Hydroxamic acid group-containing diarylethene LSD1/HDACs double-target inhibitors as well as preparation method and application thereof

A technology of diarylethene and hydroxamic acid is applied in the field of application of diarylethene LSD1/HDACs dual-target inhibitors to prepare antitumor drugs, and achieves good selectivity, is conducive to popularization and application, and has good in vitro performance. The effect of antitumor activity

Active Publication Date: 2020-08-28
XINXIANG MEDICAL UNIV
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  • Abstract
  • Description
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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 acti...

Method used

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  • Hydroxamic acid group-containing diarylethene LSD1/HDACs double-target inhibitors as well as preparation method and application thereof
  • Hydroxamic acid group-containing diarylethene LSD1/HDACs double-target inhibitors as well as preparation method and application thereof
  • Hydroxamic acid group-containing diarylethene LSD1/HDACs double-target inhibitors as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

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

[0023]

[0024] Add compound I-1a (376mg, 2.0mmol) and I-2a (601.1mg, 2.1mmo) to a 50ml two-necked flask, dissolve with 10ml of anhydrous DMF, add t-BuOK (673.3mg, 6.0mmol) under ice-cooling 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, a 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) calcd ...

Embodiment 2

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

[0026]

[0027] According to the method of Example 1, compound I-2b (601.1mg, 2.1mmol) was used to replace I-2a to obtain 288.3 mg of target compound I-3b, a 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=8.0Hz),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] The synthesis of embodiment 3 (E)-3-(3-bromostyryl) methyl 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 480 mg of target compound I-3c, 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 hydroxamic acid group-containing diarylethene LSD1/HDACs double-target inhibitors, a preparation method thereof and application thereof in preparation of antitumor drugs, andbelongs to the technical field of medicinal chemistry. The compounds have a general formula shown in the specification, wherein 3-position or 4-position monosubstitution is preferred; R2 is preferablyOH, OCH3, F or H; R3 is preferably selected from H and CH2OH; R4 is preferably selected from H, CH3, F, or OCH3; R5 is preferably selected from H, OH, CH2OH, CH3, F and OCH3; X is N or CH; Y is N orCH. The compounds provided by the invention have relatively strong inhibitory activity on LSD1 and HDAC1/6, and have very good selectivity on LSD1, and the in vitro antitumor activity of the multiplecompounds on human colon cancer HCT-116 cell strains and human gastric cancer MGC-803 cell strains is superior to that of commercially available drug SAHA. A basis is provided for research and development of LSD1/HDACs double-target inhibitor drugs, and the compounds can be used as candidates for further development or lead compounds for development of antitumor treatment drugs.

Description

technical field [0001] The invention specifically relates to a class of diarylethene LSD1 / HDACs dual-target inhibitors containing hydroxamic acid groups, a preparation method thereof and an application in the preparation of antitumor drugs, belonging 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 amino oxidase , can specifically remove the mono- and di-methyl groups of histone H3K4. The discovery of LSD1 confirmed the dynamic balance between methylation and demethylation of histones. In addition, LSD1 can also 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. A large number of studies have shown that the expression of LSD1 in various tumors such as lymphoma, acute myel...

Claims

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Application Information

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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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