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Histone deacetylase and microtubule dual target inhibitor and preparation method thereof

A deacetylase, dual-target technology, used in organic chemistry, drug combinations, anti-tumor drugs, etc., can solve the problem of few dual-target inhibitors

Active Publication Date: 2019-04-19
QINGDAO UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although microtubules are an important target for anticancer drug development, there are few reports on dual-targeted inhibitors of microtubules and HDACs

Method used

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  • Histone deacetylase and microtubule dual target inhibitor and preparation method thereof
  • Histone deacetylase and microtubule dual target inhibitor and preparation method thereof
  • Histone deacetylase and microtubule dual target inhibitor and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0059] The preparation of embodiment 1WBL-1

[0060] The structural formula of WBL-1 is:

[0061]

[0062] Its chemical name is: N-hydroxy-7-(2-methoxy-5-(3-keto-3-(3,4,5-trimethoxyphenyl)-1-(E)-propenyl ) phenoxy-heptanamide.

[0063] Its synthetic route is:

[0064]

[0065] The concrete steps of its synthetic method are as follows:

[0066] Step 1, Synthesis A: Weigh 3',4',5,-trimethoxyacetophenone (21.02g, 1mmol) and 3-hydroxy-4-methoxybenzaldehyde (15.22g, 1mmol) and dissolve in 200mL In methanol, 160 mL of 50% (W / V) sodium hydroxide solution was added to the above mixture, and the mixture was stirred overnight at room temperature under nitrogen protection. Distill methanol, and add 1M hydrochloric acid to adjust the pH value of the mixture to 1-2, extract three times with 20 ml of dichloromethane, collect the dichloromethane phase and dry the filtrate with anhydrous sodium sulfate, concentrate and purify by silica gel column chromatography (petroleum ether : e...

Embodiment 2

[0072] The preparation of embodiment 2WBL-2

[0073] The chemical formula of WBL-2 is:

[0074]

[0075] Its chemical name is: N-hydroxy-8-(2-methoxy-5-(3-keto-3-(3,4,5-trimethoxyphenyl)-1-(E)-propenyl ) phenoxy-octylamide.

[0076] Its synthetic route is:

[0077]

[0078] The concrete steps of its synthetic method are as follows:

[0079] Step 1, synthetic A: with embodiment 1 step 1;

[0080] Step 2. Synthesis of A8ES: The molar ratio of A (3.44g, 10mmol) to 8-bromooctanoic acid methyl ester is 1:1.1, the two are dissolved in 20mL of anhydrous N',N'dimethylformamide, and added twice The amount of anhydrous potassium carbonate, 60 ℃ oil bath overnight, TLC inspection reaction (petroleum ether: ethyl acetate = 2:1 (v / v)). Add water and extract with ethyl acetate, dry the ethyl acetate phase with anhydrous sodium sulfate, concentrate and purify by silica gel column chromatography (petroleum ether: ethyl acetate = 6:1) to obtain a yellow solid with a yield of 73%.

...

Embodiment 3

[0085] The preparation of embodiment 3WBL-3

[0086] The chemical formula of WBL-3 is:

[0087]

[0088] Its chemical name is: N-hydroxy-7-(2-methoxy-5-(2-methyl-3-keto-3-(3,4,5-trimethoxyphenyl)-1-( E)-propenyl)phenoxy-heptanamide.

[0089] Its synthetic route is:

[0090]

[0091] The concrete steps of its synthetic method are as follows:

[0092] Step 1, Synthesis B: Weigh 3', 4', 5'-trimethoxypropiophenone (15g, 66mmol) and 3-hydroxyl-4-methoxybenzaldehyde (33g, 66mmol) in equivalent molar amounts and dissolve in In methanol solvent, 11 mL of 50% (W / V) sodium hydroxide solution was added to the above mixture, and the mixture was stirred and reacted overnight under nitrogen protection, and the reaction was checked by TLC (petroleum ether: ethyl acetate=2:1 (v / v)). Add 1M hydrochloric acid to adjust the pH of the mixture to 1-2, and extract twice with 100 mL of dichloromethane. The dichloromethane phase was dried over anhydrous sodium sulfate, concentrated and t...

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Abstract

The invention discloses a histone deacetylase and microtubule dual target inhibitor and a preparation method thereof. The inhibitor is as shown in I) or II) in description, and the inhibitor has the dual inhibitory activity of microtubules and histone deacetylase simultaneously.

Description

technical field [0001] The invention belongs to the technical field of synthesis of histone deacetylase inhibitors, and in particular relates to a histone deacetylase and microtubule dual-target inhibitor and a preparation method thereof. Background technique [0002] Histone deacetylase (histone deacetylase, HDAC) is one of the key enzymes that maintain the balance of histone acetylation in the nucleosome, the basic unit of chromosomes. Closely related, involving many processes of promoting gene silencing, the imbalance of histone and non-histone acetylation status is closely related to the occurrence and development of tumors, so histone deacetylase is also a popular target in the design of anti-tumor drugs. [0003] Histone deacetylase inhibitors (histone deacetylase inhibitors, HDACi) are a class of compounds that interfere with the function of histone deacetylases. HDACis can inhibit tumor cell proliferation and induce tumor cell differentiation and / or apoptosis by inc...

Claims

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Application Information

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IPC IPC(8): C07C259/06A61P35/00
CPCA61P35/00C07C259/06
Inventor 栾业鹏王宝雷苗贺牟梓硕王艳
Owner QINGDAO UNIV
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