2-aryl isonicotinic acid amide LSD1/HDAC double-target inhibitor as well as preparation method and application thereof

A technology of niacinamide and inhibitor, applied in the field of medicinal chemistry, achieves the effects of strong in vitro antitumor activity, good selectivity, and favorable for popularization and application

Active Publication Date: 2021-09-28
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 / HDAC dual-target inhibitors, explore and synthesize a class of 2-arylisonicotinamide compounds, and verify their LSD1, HDAC dual-target inhibitory activity and in vitro anti-tumor activity are the starting point of this application. There are no reports on the synthesis, LSD1 / HDAC inhibitory activity and antitumor activity of this kind of compound

Method used

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  • 2-aryl isonicotinic acid amide LSD1/HDAC double-target inhibitor as well as preparation method and application thereof
  • 2-aryl isonicotinic acid amide LSD1/HDAC double-target inhibitor as well as preparation method and application thereof
  • 2-aryl isonicotinic acid amide LSD1/HDAC double-target inhibitor as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Example 1 Synthesis of methyl 4-((2-bromoisonicotinamide) methyl)benzoate (3a)

[0024]

[0025] Add compound 1a (1212.1mg, 6.0mmol), compound 2 (1451.9mg, 7.2mmol), HBTU (2502.9mg, 6.6mmol) into a 50mL two-necked flask, dissolve with anhydrous DMF (8mL), protect with nitrogen, and then add N , N-diisopropylethylamine (1705.9mg, 13.2mmol), after the addition was completed, the reaction was stirred at room temperature for 1.5 hours, then water and ethyl acetate were added to the reaction system for extraction, the ethyl acetate layers were combined, and water and saturated salt were respectively Washed with water, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the concentrate was separated and purified by silica gel column chromatography (petroleum ether: acetone = 5:1) to obtain compound 3a (850.4mg), white solid, yield: 40.6%, Mp: 114-115℃. 1H NMR (400MHz, DMSO-d 6 )δ9.51(t, 1H, J=6.0Hz), 8.57(d, 1H, J=5.2H...

Embodiment 2

[0026] Example 2 Synthesis of methyl 4-((2-bromo-5-fluoroisonicotinamide) methyl)benzoate (3b)

[0027]

[0028] According to the method of Example 1, compound 1b (660.0mg, 3.0mmol) was used to replace 1a to obtain the target compound 3b (900.1mg), a white solid, yield: 81.7%, Mp: 131-132°C. 1 H NMR (400MHz, DMSO-d 6 )δ 9.39(t, 1H, J=5.6Hz), 8.61(s, 1H), 7.96(d, 2H, J=8.0Hz), 7.90(d, 1H, J=5.2Hz), 7.49(d, 2H ,J=8.0Hz),4.56(d,2H,J=5.6Hz),3.85(s,3H). 13 C NMR (101MHz, DMSO-d 6 )δ166.53, 161.38, 155.84 (d, J C-F =259.6Hz), 144.51, 140.32(d,J C-F =27.1Hz), 136.12(d, J C-F =2.9Hz), 134.71(d, J C-F =15.2Hz), 129.80, 128.83, 127.91, 127.87, 52.58, 42.94.HRMS(ESI) calcdfor C 15 h 12 BrFN 2 NaO 3 [M+Na] + :388.9908,Found:388.9904.

Embodiment 3

[0029] Example 3 Synthesis of 4-((2-(3-hydroxyphenyl) isonicotinic acid amide) methyl) methyl benzoate (4a)

[0030]

[0031] In a 50 mL two-necked round bottom flask, add compound 3a (500.0 mg, 1.4 mmol), toluene (5 mL), ethanol (5 mL), H 2 O (1.3mL), K 2 CO 3 (359.3mg, 2.6mmol), Pd(PPh 3 ) 4 (162.0mg, 0.14mmol) and 3-hydroxyphenylboronic acid (235.0mg, 1.7mmol), under nitrogen protection, stirred and reacted at 92°C for 4 hours, after the reaction was completed, the reaction system was cooled to room temperature, extracted with water and ethyl acetate, The ethyl acetate layers were combined, washed with water and saturated brine respectively, dried over anhydrous sodium sulfate, and filtered with suction, the filtrate was concentrated under reduced pressure, and the concentrate was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1), to obtain compound 4a (312.7mg), yield: 61.5%, white solid, Mp: 185-186°C. 1 H NMR (400MH...

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Abstract

The invention relates to a 2-aryl isonicotinic acid amide LSD1 / HDAC double-target inhibitor and a preparation method thereof, and application of the 2-aryl isonicotinic acid amide LSD1 / HDAC double-target inhibitor in preparation of antitumor drugs, belonging to the technical field of medicinal chemistry. The inhibitor has a general formula as described in the specification. In the general formula, R1 is preferably selected from OH and H; R2 is preferably selected from OH, OCH3, F, H and CH3; R3 is preferably selected from H, OH, Cl, OCH3 and NH2; R4 is preferably selected from H, OH, CF3, OCH3 and CH3; and X is N or CH. The inhibitor provided by the invention has relatively strong inhibitory activity on LSD1 and HDAC1, provides a basis for research and development of LSD1 / HDAC double-target inhibitor drugs, and can be used as a further candidate or lead compound for developing antitumor therapeutic drugs.

Description

technical field [0001] The invention specifically relates to a class of 2-arylisonicotinamide-based LSD1 / HDAC dual-target inhibitors, 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) is a flavin adenine dinucleotide-dependent amino oxidase, and its main function is to specifically remove monomethyl and dimethyl on histone H3K4 Kylation modification, inhibition of gene transcription. By interacting with estrogen receptors or androgen receptors, LSD1 can also remove the single and double methylation modifications on H3K9, thereby activating the transcription of downstream genes. In addition, LSD1 can also remove the methylation modification of non-histone proteins such as p53, DNMT1, STAT3, E2F1, MYPT1, ERa and HIF-1, and further regulate the stability and activity of its downstream genes. The expression lev...

Claims

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Application Information

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IPC IPC(8): C07D213/82C07D401/12A61P35/00A61P35/02
CPCC07D213/82C07D401/12A61P35/00A61P35/02
Inventor 段迎超张少杰关圆圆于童靳林峰
Owner XINXIANG MEDICAL UNIV
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