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11, 20-dicarbonyl Jiyuan rubescensin a and L-amino acid-14-ester trifluoroacetate

A technology of ester trifluoroacetate and Rubescensin A, which is applied in the field of new-type Jiyuan Rubescensin A compounds, can solve problems such as instability, difficulty in intravenous administration, failure to reach blood drug concentration, etc., and achieve preparation The method is simple, the side effects of allergies are overcome, and the preparation method is easy to implement

Active Publication Date: 2019-09-13
ZHENGZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] However, Jiyuan Rubescensin A is an equilibrium mixture of aldehyde and hemiacetal, mainly exists in hemiacetal, which is very unstable
The oral bioavailability of Jiyuan Rubescensin A is less than 5%, and the effective blood concentration cannot be reached; at the same time, it is almost insoluble in water, and it is difficult to administer intravenously

Method used

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  • 11, 20-dicarbonyl Jiyuan rubescensin a and L-amino acid-14-ester trifluoroacetate
  • 11, 20-dicarbonyl Jiyuan rubescensin a and L-amino acid-14-ester trifluoroacetate
  • 11, 20-dicarbonyl Jiyuan rubescensin a and L-amino acid-14-ester trifluoroacetate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Preparation of 11,20-Dicarbonyl Jiyuan Oridonin (Compound 2, JDAO)

[0035] Weigh 1 g of Jiyuan Rubescensine A (JDA), add 3.5 mL of acetone to dissolve it, and add an appropriate amount of Jones reagent dropwise to the system under stirring in an ice bath, and react for about 10 minutes. After the completion of the reaction was determined by thin-layer chromatography, the system was diluted with isopropanol, and the solvent was evaporated to dryness by rotary evaporation. After diluting with 50 mL of ethyl acetate, it was washed 5 times with water and stripped once. The ester layers were combined, dried with anhydrous sodium sulfate for 1 hour, and rotary evaporated to obtain 750 mg of JDAO (11,20-dicarbonyl oridonin, compound 2) as a white solid, with a yield of 95%.

Embodiment 2

[0037] Preparation of L-alanine-14-(11,20-dicarbonyl Jiyuan oridonin) ester trifluoroacetate (compound Ⅰ-1)

[0038] Weigh 150mg JDAO, dissolve it with 2mL dichloromethane, add Boc-L-alanine, EDCI (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride successively under stirring at room temperature ), DMAP (4-dimethylaminopyridine) and DIPEA (N,N-diisopropylethylamine). The reaction can be completed after 1-2 hours. After the completion of the reaction was determined by thin-layer chromatography, 30 mL of dichloromethane was added to dilute the reaction system, and the reaction system was washed three times with saturated ammonium chloride solution, and the combined water layers were back-extracted once with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate for 1 hour, and purified by column chromatography.

[0039] The resulting white solid was dissolved in dichloromethane and ice bathed. When the temperature of the system dropped...

Embodiment 3

[0041] Preparation of L-valine-14-(11,20-dicarbonyl Jiyuan oridonin A) ester trifluoroacetate (compound I-2)

[0042] Weigh 150mg of JDAO, dissolve it in 2mL of dichloromethane, add Boc-L-valine, EDCI, DMAP and DIPEA successively under stirring at room temperature. The reaction can be completed after 1-2 hours. After the completion of the reaction was determined by thin-layer chromatography, 30 mL of dichloromethane was added to dilute the reaction system, and the reaction system was washed three times with saturated ammonium chloride solution, and the combined water layers were back-extracted once with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate for 1 hour, and purified by column chromatography.

[0043] The resulting white solid was dissolved in dichloromethane and ice bathed. When the temperature of the system dropped to 5°C, a mixed solution of dichloromethane:trifluoroacetic acid 1:1 was added to the system, and stirred in an i...

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Abstract

Belonging to the field of pharmaceutical compounds, the invention relates to 11, 20-dicarbonyl Jiyuan rubescensin a and L-amino acid-14-ester trifluoroacetate thereof, and a preparation method and usethereof. The preparation method includes: adopting Jiyuan rubescensin a as the raw material and performing oxidation with a Jones reagent, thus obtaining 11, 20-dicarbonyl Jiyuan rubescensin a, the structure of which is shown as the specification; then carrying out 14-position esterification reaction with N-BOC-L-amino acid to obtain N-BOC-L-amino acid-11, 20-dicarbonyl Jiyuan rubescensin a ester(III), then removing BOC protective group in trifluoroacetic acid, and then conducting salt forming to obtain L-amino acid-14-(11, 20-dicarbonyl Jiyuan rubescensin a)ester trifluoroacetate, which hasthe following general formula. The compound has good stability and anti-tumor activity, and provides the basis for screening antitumor drugs against esophageal cancer, gastric cancer, primary liver cancer, pancreatic cancer, cardiac carcinoma, colorectal cancer, bladder cancer, breast cancer, acute myelogenous leukemia and the like.

Description

technical field [0001] The present invention relates to the field of pharmaceutical compounds, in particular to novel Jiyuan Rubescensin A compounds: 11,20-dicarbonyl Jiyuan Rubescensin A and its L-amino acid-14-ester trifluoroacetate compounds, preparation methods and its application. Background technique [0002] As early as the 1970s, the good anti-cancer activity of Lamiaceae Lamiaceae plant Oryx sativa has attracted people's attention. It is a commonly used Chinese herbal medicine in Henan Province. After long-term research by pharmacists, it has been confirmed that It has a certain anti-tumor effect, and the main anti-tumor effect is the diterpenoids. Jiyuan Rubescensin A is a natural organic compound of kaurene diterpenoids extracted from Rubescens sativa, and it is one of the main anti-tumor active ingredients. Jiyuan Rubescensin A is the C-20 oxidized ent-kaurene diterpenoid extracted and purified from Jiyuan Rubescens for the first time by our research group. In...

Claims

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Application Information

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IPC IPC(8): C07D493/10A61P35/00A61P35/02
CPCC07D493/10A61P35/00A61P35/02Y02P20/55
Inventor 刘宏民刘瀛可钰王望
Owner ZHENGZHOU UNIV
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