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Flavonoid tankyrase-2 inhibitor and preparation method and application thereof

A technology of tankyrase and flavonoids, applied in the field of flavonoid tankyrase 2 inhibitors and its preparation, can solve the problems of limiting tumor cell proliferation and growth, achieve good inhibitory activity, novel structure, and mild reaction conditions Effect

Active Publication Date: 2021-10-26
SHANGHAI INST OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

A tankyrase inhibitor XAV939 reported by Nature in 2009 was directly synthesized based on the crystal structure of tankyrase 1 / 2, which can selectively block the Wnt / β-catenin signaling pathway by stabilizing the expression of the axis inhibitory protein activation, thereby limiting the proliferation and growth of tumor cells

Method used

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  • Flavonoid tankyrase-2 inhibitor and preparation method and application thereof
  • Flavonoid tankyrase-2 inhibitor and preparation method and application thereof
  • Flavonoid tankyrase-2 inhibitor and preparation method and application thereof

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preparation example Construction

[0048] The preparation method of the flavonoid tankyrase 2 inhibitor uses 4-oxo-4H-1-benzopyran-2-carboxylic acid and aniline derivatives or benzohydrazide derivatives as starting materials , using uronium salt as a condensing agent, carrying out a condensation reaction in an organic solvent under the condition of adding a base, to obtain the flavonoid tankyrase 2 inhibitor;

[0049] The aniline derivatives are

[0050] Described benzoyl hydrazide derivative is

[0051] in:

[0052] R 1 selected from H, CH 3 , OCH 3 , Cl, Br or 3,4,5-tri-OCH 3 ;

[0053] R 2 selected from H, CH 3 , OCH 3 , Cl or Br.

[0054] Preferably the uronium salt is selected from HATU, HBTU, HCTU, TBTU, TSTU or TNTU. Preferably, the molar ratio of 4-oxo-4H-1-chromene-2-carboxylic acid to the condensing agent is 1:1˜1:5. Preferably, the molar ratio of 4-oxo-4H-1-benzopyran-2-carboxylic acid to aniline derivatives or benzohydrazide derivatives is 1:1˜1:3. Preferably, the molar ratio of 4-o...

Embodiment 1

[0059] N-(4-Acetylphenyl)-4-oxo-4H-chromene-2-carboxamide

[0060]

[0061] 4-Oxo-4H-1-chromene-2-carboxylic acid (95mg, 0.5mmol) was dissolved in 25ml DMF, under ice-cooling conditions, HATU (228mg, 0.6mmol) and DIPEA ( 129mg, 1mmol) into a DMF solution containing 4-oxo-4H-1-chromene-2-carboxylic acid, slowly warming up to room temperature, and adding 4-aminoacetophenone (81mg, 0.6mmol) after 15 minutes . Stirring was continued at room temperature for 6 h until the reaction of 4-oxo-4H-1-chromene-2-carboxylic acid was complete. After the reaction was completed, the reaction solution was poured into ice water. Precipitate solid, collect solid and water, 10%Na 2 CO 3 , saline and ethanol sonication. The solid was purified by flash silica gel chromatography (petroleum ether / ethyl acetate=6:1) to obtain the product.

[0062] IC 50 The value is 8.74uM.

[0063] 1 H NMR (400MHz, DMSO)δ=10.94(s,1H),8.06(d,J=8.0Hz,1H),7.98(q,J=8.6Hz,4H),7.90(d,J=7.6Hz,1H ), 7.83(d, J=8.5...

Embodiment 2

[0066] N'-Benzoyl-4-oxo-4H-benzopyran-2-carbohydrazide

[0067]

[0068] 4-Oxo-4H-1-chromene-2-carboxylic acid (95mg, 0.5mmol) was dissolved in 25ml DMF, under ice-cooling conditions, HATU (228mg, 0.6mmol) and DIPEA ( 129 mg, 1 mmol) into a DMF solution containing 4-oxo-4H-1-chromene-2-carboxylic acid, slowly warming up to room temperature, and adding benzohydrazide (82 mg, 0.6 mmol) after 15 minutes. Stirring was continued at room temperature for 6 h until the reaction of 4-oxo-4H-1-chromene-2-carboxylic acid was complete. After the reaction was completed, the reaction solution was poured into ice water. Precipitate solid, collect solid and water, 10%Na 2 CO 3 , saline and ethanol sonication. The solid was purified by flash silica gel chromatography (petroleum ether / ethyl acetate=4:1) to obtain the product.

[0069] IC 50 The value is 3.54uM.

[0070] 1 H NMR (400MHz, DMSO) δ11.17(s, 1H), 10.75(s, 1H), 8.07(t, J=7.5Hz, 1H), 7.92(t, J=7.6Hz, 3H), 7.76(d ,J=7.9Hz,1H...

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Abstract

The invention relates to a flavonoid tankyrase-2 inhibitor and a preparation method and application thereof. The flavonoid tankyrase-2 inhibitor has a structure as shown in formula I. The inhibitor adopts 4-oxo-4H-1-benzopyran-2-carboxylic acid and an aniline derivative or a benzoyl hydrazine derivative as initial raw materials, adopts a uronium salt as a condensing agent, and under the condition of adding alkali, condensation reaction is conducted in an organic solvent to obtain the inhibitor. Compared with the prior art, the preparation method disclosed by the invention is simple, and the synthesized compound is novel in structure and has better activity of inhibiting tankyrase 2 and better selectivity.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a flavonoid tankyrase 2 inhibitor and a preparation method and application thereof. Background technique [0002] Tankyrase is a multifunctional protein translation modification enzyme and a member of the polyadenosine diphosphate-ribose polymerase family. Its main domain is ankyrin repeat sequence. This enzyme can not only bind to the telomere repeat sequence factor, but also bind to the highly conserved domain at the carboxy-terminal of the axis inhibitory protein, thereby realizing the inhibitory effect on telomerase, thereby regulating the extracellular factor (Wnt) / β-catenin ( β-catenin) signaling pathway to inhibit the proliferation and growth of tumor cells. A tankyrase inhibitor XAV939 reported by Nature in 2009 was directly synthesized based on the crystal structure of tankyrase 1 / 2, which can selectively block the Wnt / β-catenin signaling pathway...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D311/24A61P35/00
CPCC07D311/24A61P35/00
Inventor 庞婉李堂王杰赵泽圣张孝礼
Owner SHANGHAI INST OF TECH
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