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5-aryl nicotinamide LSD1/HDAC double-target inhibitor and preparation method and application thereof

A technology of aryl nicotinamide and reaction, which is applied in the field of medicinal chemistry, achieves good selectivity, is conducive to popularization and application, and has the effect of strong anti-tumor activity in vitro

Active Publication Date: 2021-10-22
XINXIANG MEDICAL UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In order to discover a new type of LSD1 / HDAC dual-target inhibitor, explore and synthesize a class of 5-aryl nicotinamide compounds, and verify its LSD1, HDAC dual inhibitory activity and in vitro anti-tumor activity are the starting point of this application. Synthesis, LSD1 / HDAC inhibitory activity and antitumor activity report of similar compounds

Method used

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  • 5-aryl nicotinamide LSD1/HDAC double-target inhibitor and preparation method and application thereof
  • 5-aryl nicotinamide LSD1/HDAC double-target inhibitor and preparation method and application thereof
  • 5-aryl nicotinamide LSD1/HDAC double-target inhibitor and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] Example 1 Synthesis of 2-((5-nicotinamide) methyl)methyl benzoate (3)

[0022]

[0023] Add compound 1 (404.02mg, 2.0mmol), compound 2 (443.63 mg, 2.2mmol), HBTU (834.33mg, 2.2mmol), N 2 Protected, dissolved with anhydrous DMF (8mL), added N,N-diisopropylethylamine (568.66mg, 4.4mmol), after addition, stirred at room temperature for 1.5h, then added water and ethyl acetate to the reaction system Extract, combine the ethyl acetate layers, wash with water and saturated brine respectively, and dry over anhydrous sodium sulfate. After drying, filter, the filtrate is concentrated under reduced pressure, and the concentrate is separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) Compound 3 (434.4mg), white solid, yield: 62.2%, Mp: 160-161℃. 1 H NMR (400MHz, DMSO-d 6 )δ9.43(t, 1H, J=6.0Hz), 9.04(d, 1H, J=2.0Hz), 8.89(d, 1H, J=2.0Hz), 8.49(t, 1H, J=2.0Hz) ,7.95(d,2H,J=8.0Hz), 7.49(d,2H,J=8.4Hz),4.59(d,2H,J=6.0Hz),3.85(s,3H). 1...

Embodiment 2

[0024] Example 2 Synthesis of methyl 4-((5-(2-hydroxyphenyl)nicotinamide)methyl)benzoate (4a)

[0025] In a 50mL two-necked flask, add compound 3 (500.0mg, 1.4mmol), toluene (5mL), ethanol (5mL), H 2 O (1.3 mL), K 2 CO 3 (359.3mg, 2.6mmol), Pd(PPh 3 ) 4 (162.0mg, 0.14 mmol) and 2-hydroxyphenylboronic acid (235.0mg, 1.7mmol), under nitrogen protection, stirred and heated at 92°C for 3 hours, after the reaction was completed, cooled to room temperature, extracted the reaction system with water and ethyl acetate, combined The ethyl acetate layer was washed with water and saturated brine respectively, and dried over anhydrous sodium sulfate. After drying, it was filtered with suction, and the filtrate was concentrated under reduced pressure. The concentrate was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2: 1), to obtain compound 4a (279.0mg), yield: 55.0%, white solid, Mp: 205-206℃. 1 H NMR (400MHz, DMSO-d 6 )δ9.89(s, 1H), 9....

Embodiment 3

[0026] Example 3 Synthesis of methyl 4-((5-(4-cyanophenylnicotinic acid amide))methyl)benzoate (4b)

[0027] According to the method of Example 2, replace 2-hydroxyphenylboronic acid with compound 4-cyanophenylboronic acid (249.8mg, 1.7mmol) to obtain target compound 4b (295.3mg), white solid, yield: 56.8%, Mp: 181 - 182°C. 1 H NMR (400MHz, DMSO-d 6 )δ9.46(t, 1H, J=6.0Hz), 9.14(d, 1H, J=2.0Hz), 9.11(d, 1H, J=2.0Hz), 8.61(t, 1H, J=2.0Hz) ,8.06(d,2H,J=8.4Hz), 8.02(d,2H,J=8.4Hz),7.95(d,2H,J=8.4Hz),7.52(d,2H,J=8.0Hz),4.64 (d, 2H, J=6.0Hz), 3.85(s, 3H). 13 C NMR (101MHz, DMSO-d 6 )δ166.56, 165.08, 150.72, 149.06, 145.27, 141.42, 133.89, 133.71, 133.52, 130.09, 129.79, 128.72, 128.48, 127.96, 119.13, 111.61, 52.566. 22 h 17 N 3 NaO 3 [M+Na] + :394.1162,Found:394.1165.

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Abstract

The invention relates to a 5-aryl nicotinamide LSD1 / HDAC double-target inhibitor and a preparation method and application thereof in preparation of antitumor drugs, and belongs to the technical field of medicinal chemistry. The compound has the following general formula shown in the specification, wherein R1 is preferably OH, CH3 and H; and R2 is preferably OH, OCH3, F, CN, H and CH3. The compound has relatively strong inhibitory activity to LSD1 and HDAC1, and the IC50 of most compounds to HDAC1 is less than 10 nM, which is superior to that of a positive drug SAHA. The in-vitro anti-tumor activity IC50 of a plurality of compounds on a human colon cancer HCT-116 cell strain, a human gastric cancer MGC-803 cell strain and human leukemia THP-1, MOLT-4 and MV4: 11 cell strains is less than 1.0 mu M, and the in-vitro anti-tumor activity of the compound I-4 on THP-1 is 6 times that of SAHA. The compound provides a basis for research and development of LSD1 / HDAC double-target inhibitor drugs.

Description

technical field [0001] The invention specifically relates to a class of 5-aryl nicotinamide 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) was the first histone lysine demethylase discovered. LSD1 is composed of Tower domain, C-terminal FAD (Flavin adenine dinulcleotide, FAD)-dependent amine oxidase domain and N-terminal SWIRM domain. LSD1 uses FAD as a coenzyme to specifically remove mono- and di-methylation marks on histone H3K4 (histone 3 lysine 4) and H3K9 (histone 3 lysine 9). 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. A large number of studies have shown that the expression of LSD1 in various tum...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/82A61P35/00A61P35/02A61K31/4418
CPCC07D213/82A61P35/00A61P35/02
Inventor 关圆圆于童胡姱赵媛段迎超张少杰靳林峰
Owner XINXIANG MEDICAL UNIV
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