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A class of trans-diarylethenes lsd1 inhibitors, their preparation methods and applications

A technology of diarylethenes and compounds, which is applied in the field of medicinal chemistry and achieves the effects of high yield, strong LSD1 inhibitory activity and simple synthesis method

Active Publication Date: 2020-03-27
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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  • A class of trans-diarylethenes lsd1 inhibitors, their preparation methods and applications
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  • A class of trans-diarylethenes lsd1 inhibitors, their preparation methods and applications

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 (508.6 mg, 2.89 mmol) was used instead of 2-bromopyridine to obtain 395.8 mg 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 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. The compound of the present invention has the following general formula: in vitro LSD1 enzyme inhibitory activity and antitumor activity experiments have proved that this type of compound has obvious inhibitory effect on tumor cells by inhibiting the activity of LSD1, and can be used as a lead compound for further development. In the preparation of antineoplastic drugs.

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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Patent Type & Authority Patents(China)
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