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A kind of berberine derivative and its preparation method and its application as p300 HAT small molecule inhibitor

A technology of small molecule inhibitors and derivatives, applied in anti-inflammatory agents, drug combinations, antiviral agents, etc., can solve the problems of high cytotoxicity, weak affinity, and low activity, and achieve simple synthetic routes and improved enzyme level activity Effect

Active Publication Date: 2022-02-11
WEST CHINA HOSPITAL SICHUAN UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] In view of the deficiencies or defects in the above-mentioned prior art, the purpose of the present invention is to provide a berberine derivative and its preparation method and its application as a small molecule inhibitor of p300 HAT, which can solve the problem of existing small molecule inhibitors of p300 HAT. The problems of high cytotoxicity, weak affinity, low activity and poor selectivity in

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  • A kind of berberine derivative and its preparation method and its application as p300 HAT small molecule inhibitor
  • A kind of berberine derivative and its preparation method and its application as p300 HAT small molecule inhibitor
  • A kind of berberine derivative and its preparation method and its application as p300 HAT small molecule inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] The berberine derivative compound Cpd.1 provided in Example 1, its synthesis schematic and steps are as follows:

[0050]

[0051]Preparation of nitrostyrene derivative B-1: Mix substituted benzaldehyde compound A-1 (0.0667 mol), ammonium acetate (0.130 mol), nitromethane (0.165 mol) and glacial acetic acid (11ml), and heat at 100°C Next, the reaction was stirred for 3 hours. Cool to room temperature, add water (20ml), filter, wash the filter residue with water until neutral, and dry to obtain compound B-1;

[0052] Preparation of substituted phenethylamine hydrochloride C-1: In freshly prepared zinc amalgam (50g), add compound B-1 (10g) and 95% ethanol (400ml), add concentrated hydrochloric acid (80ml) under stirring , stirred at room temperature for 1 hour, filtered, the filtrate was concentrated under reduced pressure to 140-150ml, alkalized with concentrated ammonia water to pH 9-10, extracted with chloroform, washed with water, dried over anhydrous magnesium su...

Embodiment 2

[0057] The synthetic diagram and steps of the berberine derivative compound Cpd.2 provided in Example 2 differ from Example 1 only in that the synthetic raw material substituted benzaldehyde compound D-1 is replaced with substituted benzaldehyde compound D-2 .

[0058] The structural formulas of substituted benzaldehyde compound D-2 and compound Cpd.2 are as follows:

[0059]

[0060] The NMR spectrum of compound Cpd.2 is as follows Figure 3-4 As shown, NMR characterization data: 1 H NMR (400MHz, DMSO-d 6 )δ11.99(s,1H),9.47(s,1H),8.66(s,1H),7.80(s,1H),7.70(s,1H),7.47(s,1H),7.08(s,1H ), 6.16(s, 2H), 4.74(t, J=6.1Hz, 2H), 4.01(s, 3H), 3.18(t, 2H). 13 C NMR (101MHz, DMSO-d 6 )δ157.7, 152.8, 148.1, 145.7, 138.2, 137.2, 131.0, 122.0, 121.2, 117.9, 108.9, 108.8, 107.8, 106.0, 102.5, 56.8, 54.8, 27.1. HRMS (ESI) m / z: Calcd for C 19 h 16 NO 4 + [M] + 322.1074, fo μnd 322.1074.

Embodiment 3

[0062] The synthetic diagram and steps of the berberine derivative compound Cpd.3 provided in Example 3 differ from Example 1 only in that the synthetic raw material substituted benzaldehyde compound A-1 is replaced by substituted benzaldehyde compound A-3 , the synthetic raw material substituted benzaldehyde compound D-1 was replaced by substituted benzaldehyde compound D-3.

[0063] The structural formulas of substituted benzaldehyde compound A-3, substituted benzaldehyde compound D-3 and compound Cpd.3 are as follows:

[0064]

[0065] The NMR spectrum of compound Cpd.3 is as follows Figure 5-6 As shown, NMR characterization data: 1 H NMR (400MHz, Methanol-d 4 )δ 9.33(s,1H),8.68(s,1H),7.66(s,1H),7.55(d,J=7.2Hz,2H),7.07(s,1H),6.36(s,2H),4.81 (t,J=6.4Hz,2H),4.01(s,3H),3.96(s,3H),3.28(t,J=6.5Hz,2H). 13 C NMR (101MHz, Methanol-d 4 )δ156.9, 152.6, 151.6, 149.4, 145.1, 139.8, 139.6, 128.8, 124.2, 118.8, 118.6, 110.8, 108.5, 104.0, 103.3, 102.5, 55.6, 55.3, 55.0, 26, 4. H...

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Abstract

The invention discloses a berberine derivative, its preparation method and its application as a p300 HAT small molecule inhibitor, and belongs to the technical field of medicinal chemistry. The invention takes berberine hydrochloride, an active ingredient in the natural product Coptidis Rhizoma, as the research object , after structural modification and transformation, a series of berberine hydrochloride derivatives were obtained. This type of berberine derivative has the characteristics of high activity, high selectivity and high safety for p300 HAT, which solves the problems of high cytotoxicity, weak affinity, low activity and poor selectivity in the existing small molecule inhibitors of p300 HAT question.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to a berberine derivative, a preparation method thereof and its application as a p300 HAT small molecule inhibitor. Background technique [0002] Histone acetyltransferases and histone deacetylases catalyze acetylation and deacetylation processes and are involved in the epigenetic regulation of various diseases. HDAC inhibitors have been clinically approved, while research on HAT inhibitors has been slow. Histone acetyltransferase p300 / CPB can catalyze the acetylation of histones and most non-histones, and is directly related to cell cycle regulation, cell differentiation, and apoptosis. Degenerative diseases, inflammation, tumors, viral diseases, cardiac hypertrophy and genetic disorders, etc. play a very important role. [0003] Currently, there are very limited reports of small molecule inhibitors targeting p300 HAT. The earliest reported p300 HAT inhibitors are sy...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D455/03A61P3/10A61P25/28A61P29/00A61P35/00A61P31/12A61P9/00A61K31/4375
CPCC07D455/03A61P3/10A61P25/28A61P29/00A61P35/00A61P31/12A61P9/00
Inventor 孙秋何菱
Owner WEST CHINA HOSPITAL SICHUAN UNIV
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