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Application and preparation method of gamma-carbolin-hydroxamic acid anti-tumor metastasis compound

An anti-tumor metastasis, carboline hydroxime technology, applied in the field of biomedicine, can solve problems such as poor effect

Active Publication Date: 2020-10-23
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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  • Application and preparation method of gamma-carbolin-hydroxamic acid anti-tumor metastasis compound
  • Application and preparation method of gamma-carbolin-hydroxamic acid anti-tumor metastasis compound
  • Application and preparation method of gamma-carbolin-hydroxamic acid anti-tumor metastasis compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

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

[0031] In this example, 1 H-NMR was measured with Bruker AVANCE Ⅲ HD 600 mega-NMR spectrometer; MS was measured with Agilent 6440 Triple Quad LC / MS instrument, and all were ESI methods unless otherwise noted; all solvents were re-distilled before use, and the used All the anhydrous solvents were obtained by drying according to the standard method; except for the instructions, all the reactions were carried out under the protection of argon and followed by TLC, and the post-treatment was washed with saturated saline and dried with anhydrous magnesium sulfate; the product Purification uses silica gel (200-300 mesh) column chromatography unless otherwise specified; the silica gel used, including 200-300 mesh and GF254, are produced by Qingdao Hailang Silica Gel Desiccant Co., Ltd.

[0032] Concrete synthetic steps are as follows:

[0033] (1) Dissolve phenylhydrazine hydrochloride (1000 ...

Embodiment 2

[0071] Example 2 Inhibition of HDAC1 Enzyme Activity by Compounds QY01-QY08

[0072] Using Ac-Lys-Tyr-Lys(Ac)-AMC as substrate, use fluorescence detection method to detect enzyme activity in 96-well or 384-well flat-bottom microplate: Substrate Ac-Lys-Tyr-Lys(Ac)- After AMC was deacetylated by HDAC1, the product AMC obtained by hydrolysis with trypsin emitted 460 nm fluorescence under excitation of 355 nm by a fluorescence detector. After adding the inhibitor, it will affect the intensity of the fluorescence. By detecting the change of the fluorescence signal with time, the initial velocity 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 compounds QY03-QY08 have certain inhibitory activity on HDAC1, which is significantly better than SAHA, especially the inhibitory activity of QY08...

Embodiment 3

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

[0077] Select compounds QY06-QY08 with better inhibitory activity on HDAC1, use MDA-MB-231, H157, A549, and MCF-7 as target cells, and use Beas-2B and L-02 cells as non-target cells (normal cells), The cell viability was detected by the SRB method: different cells were divided into 6×10 3 Each well was inoculated into a 96-well plate, and after conventional culture for 24 hours, the compound in Example 1 was added in sequence at different concentrations, and three replicate wells were set up for each group. After continuing to culture for 48 h, the cells were fixed, stained with SRB, and 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 50 value ...

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Abstract

The invention belongs to the field of biological medicines, and particularly relates to application and a preparation method of a gamma-carbolin-hydroxamic acid anti-tumor metastasis compound. It hasbeen proved that HDACi (histone deacetylase inhibitor) plays a role in the tumor development process through multiple mechanisms, such as promoting tumor cell invasion and migration, promoting tumor tissue angiogenesis, enhancing drug resistance of tumor cells to drugs and inhibiting tumor cell differentiation and apoptosis. The gamma-carboline derivative has various pharmacological characteristics, such as anti-tumor, anti-inflammatory and antibacterial activity. Meanwhile, the molecular weight of the gamma-carboline is small, and the bioavailability is high. According to the invention, a gamma-carboline structure is used as a CAP region and is combined with a hydroxamic acid structure to synthesize a novel anti-tumor metastasis histone deacetylase inhibitor. The synthesized compound is subjected to biological experiment detection, including a cell proliferation experiment, an anti-migration experiment and a cell apoptosis experiment.

Description

technical field [0001] The invention belongs to the field of biomedicine, and in particular relates to the use of a gamma-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 occurrence 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 more in-depth study is the highly expressed histone deacetylase (HDAC) in tumors. Histone deacetylase (HDAC) and histone acetyltransferase (HAT) cooperate to regulate the acetylation level of histone lysine residues. In addition, 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 neo...

Claims

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Application Information

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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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