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23-hydroxy betulinic acid derivative as well as preparation method and application thereof

A technology of betulinic acid and derivatives, applied in the field of medicine, can solve problems such as unclear mechanism of action

Active Publication Date: 2014-07-02
JINAN UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The latest research shows that 23-hydroxybetulinic acid also has the activity of inhibiting glycogen phosphorylase, and its specific mechanism of action is still unclear

Method used

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  • 23-hydroxy betulinic acid derivative as well as preparation method and application thereof
  • 23-hydroxy betulinic acid derivative as well as preparation method and application thereof
  • 23-hydroxy betulinic acid derivative as well as preparation method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1B

[0080] The preparation of embodiment 1B class compound:

[0081] (1) Preparation of various carbamoyl chlorides

[0082] Solid phosgene (8g, 26.9mmol) was dissolved in 40mL of dry dichloromethane, dry triethylamine (1mL, 7.1mmol) was added at -7°C, and a dichloromethane solution of various amines (29.7mmol) was slowly added dropwise (35mL), the dropwise addition was completed in 50 minutes. Stir at 25°C for 12 hours, filter, and spin dry the filtrate to obtain a solid that is directly put into the next reaction.

[0083] (2) General Preparation Method of Class B Compounds

[0084] The carbamoyl chloride obtained in the previous step was dissolved in 50-120 mL of dry pyridine, 23-hydroxybetulinic acid (1.0 g, 2.1 mmol) was added, and the reaction was stirred at 25°C for 16 hours. Add 100 mL of ethyl acetate to the reaction solution, adjust the pH to 4-5 with 10% dilute hydrochloric acid, separate the organic layer, wash with saturated brine (100 mL×3), and dry over anhydrous...

Embodiment 2

[0098] Embodiment 2C compound preparation method

[0099] (1) Preparation of 3,23-O-diacetyl betulinic acid:

[0100] 23-Hydroxybetulinic acid (0.30 g, 0.63 mmol) was dissolved in 12 mL of dry pyridine, acetic anhydride (1 mL) was added, and stirred at 25°C for 8 hours. Add 25 mL of ethyl acetate to the reaction solution, adjust the pH to 4-5 with 10% dilute hydrochloric acid, separate the organic layer, wash with saturated brine (50 mL*3), and dry over anhydrous sodium sulfate. Filtration, concentration, and silica gel (200-300 mesh) column chromatography using petroleum ether: ethyl acetate = 10:1 as the developing solvent gave a white foamy solid (0.32 g, 91.4%), namely 3,23-O- Diacetyl Betulinic Acid (B2C). m.p.144-146°C. MS(EI): m / z 579.5 [M+Na] + . HR-ESI-MS: m / z 579.3652 [M+Na] + (calcd:579.3656). 1 H-NMR (CDCl 3 , 400MHz) δ0.80, 0.88, 0.93, 0.97 (each 3H, s, 24, 25, 26, 27-CH 3 ), 1.69 (3H, s, 30-CH 3 ), 1.79 (1H, m, H-18), 1.95 (1H, m, H-19), 2.01 (3H, s, 3-...

Embodiment 3D

[0115] The preparation method of embodiment 3D class compound:

[0116] (1) General preparation method of B6D1, B6D2, B6D3, B6D4, B6D5, B6D6, B6D7, B6D10:

[0117] 0.2mmol of 3,23-dihydroxy-28-betulinamide glycine, 3,23-dihydroxy-28-betulinamide methionine, 3,23-dihydroxy-28-betulinamide obtained by referring to the preparation method of the above-mentioned C compounds The acid amide proline was dissolved in 30 mL of dry dichloromethane, and the corresponding amino acid methyl ester hydrochloride (2 equiv mol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC·HCl) (2 equiv mol) and anhydrous 1-hydroxy-benzo-triazole (HoBt) (2.5 equiv mol), reflux reaction for 10 hours, the reaction solution with saturated saline (20mL) and water (20mL) Washed three times and dried over anhydrous sodium sulfate. Filtration, concentration, and silica gel (200-300 mesh) column chromatography using petroleum ether: acetone = 3:1 as the developing solvent, yielded B6D1, B6D2, B6D3,...

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Abstract

The invention discloses a 23-hydroxy betulinic acid derivative as well as a preparation method and application thereof. The derivative has a structure as shown in a formula (I). The 23-hydroxy betulinic acid derivative can be used for resisting tumors and used as a tumor medicament resistance reversal agent. The 23-hydroxy betulinic acid derivative can be used for effectively inhibiting the proliferation of tumor cells and also can be used for obviously increasing the antipersonnel force of DOX (doxorubicin) on a P-glycoprotein overexpression cell strain HepG2 / ADM under the condition of non-toxicity dosage.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to a chemically modified 23-hydroxy betulinic acid derivative. The invention discloses a plurality of series of 23-hydroxy betulinic acid derivatives and their preparation methods and are used for anti-tumor and anti-tumor Use of drug reversal agents. Background technique [0002] Natural products play an important role in the fight against cancer. At present, natural sources of compounds account for more than 60% of anticancer drugs, among which camptothecin, paclitaxel, vinblastine, etc. have been used clinically, and continue to search for and develop natural products with good curative effect, low toxicity and strong specificity New anticancer drugs that can reverse chemoresistance are still the focus of attention. [0003] 23-hydroxybetulinic acid (23-HBA) is a betulinic acid analogue isolated from the traditional Chinese medicine Pulsatilla pulsatillae. Its structure and ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J63/00A61K31/56A61K31/58A61P35/00A61P35/02
Inventor 叶文才陈卫民蓝平张冬梅王娇舒畅曹惠慧于淼
Owner JINAN UNIVERSITY
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