Rheum emodin double-chain biquaternary ammonium salt with anti-cancer activity and preparation method of rheum emodin double-chain biquaternary ammonium salt

A technology of double quaternary ammonium salt and anticancer activity, which is applied in the field of emodin double chain double quaternary ammonium salt with anticancer activity and its preparation. problems, to achieve good application prospects and good anticancer activity

Inactive Publication Date: 2015-01-28
FUZHOU UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, there are still some shortcomings in itself, such as poor water solubility a...

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  • Rheum emodin double-chain biquaternary ammonium salt with anti-cancer activity and preparation method of rheum emodin double-chain biquaternary ammonium salt

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Embodiment 1

[0021] Embodiment 1: dibromomethylbenzyl emodin 1 and 2 Synthesis

[0022] 100mg (0.37mmol) emodin, 100mg (0.74mmol) K 2 CO 3 Put 100ml of acetone into a 250ml three-necked flask, control the temperature of the oil bath at 65°C, heat and reflux for 20 minutes, add 195mg (0.74mmol) of p-dibenzyl bromide, react for 2 hours, cool to room temperature, and add dilute hydrochloric acid solution to the solution Adjust the pH to 6, add 200 mL of water to precipitate a large amount of yellow solid, filter with suction, dry and dissolve the obtained solid, apply the dry method, and separate the orange solid through silica gel column chromatography with dichloromethane as the eluent. After determination, it is the compound 6-methyl-8-hydroxyl-1,3-bis(p-bromomethylbenzyloxy)-9,10-anthraquinone ( 1 ) and 6-methyl-1-hydroxy-3,8-di(p-bromomethylbenzyloxy)-9,10-anthraquinone ( 2 ), abbreviated as 1 + 2 , the molar ratio of the two is about 2:1, R f =0.87. Product characterization da...

Embodiment 2

[0024] Embodiment 2: 1, the synthesis of 3 double quaternary ammonium salts and 3,8 double quaternary ammonium salts

[0025] Get the dibromomethylbenzyl emodin that embodiment 1 obtains ( 1 + 2） Add 100mg (0.16mmol) and 20ml chloroform together into a 100ml three-neck flask, heat and dissolve under reflux, add 0.32mmol tertiary amine, stir and reflux for 12h, cool to room temperature, and remove the solvent by rotary evaporation. Chloromethane: ethanol = 20: 1 (v / v) was used as the eluent, and an orange solid was isolated. After determination, it is emodin 1,3 biquaternary ammonium salt ( 3a-3b ) and emodin 3,8-position diquaternary ammonium salt ( 4a-4b ), abbreviated as 3a-3b + 4a-4b . Depending on the tertiary amine, the compound 3 and 4 The molar ratio is different, and the product characterization data are as follows:

[0026] compound 3a + 4a(The molar ratio is about 5:1), the yield is 41%; m.p. 128-130°C. 1 H NMR (400Hz, CDCl 3 ) δ: 13.21 (s, 1.0H, OH),...

Embodiment 3

[0028] Embodiment 3: Cancer cell proliferation inhibition experiment

[0029] Emodin 1,3 and 3,8 diquaternary ammonium salts ( 3a+4a )and( 3b+4b ) was used as the test drug, and the drug was diluted with the medium; the liver cancer cell Hep2 and the normal cell HELF were taken, and their density was adjusted to 1×10 5 cells / ml, seeded in 96-well plate, 100 μl per well, placed at 37°C, 5% CO 2 Cultivate in the incubator for 24 h; remove the old medium, add the test drug, 100 μl per well, and set up blank control group and emodin group, and set 3 duplicate wells for each group. After 24 hours of drug action, discard the drug-containing medium, add 100 μl of serum-free and phenol red-free 1640 medium to each well, then add 10 μl of MTT solution, continue to incubate for 4 hours, and terminate the culture; For supernatant, add 100 μl DSMO to each well, shake for 10 minutes, measure the light absorption value (OD value) of each well on a microplate reader at a wavelength of 5...

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Abstract

The invention discloses a rheum emodin double-chain biquaternary ammonium salt with the anti-cancer activity and a preparation method of the rheum emodin double-chain biquaternary ammonium salt. The rheum emodin double-chain biquaternary ammonium salt is a mixture of a rheum emodin 1,3-site biquaternary ammonium salt and a rheum emodin 3,8-site biquaternary ammonium salt. The preparation method comprises the following steps: performing Williamson etherification reaction on rheum emodin and p-benzyl bromide in the presence of K2CO3 so as to generate a mixture of 1,3-site dibromomethylbenzyl rheum emodin and 3,8-site dibromomethylbenzyl rheum emodin, and further reacting the dibromomethylbenzyl rheum emodin mixture with tertiary amine so as to obtain the mixture of 1,3-site biquaternary ammonium salt and rheum emodin 3,8-site biquaternary ammonium salt, wherein the two biquaternary ammonium salts are isomerides which cannot be separated on a chromatographic column. The anti-cancer activity evaluation shows that the activity of the rheum emodin double-chain biquaternary ammonium salt disclosed by the invention is higher than that of monoquaternary ammonium salt, and the rheum emodin double-chain biquaternary ammonium salt can be used in a medicine for treating malignant tumor, is particularly applicable to treatment on liver cancer, has a relatively small inhibition effect on normal cells, and has relatively great application prospect.

Description

technical field [0001] The invention specifically relates to an emodin double-chain diquaternary ammonium salt with anticancer activity and a preparation method and application thereof. Background technique [0002] Emodin (1,3,8-trihydroxy-6-methylanthraquinone, emodin) is a natural anthraquinone derivative isolated from Polygonaceae plants, and its structural formula is: . Modern medicine has confirmed that emodin has spectrum anti-cancer activity, and has inhibitory effect on dozens of cancer cells such as liver cancer and gastric cancer. However, it still has some disadvantages, such as poor water solubility and insufficient anticancer activity, which cannot meet the requirements of direct medicine. Therefore, chemical modification of emodin to improve its water solubility and anticancer activity is the main research direction to develop it into a new anticancer drug. Wang Conghui et al. (Wang Conghui, Zhang Fengsen, Du Huadong, etc., "Synthesis and anticancer activi...

Claims

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Application Information

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IPC IPC(8): C07C213/02C07C217/48A61P35/00
Inventor 王文峰祝云辉王建龙郝宪宵罗舒维邵敬伟
Owner FUZHOU UNIV
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