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Diphenyl ether chalcone tubulin inhibitor as well as preparation method and application thereof

A technology of tubulin inhibition and chalcone class, applied in the preparation of carbon-based compounds, chemical instruments and methods, preparation of organic compounds, etc., can solve the problems of difficult synthesis and preparation, large side effects, complex structure, etc. Low, simple preparation method, the effect of inhibiting tubulin polymerization

Active Publication Date: 2020-01-31
GUIZHOU MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these tubulin inhibitor anti-tumor drugs in clinical use also have many disadvantages, such as drug resistance, large side effects, complex structure and difficult synthesis and preparation, etc.

Method used

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  • Diphenyl ether chalcone tubulin inhibitor as well as preparation method and application thereof
  • Diphenyl ether chalcone tubulin inhibitor as well as preparation method and application thereof
  • Diphenyl ether chalcone tubulin inhibitor as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Example 1: (E)-3-(4-chlorophenyl)-1-(4-methoxy-2-(3,4,5-trimethoxyphenoxy)phenyl)propane-2- Preparation of en-1-one (1)

[0027]

[0028] Step 1: 1-(2-fluoro-4-methoxyphenyl)ethan-1-one (1mmol), 3,4,5-trimethoxyphenol (1mmol), potassium hydroxide (2mmol), add 10ml of dimethyl sulfoxide was reacted at 100°C for 8 hours, cooled to room temperature, poured into water, extracted with ethyl acetate, spin-dried, separated and purified by silica gel column chromatography to obtain a solid powder.

[0029] Step 2: 1-(4-methoxy-2-(3,4,5-trimethoxyphenoxy)phenyl)ethan-1-one (1mmol), p-chlorobenzaldehyde (1mmol), methanol (10ml) was placed in a round-bottomed flask, added 3ml of 50% potassium hydroxide aqueous solution, stirred warmly for 48 hours, stopped the reaction, poured into water, adjusted the pH to neutral with dilute hydrochloric acid, filtered, dried, and recrystallized from ethanol to obtain a solid powder , yield 63%. 1 H NMR (CDCl 3 ,400MHz)δ:3.73(s,6H),3.77(s...

Embodiment 2

[0031] Example 2: (E)-3-(4-methoxyphenyl)-1-(4-methoxy-2-(3,4,5-trimethoxyphenoxy)phenyl)propane- Preparation of 2-en-1-one (2)

[0032]

[0033] Step 1: 1-(2-fluoro-4-methoxyphenyl)ethan-1-one (1mmol), 3,4,5-trimethoxyphenol (1mmol), potassium hydroxide (2mmol), add 10ml of dimethyl sulfoxide was reacted at 100°C for 8 hours, cooled to room temperature, poured into water, extracted with ethyl acetate, spin-dried, separated and purified by silica gel column chromatography to obtain a solid powder.

[0034] Step 2: 1-(4-methoxy-2-(3,4,5-trimethoxyphenoxy)phenyl)ethan-1-one (1mmol), p-methoxybenzaldehyde (1mmol) 1. Methanol (10ml) was placed in a round-bottomed flask, added 3ml of 50% potassium hydroxide aqueous solution, stirred warmly for 48 hours, stopped the reaction, poured into water, adjusted the pH to neutral with dilute hydrochloric acid, filtered, dried, and recrystallized from ethanol to obtain Solid powder, yield 52%. 1 H NMR (CDCl 3 ,400MHz)δ:3.73(s,6H),3.78(...

Embodiment 3

[0035] Example 3: (E)-3-(4-diethylaminophenyl)-1-(4-methoxy-2-(3,4,5-trimethoxyphenoxy)phenyl)propane Preparation of -2-en-1-one (3)

[0036]

[0037] Step 1: 1-(2-fluoro-4-methoxyphenyl)ethan-1-one (1mmol), 3,4,5-trimethoxyphenol (1mmol), potassium hydroxide (2mmol), add 10ml of dimethyl sulfoxide was reacted at 100°C for 8 hours, cooled to room temperature, poured into water, extracted with ethyl acetate, spin-dried, separated and purified by silica gel column chromatography to obtain a solid powder.

[0038] Step 2: Add 1-(4-methoxy-2-(3,4,5-trimethoxyphenoxy)phenyl)ethan-1-one (1mmol), p-diethylaminobenzaldehyde (1mmol ), methanol (10ml) was placed in a round-bottomed flask, 3ml of 50% aqueous potassium hydroxide solution was added, stirred warmly for 48 hours, the reaction was stopped, poured into water, adjusted to neutral pH with dilute hydrochloric acid, filtered, dried, ethanol recrystallized A solid powder was obtained with a yield of 46%. 1 H NMR (CDCl 3 ,400...

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Abstract

The invention discloses a preparation method and application of a diphenyl ether chalcone tubulin inhibitor, and the method comprises the following steps: putting 1-(2-fluoro-4-methoxyphenyl) ethyl-1-ketone, 3, 4, 5-trimethoxyphenol and potassium hydroxide into a reaction bottle, adding dimethyl sulfoxide, and reacting to obtain 1-(4-methoxy-2-(3, 4, 5-trimethoxyphenyl) ethoxy) phenyl ethyl-1-ketone; and then putting the product and substituted benzaldehyde into a reaction bottle, adding methanol and a 50% potassium hydroxide aqueous solution, and stirring for reaction to obtain the diphenyl ether chalcone tubulin inhibitor. The diphenyl ether chalcone tubulin inhibitor prepared by the invention has good tubulin polymerization inhibition activity, has proliferation inhibition activity on human breast cancer MCF-7 cells, human liver cancer HepG2 cells and human colon cancer HCT116 cells, and can be used as a novel anti-cancer lead compound.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical compounds, and more specifically relates to a diphenyl ether chalcone tubulin inhibitor, a preparation method and application thereof. Background technique [0002] Tubulin is an important part of the eukaryotic cytoskeleton. It is a heterodimer composed of α-tubulin and β-tubulin stacked by non-covalent bonds, and has the dynamic characteristics of polymerization and depolymerization. Tubulin plays a very important role in cell division, cell signal transduction, and maintenance of cell shape. [0003] By interfering with the dynamic process of tubulin polymerization and depolymerization with chemical drugs, it can interfere with the formation of the spindle, make tumor cells stagnate in the G2 / M phase of cell mitosis, induce tumor cell apoptosis, and play an anti-tumor effect. Due to the important role of tubulin in cell mitosis, inhibiting tubulin can have a better anti-tumor effect. At...

Claims

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Application Information

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IPC IPC(8): C07C49/84C07C45/68C07C221/00C07C225/22C07C205/45C07C201/12A61P35/00
CPCC07C49/84C07C225/22C07C205/45A61P35/00
Inventor 王广成彭知云王亚静李勇军马雪
Owner GUIZHOU MEDICAL UNIV
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