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Compound with hydroxamic acid structure as well as preparation method and application thereof

A technology of hydroxamic acid and compounds, which is applied in the field of compounds with hydroxamic acid structure and its preparation, and can solve the problems of dose limit toxicity, etc.

Active Publication Date: 2022-04-08
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, combining agents acting on different targets, or combining targeted therapeutics with standard chemotherapeutics or radiation, in most cases, dose-limiting toxicity occurs before pharmacologically meaningful effects are achieved, And currently, this combination is limited to a limited number of drugs with compatible pharmacokinetic or pharmacodynamic properties.

Method used

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  • Compound with hydroxamic acid structure as well as preparation method and application thereof
  • Compound with hydroxamic acid structure as well as preparation method and application thereof
  • Compound with hydroxamic acid structure as well as preparation method and application thereof

Examples

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preparation example Construction

[0058] In the present invention, the preparation method of the compound having the chemical structure shown in formula I comprises the following steps:

[0059] (1) Mixing a compound having the structure shown in Formula A-4, a compound having the structure shown in Formula V, a basic compound and an organic solvent for sulfonamidation reaction to obtain a compound having the structure shown in Formula A-5;

[0060] (2) The compound having the structure shown in formula A-5 obtained in the step (1), hydroxylamine hydrochloride, methanol and sodium methoxide are mixed for amidation reaction to obtain the compound having the structure shown in formula I

[0061]

[0062] In the present invention, unless otherwise specified, the raw materials used are conventional commercially available products in this field.

[0063] In the present invention, unless otherwise specified, the operations performed are at room temperature.

[0064] In the present invention, the compound having ...

Embodiment 1

[0157]

[0158] 1. (E)-3-(3-chlorosulfonylphenyl) methyl acrylate (with R in the structure shown in formula A-4 3 For a hydrogen atom, -CH=CH-CO-NH-OH in R 3 The preparation method of the para-position compound)

[0159] (1) Add fuming sulfuric acid (25mL) into a 100mL three-necked flask, stir and cool down in an ice-water bath, when the temperature is lower than 10°C, add benzaldehyde (10mL, 9.4mmol) dropwise, control the temperature not higher than 30°C, and drop , the temperature was raised to 60°C for 9 hours, and the reaction was complete. Pour the reaction solution into 200 g of crushed ice, adjust the pH to 6 with calcium carbonate, and filter with suction. Adjust the pH of the filtrate to 8 with sodium carbonate, filter with suction, and evaporate the filtrate to dryness. Filtered, and the filtrate was evaporated to dryness to obtain sodium 3-formylbenzenesulfonate, a white solid, 12.42 g, yield 63.3%;

[0160] (2) In a 100mL eggplant-shaped bottle, add the sodiu...

Embodiment 2

[0167] Compound a2 was prepared according to the method of Example 1;

[0168] The difference from Example 1 is that the raw material is replaced by the compound corresponding to compound a2.

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Abstract

The invention provides a compound with a hydroxamic acid structure as well as a preparation method and application thereof, and belongs to the field of chemical medicines. The compound with the hydroxamic acid structure provided by the invention has a chemical structure as shown in a formula I, II or III, a pharmacodynamic group of a hedgehog signal channel antagonist is spliced with a hydroxamic acid fragment, so that the chelation between the compound and zinc ions in HDAC (Hexamic Acid) is increased; the compound shows a relatively strong HDAC (histone deacetylase) inhibition effect while keeping an antagonism effect on a hedgehog signal channel. The compound with the hydroxamic acid structure provided by the invention has an HDAC inhibition rate of 93.43% when the concentration is 10 [mu] M, down-regulation expression of a hedgehog signal channel transcription factor Gli1 can reach-87.10% when the concentration is 5 [mu] M, has a relatively strong inhibition effect on the activity of a hedgehog signal channel, and has a relatively strong inhibition effect on the activity of the hedgehog signal channel when the concentration is 10 [mu] M. The inhibition rate of A549 non-small cell lung cancer cell proliferation reaches up to 86.84%, and the IC50 value for inhibiting Jurkat leukemia cells is as low as 0.57 [mu] M.

Description

technical field [0001] The invention relates to the field of chemical medicine, in particular to a compound with a hydroxamic acid structure and a preparation method and application thereof. Background technique [0002] Acetyltransferase (HAT) and histone deacetylase (HDAC) are key enzymes that regulate intracellular acetylation modification. HAT can transfer the acetyl part of acetyl-CoA to the amino group of histone lysine residues, promote the unfolding of chromosomal DNA conformation, recruit transcription factors for gene expression, and HDAC can remove the acetyl on histone lysine residues base, make the chromatin structure compact and inhibit the transcriptional expression of genes. HDAC function and expression are disturbed in a variety of cancers and are often associated with poor prognosis, and inhibition of HDAC can have multiple effects on cancer cells. [0003] In addition, in 1980, the hedgehog signaling pathway was discovered in Drosophila. There are three ...

Claims

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Application Information

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IPC IPC(8): C07D213/42C07D235/14C07D213/40A61K31/4184A61K31/4402A61P35/00
Inventor 陈国良包雪飞包宇鲍长顺童画吕冰清王林景永奎
Owner SHENYANG PHARMA UNIVERSITY
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