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Trans-diaryl ethylene LSD1 (lysine specific histone demethylase 1) inhibitor, as well as preparation method and application thereof

A diarylethene, reaction technology, applied in the directions of organic chemistry, drug combination, anti-tumor drugs, etc., achieves strong in vitro anti-tumor activity, strong LSD1 inhibitory activity, and is conducive to popularization and application.

Active Publication Date: 2017-12-22
XINXIANG MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In order to find a new type of LSD1 small molecule inhibitor, the present invention synthesized a class of trans-diarylethene compounds, which have significant LSD1 inhibitory activity and anti-tumor activity in vitro, and no such compounds have been synthesized, LSD1 Inhibitory Activity and Antitumor Activity Reported

Method used

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  • Trans-diaryl ethylene LSD1 (lysine specific histone demethylase 1) inhibitor, as well as preparation method and application thereof
  • Trans-diaryl ethylene LSD1 (lysine specific histone demethylase 1) inhibitor, as well as preparation method and application thereof
  • Trans-diaryl ethylene LSD1 (lysine specific histone demethylase 1) inhibitor, as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Example 1 4-methoxy-3-(pyridin-2-yl)benzaldehyde (1a)

[0027]

[0028] Add 2-bromopyridine (456.5mg, 2.89mmol), toluene (7mL), K 2 CO 3 Aqueous solution (2.76g potassium carbonate dissolved in 10mL water, 2mL), tetrakis(triphenylphosphine)palladium (45.2mg, 0.04mmol), stirred at room temperature under nitrogen protection for 15 minutes, then added 5-formyl-2-methoxy Phenylboronic acid (400mg, 2.22mmol) in absolute ethanol (3mL), heated at 92°C for 4 hours, poured the reaction system into water, extracted with ethyl acetate, combined the ethyl acetate layers, followed by water, saturated saline Washed, dried over anhydrous sodium sulfate, suction filtered, the filtrate was concentrated under reduced pressure, and the concentrate was separated by column chromatography (petroleum ether: ethyl acetate = 6:1) to obtain 414.6 mg of white solid, yield 87.5%, Mp: 52-53 ℃. 1 H NMR (400MHz, CDCl 3 )δ9.98(s,1H),8.73(m,1H),8.31(d,1H,J=2.4Hz),7.96(dd,1H,J 1 = 2.4 Hz,J 2 =8...

Embodiment 2

[0029] Example 2 4-methoxy-3-(4-fluoropyridin-2-yl)benzaldehyde (1b)

[0030]

[0031] According to the method of Example 1, 2-bromo-4-fluoropyridine (508.6mg, 2.89mmol) was used instead of 2-bromopyridine to obtain 395.8mg of white solid, yield 77.1%, Mp: 73-74°C.1 H NMR (400MHz, CDCl 3 )δ 10.00(s,1H),8.72(dd,1H,J 1 =5.6Hz,J 2 =8.8Hz),8.40(t,1H,J=2.0Hz),8.00(dd,1H,J 1 =1.2Hz,J 2 =8.8Hz),7.65(d,1H,J=10.4Hz),7.16(d,1H,J=8.4Hz),7.05(m,1H),4.01(s,3H). 13 C NMR (101MHz, CDCl 3 )δ190.88,175.95,169.87,167.27, 161.69,157.37,157.29,151.61,151.54,134.23,131.67,130.04,128.13,128.10, 113.06,112.87,111.74,110.42,110.25,56.11.HRMS(ESI)calcd for C 13 h 10 FNNaO 2 [M+Na] + :254.0588,Found:254.0582.

Embodiment 3

[0032] Example 3 4-methoxy-3-(pyrimidin-2-yl)benzaldehyde (1c)

[0033]

[0034] According to the method of Example 1, 2-bromopyridine was replaced with 2-bromopyrimidine (445.1 mg, 2.80 mmol) to obtain 414.2 mg of white solid, yield 87.1%, Mp: 80-81°C. 1 H NMR (400MHz, CDCl 3 )δ 9.96(s,1H),8.88(d,2H,J=4.8Hz),8.26(d,1H,J=2.4Hz),8.00(dd,1H,J 1 = 2.4 Hz,J 2 =8.8Hz),7.29(t,1H,J=4.8Hz),7.16(d,1H,J=8.8Hz),3.96(s,3H). 13 C NMR (101MHz, CDCl 3 )δ190.61, 164.71, 162.41, 157.17, 134.47, 132.52, 129.64, 128.77, 119.23, 112.05, 56.44. HRMS (ESI) calcdfor C 12 h 10 N 2 NaO 2 [M+Na] + : 237.0634,Found: 237.0639.

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Abstract

The invention discloses an LSD1 (lysine specific histone demethylase 1) inhibitor with a trans-diaryl ethylene structure, as well as a preparation method and application thereof in preparation of an anti-tumour medicament, and belongs to the technical field of medicinal chemistry. The compound disclosed by the invention has a general formula which is as shown in the description; in-vitro LSD1 enzyme inhibiting activity and anti-tumour activity experiments prove that the compound has an obvious inhibiting effect on tumour cells by inhibiting the activity of LSD1, can serve as a lead compound for further development, and is applied to preparation of anti-tumour medicaments.

Description

technical field [0001] The invention specifically relates to a class of LSD1 inhibitors with a trans-diarylethene structure, its preparation method and its application in the preparation of antitumor drugs, belonging to the technical field of medicinal chemistry. Background technique [0002] Histone lysine-specific demethylase 1 (Lysine specific histone demethylase 1, LSD1) is the first discovered histone demethylase. LSD1 is a flavin adenine dinucleotide-dependent demethylase that acts on different substrates by binding to different molecular partners to produce different biological functions. LSD1 binds to target genes through CoREST, and can specifically remove the single or double methylation of H3K4 (Histone 3, Lysine 4), resulting in gene transcriptional repression. When LSD1 binds to the androgen receptor or the estrogen receptor, it can specifically remove the mono- or di-methylation of H3K9 (Histone 3, Lysine 9), causing hormone receptor-dependent gene transcripti...

Claims

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Application Information

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IPC IPC(8): C07D213/38C07D213/61C07D213/79C07D213/803C07D239/26C07D213/63C07D213/42A61P35/00
CPCC07D213/38C07D213/42C07D213/61C07D213/63C07D213/79C07D213/803C07D239/26
Inventor 段迎超翟晓雨关圆圆谢智宇秦文平郑一超
Owner XINXIANG MEDICAL UNIV
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