Gamma carboline compound as well as preparation method and application thereof

A compound, carboline technology, applied in the field of medicine, can solve the problem of few research reports on carboline compounds

Inactive Publication Date: 2012-11-14
EAST CHINA UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Many drug structures contain a carboline parent ring (CN 101175754A, Biorg.Med.Chem.2008, 16, 4908), but there are relatively few research reports on the use of carboline compounds for histone deacetylase inhibitors

Method used

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  • Gamma carboline compound as well as preparation method and application thereof
  • Gamma carboline compound as well as preparation method and application thereof
  • Gamma carboline compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] The preparation of embodiment 1 compound I-10a~v

[0059] step 1

[0060] Preparation of 8-bromo-2,3,4,5-tetrahydro-1H-pyridin[4,3-b]indole hydrochloride (I-1)

[0061] 22.35 g (0.1 mol) of p-bromophenylhydrazine hydrochloride and 15.36 g (0.1 mol) of 4-piperidone hydrochloride were dissolved in 400 mL of ethanol-saturated hydrogen chloride solution, and a white solid precipitated after reflux for 3 hours. After cooling to room temperature, the precipitated white solid was filtered, the filter cake was washed with absolute ethanol, and dried in a vacuum oven to obtain 22.2 g of white solid product I-1, with a yield of 77%.

[0062] 1 H NMR (400MHz, DMSO): δ (ppm): 11.51 (s, 1H), 9.74 (s, 2H), 7.69 (s, 1H), 7.31 (d, J=8.6Hz, 1H), 7.19 (dd, J=8.6, 1.6Hz, 1H), 4.25(s, 2H), 3.42(t, J=5.3Hz, 2H), 3.04(t, J=5.3Hz, 2H).

[0063] 13 C NMR (100MHz, DMSO) δ135.01, 132.93, 127.21, 124.08, 120.52, 113.52, 111.90, 102.02, 41.04, 40.10, 20.54.

[0064] step 2

[0065] Preparat...

Embodiment 2

[0286] Example 2 Compounds of the present invention have inhibitory effects on the proliferation of various tumor cell lines:

[0287] 1. Experimental materials:

[0288] Cell lines and culture conditions: human breast cancer cell line (MCF-7), human colon cancer cell line (HCT116), human lung cancer cell line (A549), human cervical cancer cell line (HeLa) and human leukemia cell line (K562) , the above cell lines were purchased from the Cell Resource Center of Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences. MCF-7 was cultured in modified complete medium (DMEM, Dulbecco's Modified Eagle Medium) medium containing 10% fetal bovine serum (FBS, fetal bovine serum), and A549 was cultured in DMEM:F12 containing 10% FBS ( 1:1) medium, HCT116, HeLa and K562 were cultured in RPMI1640 medium containing 10% FBS, each medium was purchased from GIBCO, and contained penicillin and streptomycin at a final concentration of 100U / mL and 100U / mL white.

[0289] 2. Exp...

Embodiment 3

[0297] Example 3 Enzyme inhibitory activity of compounds of the present invention on HDACs and HDAC1 in vitro

[0298] Histone deacetylase (HDACs) inhibitory activity detection kit-histone deacetylase fluorescent detection kit (HDAC Fluorimetric Assay / Drug Discovery Kit, AK-500, Biomol) and histone deacetylase 1 ( HDAC1) Inhibition Activity Detection Kit Histone deacetylase 1 Fluorescent Detection Kit (HDAC1 Fluorimetric Assay / Drug Kit, AK-511, Biomol), with fluorescent substrate (Fluror de lys TM ) as the substrate, respectively detect the compound in the present invention to HDACs and HDAC1 half maximal inhibitory concentration (IC 50 ). All operations were carried out in accordance with the operation guide provided in the kit, and the specific operation steps were as follows: prepare the mother solution of the compound to be tested, and perform gradient concentration dilution. The assay reaction of HDACs and HDAC1 is as follows: Add the Hela cell nucleus extract and HDAC1...

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Abstract

The invention relates to a gamma carboline compound as well as a preparation method and application thereof, in particular relates to a histone deacetylase inhibitor based on gamma carboline as a skeleton as well as a preparation method and application thereof. The inhibitor in the invention is a compound having a structural formula as follows (shown in the specification). According to the invention, the synthesis method is simple, the condition is mild, and the compound has high tumor inhibiting rate and is hopeful to become a non-cytotoxins antineoplastic medicament.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a gamma carboline compound, its preparation method and application, which is used for the preparation of histone deacetylase inhibitors and can be used for the preparation of non-cytotoxic anti-tumor drugs. Background technique [0002] In eukaryotes, DNA is packaged with histones to form chromatin, which is further condensed to form chromosomes. Reversible acetylation of specific lysine residues at the ends of histones plays an important role in the regulation of gene expression. This reversible regulation is controlled by two enzymes with opposite functions: histone acetyltransferases (HATs) and histone deacetylases (HDACs). Acetylation of the epsilon amino acid of a specific lysine residue removes its positive charge, thus reducing the affinity between negatively charged DNA and histones. This accelerates the proximity of various transcription factors to the DNA, activating...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04A61K31/437A61P35/00A61P29/00A61P25/28A61P9/00
CPCY02P20/55
Inventor 邓卫平刘建文刘力锋金惠安娜梁雷皮红军刘华应俊
Owner EAST CHINA UNIV OF SCI & TECH
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