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Oleanolic acid-pyrimidine conjugate as well as preparation method and application thereof

A technology of oleanolic acid and conjugates, applied in the field of medicine, can solve problems such as obstruction and weak anti-tumor activity

Inactive Publication Date: 2012-08-15
GUANGXI NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Oleanolic acid has good broad-spectrum anti-tumor activity while protecting the liver and liver, and can act on different stages of tumorigenesis, including inhibiting tumor formation, hindering tumor induction and inducing tumor cell differentiation, and effectively inhibiting tumor formation. Angiogenesis prevents tumor cell invasion and metastasis (Ovesna, Z., Vachalkova, A. et al. Pentacyclic triterpenoic acids: New chemoprotective compounds. Neoplasma, 2004, 51(5): 327-333); although olean Acid can act on different stages of tumorigenesis, but its antitumor activity is relatively weak (Huang Minshan, Huang Wei, Wu Qinian, etc. Oleanolic acid induces apoptosis of human breast cancer cells and interacts with intracellular Ca 2+ Level of research, Chinese Journal of Modern Medicine, 2004, 14(16): 58-60)

Method used

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  • Oleanolic acid-pyrimidine conjugate as well as preparation method and application thereof
  • Oleanolic acid-pyrimidine conjugate as well as preparation method and application thereof
  • Oleanolic acid-pyrimidine conjugate as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0119] Example 1: 3β-Hydroxy-oleanane-12-ene-28-acid-[(uracil-1)-ethyl]ester (I 1 ) and 1,3-bis-(3β-hydroxy-oleanane-12-ene-28-acyloxyethyl)-2,4(1H,3H)-pyrimidinedione (II 1 ) preparation

[0120] a) Dissolve 4.99mmol (2.28g) of oleanolic acid in 10mL of DMF, add 24.95mmol (3.44g) of potassium carbonate and 6.49mmol (0.56mL) of 1,2-dibromoethane, and stir at 60°C for 0.5 hours , spin off the solvent under reduced pressure, the residue was dissolved in 50 mL of ethyl acetate, washed successively with 1N HCl, water, saturated sodium bicarbonate, water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to obtain a residue Purified by silica gel column chromatography, eluted with a mixed solvent of petroleum ether: ethyl acetate = 8:1 (volume ratio), and the eluent was evaporated to dryness to obtain 3β-hydroxy-oleanane-12-ene-28 -Acid-(2-bromoethyl)ester 1.60g (white solid, yield 57%); 1 H NMR (500MHz, CDCl 3 )0.74, 0.78, ...

Embodiment 2

[0130] Example 2: 3β-Hydroxy-oleanane-12-ene-28-oic acid-[(thymine-1)-ethyl]ester (I 2 ) and 5-methyl-1,3-bis-(3β-hydroxy-oleanane-12-ene-28-acyloxyethyl)-2,4(1H,3H)-pyrimidinedione (II 2 ) preparation

[0131] a) Dissolve 4.99mmol (2.28g) of oleanolic acid in 10mL of DMF, add 24.95mmol (3.44g) of potassium carbonate and 6.49mmol (0.56mL) of 1,2-dibromoethane, and stir at 60°C for 0.5 hours , spin off the solvent under reduced pressure, the residue was dissolved in 50 mL of ethyl acetate, washed successively with 1N HCl, water, saturated sodium bicarbonate, water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to obtain a residue Purified by silica gel column chromatography, eluted with a mixed solvent of petroleum ether: ethyl acetate = 8:1 (volume ratio), and the eluent was evaporated to dryness to obtain 3β-hydroxy-oleanane-12-ene-28 -Acid-(2-bromoethyl)ester 1.60g (white solid, yield 57%); 1 H NMR (500MHz, CDCl 3...

Embodiment 3

[0141] Example 3: 3β-Hydroxy-oleanane-12-ene-28-acid-[(uracil-1)-n-butyl]ester; (I 3 ) and 1,3-bis-(3β-hydroxy-oleanane-12-ene-28-acyloxybutyl)-2,4(1H,3H)-pyrimidinedione (II 3 ) preparation

[0142] a) Dissolve 4.99mmol (2.28g) of oleanolic acid in 10mL of DMF, add 14.97mmol (2.07g) of potassium carbonate and 0.72mL (5.99mmol) of 1,4-dibromobutane, and stir at 0°C for 72 hours , spin off the solvent, the residue was dissolved in 50 mL of ethyl acetate, washed with 1N HCl, water, saturated sodium bicarbonate, water and saturated brine in sequence, dried over anhydrous magnesium sulfate, filtered, the filtrate was concentrated, and the obtained residue was washed with silica gel Purified by column chromatography, eluted with a mixed solvent of petroleum ether: ethyl acetate = 4:1 (volume ratio), and the eluent was evaporated to dryness to obtain 3β-hydroxy-oleanane-12-ene-28 acid- (4-bromobutyl) ester 1.78g (white solid, yield 61%); 1 H NMR (500MHz, CDCl 3 )0.72, 0.77, 0.89...

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Abstract

The invention discloses an oleanolic acid-pyrimidine conjugate and a preparation method thereof as well as application of the oleanolic acid-pyrimidine conjugate in the pharmaceutical field. An applicant finds that the anti-tumor activity of the oleanolic acid-pyrimidine conjugate is higher than that of a parent body namely oleanolic acid, and a lead compound is provided for developing new anti-tumor medicaments. The conjugate has a structure as shown in the following general formula (I), (II) or (III).

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to an oleanolic acid-pyrimidine conjugate and a preparation method and application thereof. Background technique [0002] Tumors, especially malignant tumors, are still very harmful diseases to human life and health. The International Agency for Research on Cancer (IARC) pointed out according to the global cancer incidence information database that the incidence of cancer is spreading from developed countries to developing countries, and the death caused by various tumor diseases is the second largest cause of death after cardiovascular diseases. In recent years, tumor chemotherapy has made considerable progress, and the survival time of tumor patients has been significantly prolonged, especially breakthroughs have been made in the treatment of leukemia and malignant lymphoma. The treatment of more than 90% of solid tumors has not yet achieved satisfactory results. Therefore, exper...

Claims

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Application Information

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IPC IPC(8): C07J63/00A61K31/58A61P35/00
Inventor 程克光梁宏苏春华陈振锋王恒山莫伟彬
Owner GUANGXI NORMAL UNIV