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Berberine derivatives, preparation method thereof and application of berberine derivatives as p300 HAT small molecule inhibitor

A derivative, the technology of berberine, applied in the field of medicinal chemistry, can solve the problems of weak affinity, high cytotoxicity, poor selectivity, etc., and achieve the effect of improved enzyme level activity and simple synthetic route

Active Publication Date: 2021-02-09
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

Method used

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  • Berberine derivatives, preparation method thereof and application of berberine derivatives as p300 HAT small molecule inhibitor
  • Berberine derivatives, preparation method thereof and application of berberine derivatives as p300 HAT small molecule inhibitor
  • Berberine derivatives, preparation method thereof and application of berberine derivatives as p300 HAT small molecule inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

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

[0050]

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

[0052]Preparation of substituted phenethylamine hydrochloride C-1: To 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, basified with concentrated ammonia water to pH 9~10, extracted with chloroform, washed with water, dried with anhydrous magnesium sulfate, evaporated under ...

Embodiment 2

[0057]The compound Cpd.2 of the berberine derivative provided in the present example 2 is different from the example 1 in the synthesis schematic diagram and the steps: 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 followsFigure 3-4 As shown, the NMR characterization data:1H NMR(400MHz, DMSO-d6)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).13C NMR(101MHz, DMSO-d6)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 C19H16NO4+[M]+322.1074, foμnd 322.1074.

Embodiment 3

[0062]The berberine derivative compound Cpd.3 provided in this example 3, its synthesis schematic and steps are different from Example 1 only in that: the synthetic raw material substituted benzaldehyde compound A-1 is replaced with substituted benzaldehyde compound A-3 , The synthetic raw material substituted benzaldehyde compound D-1 was replaced with 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 followsFigure 5-6 As shown, the NMR characterization data:1H NMR(400MHz, Methanol-d4)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).13C NMR(101MHz, Methanol-d4)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.HRMS(ESI)m / z :Calcd for C20H18NO4+[M...

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Abstract

The invention discloses berberine derivatives, a preparation method thereof and an application of the berberine derivatives as a p300 HAT small molecule inhibitor, and belongs to the technical field of medicinal chemistry. An effective component berberine hydrochloride in a natural product coptis chinensis is taken as a research object and is subjected to structural modification and transformationso as to obtain a series of berberine hydrochloride derivatives. The berberine derivatives have the characteristics of high activity, high selectivity and high safety for p300 HAT, and solves the problems of high cytotoxicity, weak affinity, low activity and poor selectivity of existing p300 HAT small molecule inhibitors.

Description

Technical field[0001]The present 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 acetyltransferase and histone deacetylase catalyze the process of acetylation and deacetylation, and participate in the epigenetic regulation of many diseases. HDAC inhibitors have been clinically approved, but the research of HAT inhibitors is progressing slowly. Histone acetyltransferase p300 / CPB can catalyze the acetylation of histones and most non-histone proteins, and has a direct connection with cell cycle regulation, cell differentiation, and cell apoptosis. It is important for the occurrence of various diseases such as diabetes, nerves Degenerative diseases, inflammation, tumors, viral diseases, myocardial hypertrophy and genetic disorders play a very important role.[0003]Currently, there are very limited reports of s...

Claims

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Application Information

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Patent Type & Authority Applications(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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