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Bexarotene hydroximic acid as well as preparation method and application thereof

A technology of bexarotene hydroxamic acid and bexarotene hydroxime, which is applied in the field of medicine, can solve problems such as molecular expression imbalance, cell malignant transformation and the like, and achieves the effect of a simple preparation method

Inactive Publication Date: 2012-06-20
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the state of cells undergoing transformation, the activity of HDACs is significantly enhanced, which breaks the original balance of gene expression, leading to an imbalance in the expression of some molecules that affect cell proliferation and regulation of the cell cycle, which in turn leads to malignant transformation of cells.

Method used

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  • Bexarotene hydroximic acid as well as preparation method and application thereof
  • Bexarotene hydroximic acid as well as preparation method and application thereof
  • Bexarotene hydroximic acid as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Example 1. Preparation of methyl 4-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene-2-carbonyl)benzoate (Ⅲ):

[0026] Into a 2 L three-necked flask, add 100 g of monomethyl terephthalate monoacyl chloride (II) and 80 g of pentamethyltetrahydronaphthalene (I), then add 500 mL of dichloromethane, stir to dissolve, and add 200 g of trichloro Iron oxide, then reacted at 30-35°C for 20 hours, slowly poured the reaction solution into 2 L of ice-water mixture under stirring, separated the layers, separated the dichloromethane layer, extracted the water layer with 500ml×3 dichloromethane, and combined organic layer. The combined organic layers were washed with saturated NaHCO 3 Wash three times with 300 ml of aqueous solution × 3, wash once with 300 ml of saturated NaCl aqueous solution, dry over anhydrous magnesium sulfate for 1 h, and evaporate the solvent to obtain a light yellow solid product with a crude yield of 95%.

Embodiment 2

[0027] Example 2. Methyl 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)vinyl]benzoate (IV) Preparation of:

[0028] Into a 500 mL three-necked flask, put 50 g of methyltriphenylphosphine bromide, 4.6 g of sodium hydroxide and 22.4 g of 4-(3,5,5,8,8-pentamethyl-5,6 , 7,8-tetrahydronaphthalene-2-carbonyl)methyl benzoate (Ⅲ), then add 230 mL THF, slowly raise the temperature and reflux for 10 hours, distill off THF under reduced pressure to obtain 4-[1-(3,5 , 5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene-2-yl)vinyl]methyl benzoate, the yield was 65%.

Embodiment 3

[0029] Example 3. Preparation of Bexarotene Hydroxamic Acid:

[0030] To a 500mL eggplant-shaped bottle, add 20g of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene-2-yl)vinyl]benzoic acid Methyl ester, 6g of hydroxylamine hydrochloride and 9g of sodium hydroxide, then add 200mL of ethanol, stir and react at room temperature for 20 hours, filter, evaporate the filtrate to remove the solvent under reduced pressure to obtain the crude product of bexarotene hydroxamic acid, and recrystallize from ethanol to obtain the refined product. ESI-MS: 364.2 [M+H] + , 362.1[M-H] - 1 H-NMR (CDCl 3 ) δ: 1.28(s, 6H), 1.31(s, 6H), 1.70(s, 4H), 1.95(s, 3H), 5.35(d, 1H), 5.83(d, 1H), 7.08(s, 1H ), 7.13(s, 1H), 7.38(d, 2H), 8.03(d, 2H)

[0031] Experimental part of biological activity test

[0032] 2.1 The target compound bexarotene hydroxamic acid U87 Cell line proliferation inhibitory activity test

[0033] 2.1.1 Purpose of the experiment

[0034]For the proposed synthe...

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Abstract

The invention belongs to the technical field of medicine and discloses bexarotene hydroximic acid as well as a preparation method and application thereof. The formation of the compound is as shown in the picture and the objective compound is prepared mainly by taking 1,1,4,4,6- pentamethyl-1,2,3,4-tetrahydronaphthalene as the initial material through the steps of Friedel-Crafts acylation, Wittig reaction and condensation reaction. The method is simple in operation, convenient in post-processing and high in yield. The objective compound has good inhibitory action on various cancer cells by the multiple action mechanisms of bonding the retinoic acid X receptors and restraining the histone deacetyltransferases, and the anti-cancer activity of the bexarotene hydroximic acid is obviously better than that of bexarotene. Therefore, the bexarotene hydroximic acid can be applied to treatment of cancers.

Description

[0001] Technical field: [0002] The invention belongs to the technical field of medicine, and relates to bexarotene hydroxamic acid and its preparation method and application. [0003] Background technique: [0004] In recent years, research on retinoic acid receptors and retinoic acid drugs has become a hot spot in anticancer drug research. Retinoic acid receptors are interconnected and co-regulated with many other signaling pathways through transcriptional regulation, translational regulation and phosphorylation regulation, and play a very important role in the proliferation, differentiation and apoptosis of tumor cells. Retinoic acid analogs induce a variety of The effect of tumor cell differentiation and reversing the malignant phenotype of tumor cells is remarkable. Retinoic acid receptors belong to a subfamily of the nuclear receptor superfamily. The retinoic acid receptor subfamily includes two types of receptors, RARs (retinoic acid receptors) and RXRs (retinoid X...

Claims

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Application Information

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IPC IPC(8): C07C259/10A61P35/00A61P35/02
Inventor 陈国良苏专专包雪飞杨静玉王立辉孙兆柱赵嫚吴春福
Owner SHENYANG PHARMA UNIVERSITY
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