549, MCF-7 were used as target cells, and Beas-2B and L-02 cells were used as non-target cells (normal cells). Cell viability was detected by SRB method: different cells were divided into 6 × 10 3 The cells were inoculated into a 96-well plate at a density of 1 / well, and after 24 h of conventional culture, the compounds in Example 1 at different concentrations were added in sequence, and each group was set up with 3 replicate wells. After culturing for 48 h, the cells were fixed, stained with SRB, the 96-well plate was placed in a microplate reader, and the OD value was measured at a wavelength of 440 nm. Statistical analysis of the effect of drugs on the survival rate of different cells, the results are shown in Table 2:

[0078] Table 2 IC of different compounds on different cell proliferation ...

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Abstract

The invention belongs to the field of biomedicine, and specifically relates to the use of a γ-carboline hydroxamic acid anti-tumor metastasis compound and a preparation method thereof. It has been proved that HDACi (histone deacetylase inhibitor) plays a role in tumor development through various mechanisms, such as promoting tumor cell invasion and migration, promoting tumor angiogenesis, enhancing tumor cell resistance to drugs, Inhibit tumor cell differentiation and apoptosis. γ-carboline derivatives have various pharmacological properties, such as antitumor, anti-inflammatory and antibacterial activities, etc. At the same time, the molecular weight of γ-carboline is small and the bioavailability is high. The invention combines the γ-carboline structure as the CAP region with the hydroxamic acid structure to synthesize a novel anti-tumor metastasis histone deacetylase inhibitor. And the synthesized compounds were tested by biological experiments, including cell proliferation experiments, anti-migration experiments and cell apoptosis experiments.

Description

technical field [0001] The invention belongs to the field of biomedicine, and in particular relates to a use of a γ-carboline hydroxamic acid anti-tumor metastasis compound and a preparation method thereof. Background technique [0002] Cancer is one of the deadliest diseases in the world. In addition to genetic factors, the development of cancer also involves epigenetic modifications, including covalent modifications of DNA (methylation and demethylation) and histones. Epigenetic regulation is reversibly modified by corresponding enzymes, among which the most in-depth study is the highly expressed histone deacetylase (HDAC) in tumors. Histone deacetylases (HDACs) and histone acetyltransferases (HATs) work together to regulate the level of acetylation of histone lysine residues. In addition, HDACi (histone deacetylase inhibitors) have been shown to play a role in tumor development through various mechanisms, such as promoting tumor cell invasion and migration, promoting tu...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04A61K31/437A61P35/04A61P35/00A61P29/00
CPCC07D471/04A61P35/04A61P35/00A61P29/00
Inventor 杨飞飞曲玉花张华赵娜
Owner UNIV OF JINAN
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