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A class of diarylethene lsd1/hdacs dual-target inhibitors containing hydroxamic acid group, preparation method and application thereof

A technology of diarylethene and hydroxamic acid, which is applied in the field of application of diarylethene LSD1/HDACs dual-target inhibitors in the preparation of anti-tumor drugs, to achieve good in vitro anti-tumor activity, good selectivity, and effective The effect of promoting the application

Active Publication Date: 2022-07-19
XINXIANG MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In order to discover new LSD1 / HDACs dual-target inhibitors, explore the synthesis of a class of diarylethene compounds containing hydroxamic acid groups, and verify its LSD1, HDACs dual inhibitory activity and in vitro anti-tumor activity are the starting point of this application. So far, there are no reports on the synthesis, LSD1 / HDACs inhibitory activity and antitumor activity of this kind of compound

Method used

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  • A class of diarylethene lsd1/hdacs dual-target inhibitors containing hydroxamic acid group, preparation method and application thereof
  • A class of diarylethene lsd1/hdacs dual-target inhibitors containing hydroxamic acid group, preparation method and application thereof
  • A class of diarylethene lsd1/hdacs dual-target inhibitors containing hydroxamic acid group, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Example 1 (E)-Synthesis of methyl 4-(2-(2-bromo-pyridin-4-yl)alkenyl)benzoate (I-3a)

[0023]

[0024] Compound I-1a (376 mg, 2.0 mmol) and I-2a (601.1 mg, 2.1 mmol) were added to a 50-mL two-necked flask, dissolved in 10 mL of anhydrous DMF, and t-BuOK (673.3 mg, 6.0 mmol) was added under ice bath. After the addition was completed, the reaction was stirred at room temperature for 0.5 hours, and then the reaction system was slowly added to ice water (50 mL), and a solid was precipitated. The solid was collected by suction filtration, separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=5:1) to obtain 396.4 mg of compound I-3a, white solid, yield: 62.3%, Mp: 106-107°C. 1 H NMR (400 MHz, CDCl 3 )δ8.36(d,1H,J=5.2Hz),8.08(d,2H,J=8.4Hz),7.60-7.57(m,3H),7.34-7.29(m,2H),7.04(d,1H) , J=16.4Hz), 3.95(s, 3H). 13 CNMR (101MHz, CDCl 3 )δ166.57,150.44,146.96,143.04,139.95,133.46,130.39,130.20,127.05, 126.87,125.16,120.09,52.27.HRMS(ESI)cal...

Embodiment 2

[0025] Example 2 (E)-Synthesis of methyl 4-(2-(2-bromo-pyridin-4-yl)alkenyl)benzoate (I-3b)

[0026]

[0027] According to the method of Example 1, compound I-2b (601.1 mg, 2.1 mmol) was used to replace I-2a to obtain the target compound I-3b 288.3 mg, white solid, yield: 45.4%, Mp: 73-74°C. 1 H NMR (400MHz, CDCl 3 )δ8.33(d,1H,J=5.2Hz),8.21(t,1H,J=2.0Hz),8.00(dt,1H,J 1 =1.2Hz, J2 =8.0Hz),7.70(dt,1H,J 1 =1.6Hz,J 2 =8.0Hz), 7.57(s, 1H), 7.48(t, 1H, J=8.0 Hz), 7.35-7.30(m, 2H), 7.03(d, 1H, J=16.4Hz), 3.96(s, 3H ).HRMS(ESI)calcd for C 15 H 12 BrNNaO 2 [M+Na] + :339.9944,Found:339.9943.

Embodiment 3

[0028] Example 3 (E)-Synthesis of methyl 3-(3-bromostyryl) formate (I-3c)

[0029]

[0030] According to the method of Example 1, compound I-1b (370 mg, 2.0 mmol) was used to replace I-1a to obtain the target compound I-3c 480 mg, yield: 75.6%, Mp: 177-178 ° C. 1 H NMR (400MHz, DMSO-d 6 ) δ7.97(d,2H,J=8.4Hz),7.89(t,1H,J=2.0Hz),7.74(d,2H,J=8.4Hz),7.64(dt,1H,J 1 =1.2Hz,J 2 =8.0Hz), 7.51-7.48(m, 1H), 7.43(d, 2H, J=4.0Hz), 7.37(t, 1H, J=8.0Hz), 3.86(s, 3H). 13 C NMR (101MHz, DMSO-d 6 )δ166.41,141.90,139.66, 131.31,131.20,130.09,129.65,129.38,129.04,127.28,126.38,122.76,52.57. HRMS(ESI)calcd for C 16 H 13 BrNaO 2 [M+Na] + :338.9991,Found:338.9996.

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Abstract

The invention relates to a class of diarylethene LSD1 / HDACs dual-target inhibitors containing a hydroxamic acid group, a preparation method and application thereof in the preparation of antitumor drugs, and belongs to the technical field of medicinal chemistry. Described compound has following general formula: wherein preferably 3-position or 4-position unit is substituted; R 2 OH, OCH are preferred 3 , F, H; R 3 Preferably H, CH 2 OH;R 4 Preferably H, CH 3 , F, OCH 3 ;R 5 H, OH, CH preferred 2 OH, CH 3 , F, OCH 3 ; X is N or CH; Y is N or CH. The compounds of the present invention have strong inhibitory activities on both LSD1 and HDAC1 / 6, and have good selectivity for LSD1, and a plurality of compounds have strong inhibitory effects on human colon cancer HCT-116 cell line and human gastric cancer MGC-803 cell line The in vitro antitumor activity is better than the marketed drug SAHA. It provides a basis for the research and development of LSD1 / HDACs dual-target inhibitor drugs, which can be used as candidates for further development or lead compounds for the development of anti-tumor therapeutic drugs.

Description

technical field [0001] The invention specifically relates to a class of diarylethylene LSD1 / HDACs dual-target inhibitors containing a hydroxamic acid group, a preparation method and application thereof in the preparation of antitumor drugs, and belongs to the technical field of medicinal chemistry. Background technique [0002] Histone lysine-specific demethylase 1 (LSD1) was first reported by Professor Shi Yang of Harvard University in 2004. It is a Flavin adenine dinulcleotide (FAD)-dependent aminooxidase. , which can specifically remove the mono- and di-methyl groups of histone H3K4. The discovery of LSD1 confirms that there is a dynamic balance between methylation and demethylation of histones. In addition, LSD1 can demethylate non-histone proteins such as p53, DNMT1, STAT3, E2F1, MYPT1, ERa, and HIF-1, further regulating the stability and activity of its downstream genes. Numerous studies have shown that LSD1 is expressed in various tumors including lymphoma, acute my...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/61C07D213/55C07D213/56C07C69/84C07C259/10C07C67/343A61P35/00
CPCC07D213/61C07D213/55C07D213/56C07C69/84C07C259/10A61P35/00
Inventor 段迎超靳林峰关圆圆袁航文郁康陈书慧秦文平张少杰
Owner XINXIANG MEDICAL UNIV
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