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Rheum emodin single-chain biquaternary ammonium salt with antitumor activity and preparation method thereof

A technology of double quaternary ammonium salt and anticancer activity, which is applied in the field of emodin single chain double quaternary ammonium salt with anticancer activity and its preparation, which can solve the problem of insufficient anticancer activity, lack of direct medicine, poor water solubility, etc. problems, to achieve good application prospects and good anticancer activity

Inactive Publication Date: 2015-02-18
FUZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are still some shortcomings in itself, such as poor water solubility and insufficient anticancer activity, which cannot meet the requirements of direct medicine.

Method used

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  • Rheum emodin single-chain biquaternary ammonium salt with antitumor activity and preparation method thereof
  • Rheum emodin single-chain biquaternary ammonium salt with antitumor activity and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] Example 1: Synthesis of iodobutyl quaternary ammonium salt

[0022] Take 0.45 mL of methyl bisoctyl tertiary amine or methyl bisdecyl tertiary amine, place it in a 50 mL three-necked flask, add 15 mL of ethylene glycol methyl ether, heat and stir at 100°C, slowly add 0.25 mL of 1,4-diiodo Butane, react for 12 hours and then cool to room temperature. After the solvent is removed by rotary evaporation, the obtained solid is subjected to silica gel column chromatography using dichloromethane-acetone as eluent, and the volume ratio is 45:1→30:1→15:1→ 10:1 gradient elution to obtain iodobutyl quaternary ammonium salt 1a or 1b The characterization data are as follows:

[0023] N-(4-iodobutyl)-N-methyl-N-octyloctane-1-ammonium iodide ( 1a ): Red-brown solid, yield 75%. 1 H-NMR (400MHz, CDCl 3 ) δ: 3.58 (t, J =5.6Hz, 2H, C H 2 I), 3.43 (t, J =1.6Hz, 2H, N + C H 2 (CH 2 ) 3 I), 3.39 (s, 3H, N + C H 3 ), 3.34 (t, J =5.6Hz, 4.0H, 2×N + C H 2 (CH 2 ) 8 CH 3 ), 1.95 (m, 4H, (C H 2 ) 2 CH...

Embodiment 2

[0025] Example 2: Synthesis of double-protected bromo-emodin

[0026] Dissolve 1.6g (5.9mmol) of emodin in 200ml of acetone, add 10g (73mmol) of anhydrous potassium carbonate, slowly add 4ml (43mmol) of dimethyl sulfate under reflux, and react under reflux for 24 hours. Cool to room temperature and After removing part of the solvent by rotary evaporation, add 80ml of water and stir for 30min, then filter with suction. Wash the filter cake with acetone to obtain 1.34g of bright yellow solid trimethylemodin; dissolve 0.8g (2.56mmol) of trimethylemodin in 60ml CCl 4 , Add 0.20g initiator benzoyl peroxide (BPO) and 1.6g (9.0mmol) brominated reagent N-bromosuccinimide (NBS), reflux reaction in a three-necked flask for 25 h, and cool to room temperature to obtain Yellow solid, use a small amount of CCl 4 After washing with acetone, water and acetone, it was subjected to silica gel column chromatography and separated with dichloromethane as the eluent to obtain 0.83 g of yellow solid di-...

Embodiment 3

[0028] Example 3: Synthesis of double-protected emodin tertiary amine

[0029] 100mg (0.26mmol) of the double-protected bromo-emodin synthesized in Example 2 was dissolved in chloroform, poured into a 50mL three-necked flask, and 140mg (2.5mmol) KOH, 5mL water, 50mg TEBA (benzyl triethyl chloride) Ammonium chloride, as a phase transfer catalyst), and 0.35 mL of 33% mass concentration of dimethylamine in water (2.6 mmol), stirred at room temperature for 4 hours, after the reaction, the solution was extracted with 15 mL of chloroform three times, combined the organic layers, and rotary evaporated After removing the solvent, the obtained solid is subjected to silica gel column chromatography with dichloromethane-acetone as the eluent, and the volume ratio is 45:1→30:1→15:1→10:1→5:1→2:1 Gradient elution to obtain double-protected emodin tertiary amine 2 (64.7mg, 0.18mmol), the product characterization data are as follows:

[0030] 3-[(Dimethylamino)methyl]-1,6,8-trimethoxy-9,10-anthr...

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Abstract

The invention discloses rheum emodin single-chain biquaternary ammonium salt with antitumor activity and a preparation method thereof. The rheum emodin single-chain biquaternary ammonium salt is double protected site-6 rheum emodin biquaternary ammonium salt or double deprotected site-6 rheum emodin biquaternary ammonium salt. The preparation method comprises the following steps: carrying out reaction on 1,4-diiodobutane and methyl dioctyl tertiary amine or methyl didecyl tertiary amine to obtain iodobutyl quaternary ammonium salt; carrying out reaction on double protected rheum emodin or double deprotected rheum emodin and dimethylamine to obtain double protected rheum emodin tertiary amine or double deprotected rheum emodin tertiary amine; and carrying out nucleophilic substitution with iodobutyl quaternary ammonium salt to obtain the rheum emodin single-chain biquaternary ammonium salt. An in-vitro cancer cell inhibiting test verifies that the rheum emodin single-chain biquaternary ammonium salt has good antitumor activity, wherein the double deprotected site-6 rheum emodin biquaternary ammonium salt can be used for effectively inhibiting growth of liver cancer HepG2 and is relatively less in toxic and side effects on normal cells. The rheum emodin single-chain biquaternary ammonium salt can be used as an anti-malignant tumor drug, is particularly suitable for treating liver cancer, and has relatively huge application prospect.

Description

technical field [0001] The invention specifically relates to an emodin single-chain diquaternary ammonium salt with anticancer activity and a preparation method 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 activity of double lon...

Claims

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Application Information

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IPC IPC(8): C07C225/24C07C221/00A61P35/00
Inventor 邵敬伟陈秀芬胡秀芳杨祥蒋伟王文峰
Owner FUZHOU UNIV
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