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Betulinic acid derivative, preparation method and application thereof

A technology of betulinic acid and derivatives, applied in the field of biomedicine, can solve problems such as no betulinic acid derivatives yet, and achieve the effects of good water solubility, convenient vascular administration, and reduction of toxic and side effects

Active Publication Date: 2020-06-26
湖南省中医药研究院
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The most important thing is that so far, no biotin-modified betulinic acid derivatives have been seen, nor have biotin-modified betulinic acid specifically combined with avidin to construct nano-medicine systems and biomedical applications

Method used

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  • Betulinic acid derivative, preparation method and application thereof
  • Betulinic acid derivative, preparation method and application thereof
  • Betulinic acid derivative, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] The preparation of embodiment 1 betulinic acid derivative (biotin-betulinic acid)

[0051] Preparation of biotin-betulinic acid: Dissolve betulinic acid (0.15mmol) in 60ml of DMSO, under the action of dehydrating agent DCC (3.0mmol) and catalyst DMAP (3.0mmol), stir at 0°C for 6h; Fatty acid molar ratio 1:3 times, add biotin (B), raise temperature from ice bath to room temperature 25°C, and stir overnight in the dark. Concentrate the filtrate, recrystallize with glacial ether or isopropanol, purify by chromatography or preparative liquid phase, and freeze-dry to obtain betulinic acid derivative (B-BA) (yield is about 67%). The ion peak identified by mass spectrometry [M +H] + For: 683.6.

[0052] 1 H-NMR (400MHz, DMSO): The characteristic peaks of biotin: 10.76-10.82 (NH, 2H, broad peak), 4.47-4.65 (2C-H, 2H), 2.80-3.10 (CH 2 , 2H), 3.24(CH, 1H), 2.32(CH 2 , 2H), 1.23-1.68 (3CH 2 , 6H); characteristic peaks of betulinic acid: 0.85-1.05 (2CH2, 6CH, 10H), 1.34-1.78 ...

Embodiment 2

[0056] Preparation of embodiment 2 betulinic acid derivatives (biotin-ethylene glycol-betulinic acid)

[0057] 1) Preparation of biotin-ethylene glycol carboxylic acid: take biotin (0.57g, 2.3mmol) and dissolve it in 40ml of DMSO, in dehydrating agent (N,N'-dicyclohexylcarbodiimide, DCC, 0.47 g, 2.3mmol) and catalyst (p-dimethylaminopyridine, DMAP, 0.29g, 2.3mmol), stirred at 0°C for 4h; then added ethylene glycol carboxylic acid (HOCH 2 CH 2 OCH 2 COOH), raise the temperature from an ice bath to room temperature 25°C, and stir overnight for 24 hours in the dark; filter to remove by-products, concentrate the filtrate, precipitate and recrystallize with ice ether or prepare liquid phase purification, and freeze-dry to obtain biotin-ethylene glycol Carboxylic acid coupling product (B-COOCH 2 CH 2 OCH 2 COOH).

[0058] 2) Preparation of biotin-ethylene glycol-betulinic acid: Dissolve betulinic acid (0.15mmol) in 60ml of DMSO, under the action of dehydrating agent DCC (3.0mm...

Embodiment 3

[0062]Example 3 Synthesis of Biotin-Aminoethylene Glycol-Betulinic Acid and Preparation of Avidin Composite Nano

[0063] 1) Synthesis of biotin active ester (B-NHS): Dissolve biotin (0.57g, 2.3mmol) in 40ml of anhydrous DMSO, add 0.5ml of TEA triethylamine, mix and stir at room temperature in an anhydrous environment and avoid light Overnight; then mix 0.47g (2.3mmol) of DCC and 0.26g (2.3mmol) of NHS, avoid light and stir for 24h, filter to remove the by-product dicyclohexylurea, and dry under low temperature vacuum to remove DMSO and TEA to obtain biotin active ester.

[0064] 2) Synthesis of biotin-aminoethylene glycol carboxylic acid: Dissolve the biotin active ester in vacuum in 1.5ml of anhydrous DMSO / TEA (volume ratio 2:1) mixed solution, take the biotin active ester, etc. moles of NH 2 - Ethylene glycol carboxylic acid is added to the mixed solution and reacted overnight under anhydrous conditions, and the reaction solution is vacuum dried to obtain biotin-coupled et...

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Abstract

The invention belongs to the technical field of biological medicines, and discloses a betulinic acid derivative, a preparation method and application thereof. The preparation method comprises the following steps: preparing biotin esterification coupled oligomerization ethylene glycol carboxylic acid or biotin amide coupled oligomerization ethylene glycol carboxylic acid; dissolving betulinic acidin a solvent, and carrying out a stirring reaction at 0 DEG C for 1-6 hours under the action of a dehydrating agent and a catalyst; adding biotin or the biotin esterification coupled oligomerization ethylene glycol carboxylic acid or biotin amide coupled oligomerization ethylene glycol carboxylic acid according to a betulinic acid molar ratio of 1:1-3, heating to room temperature from an ice bath,and stirring in a dark place overnight; and concentrating the filtrate, re-crystallizing with ice diethyl ether or isopropanol, carrying out chromatography or preparative liquid phase purification, and freeze-drying to obtain the betulinic acid derivative. The betulinic acid derivative, the pharmaceutically acceptable salt and the isotope marker thereof can be applied to preparation of anti-cancer drugs and drugs for treating obesity or non-alcoholic fatty liver disease.

Description

technical field [0001] The invention belongs to the technical field of biomedicine, and in particular relates to a betulinic acid derivative and a preparation method and application thereof. Background technique [0002] Betulinic acid (Betulinic acid, BA) is a pentacyclic triterpenoid compound, a pentaterpenoid organic acid, insoluble in water, slightly soluble in methanol, ethanol, acetone, easily soluble in tetrahydrofuran, pyridine, widely present in many Among various plant medicinal materials, such as Chinese Camellia oleifera, white birch, Prunella vulgaris, papaya, rosemary, oleander and other plants, especially the applicant’s project team newly found that BA is highly enriched in Camellia oleifera cake, which has profound development value. Has anti-tumor (Cancer Res., 2011; 71 (15): 5182-93.), anti-AIDS virus (Med. Chem. Res., 2011; 20: 1247-59.; Proc Natl Acad Sci U SA.1994; 91(9):3564-8.), anti-inflammatory, immune regulation, liver protection, anti-oxidative ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J63/00A61K31/58A61P35/00A61P1/16A61P3/04A61K47/54
CPCA23V2002/00A61K31/56A23L33/12A61K47/557A61P1/16A61P3/04A61P35/00C07J63/008A23V2200/308A23V2200/32A23V2200/332
Inventor 彭咏波张水寒郭新红万丹曹科李雄曾宏亮周融融
Owner 湖南省中医药研究院
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