11,20-Dicarbonyl Jiyuan Rubescensin A 14-O-benzoate derivative and its preparation method and use

A technology of oridonin A and benzoate, applied in the directions of organic chemistry, drug combination, antitumor drugs, etc., can solve the problems of poor water solubility, difficult oral absorption, poor stability, etc.

Active Publication Date: 2022-07-22
ZHENGZHOU UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although most of these compounds have good antitumor effects, they generally have disadvantages such as poor water solubility, poor stability, and difficulty in oral absorption, which limit their clinical application.

Method used

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  • 11,20-Dicarbonyl Jiyuan Rubescensin A 14-O-benzoate derivative and its preparation method and use
  • 11,20-Dicarbonyl Jiyuan Rubescensin A 14-O-benzoate derivative and its preparation method and use
  • 11,20-Dicarbonyl Jiyuan Rubescensin A 14-O-benzoate derivative and its preparation method and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021]

[0022] Weigh 300 mg of JOA, add 11 mL of acetone to dissolve it completely, and add 0.75 mL of Jones reagent (6 mL of acetone for dilution) under stirring conditions. Spin to dryness, add 30 mL of ethyl acetate to the reaction system to dilute, wash the reaction system with saturated NaCl solution three times, reverse-extract with water once with ethyl acetate, combine the organic phases and dry with anhydrous magnesium sulfate, concentrate, and perform column chromatography. After purification, 270 mg of the target compound 11,20-dicarbonyl Jiyuan oridonin A was obtained with a yield of 74%. 1 H NMR (400MHz, DMSO-d 6 )δ6.14(s,1H),6.08(d,J=2.9Hz,1H),5.79(s,1H),4.79(dd,J=3.9,1.7Hz,1H),3.74–3.71(m,1H) ), 3.10(d, J=8.3Hz, 1H), 2.96(s, 1H), 2.92–2.83(m, 2H), 2.66(dd, J=16.3, 8.4Hz, 1H), 2.55(s, 1H) ,1.76(ddd,J=14.4,7.6,4.0Hz,1H),1.59(dp,J=12.6,5.1,4.3Hz,2H),1.36(d,J=11.6Hz,2H),1.09(td,J =11.4,10.0,5.2Hz,1H),0.98(td,J=14.0,4.4Hz,1H),0.81(s,3H),0.72(s,3H). 13 C NMR (...

Embodiment 2

[0024] Compound 1a

[0025] Weigh 200mg 11,20-dicarbonyl Jiyuan Rubescensine A and dissolve it in 10mL of dichloromethane, add 92mg of benzoic acid under stirring, then add catalyst 1-(3-dimethylaminopropyl group in turn )-3-ethylcarbodiimide hydrochloride (EDCI) 144 mg and 4-dimethylaminopyridine (DMAP) 9 mg. After the completion of the reaction monitored 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 sodium bicarbonate solution, the aqueous layers were combined and back-extracted once, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, column Chromatography gave the product as a white solid in 85% yield. 1 H NMR (400MHz, DMSO-d 6 )δ7.62(d,J=7.8Hz,2H),7.44(d,J=7.5Hz,1H),7.29(t,J=7.5Hz,2H),6.04(s,1H),5.68(s, 1H), 4.79(s, 1H), 4.60(d, J=3.5Hz, 1H), 3.10(s, 2H), 3.07(s, 1H), 2.66(d, J=13.8Hz, 2H), 2.59( t, J=8.3Hz, 1H), 2.26(s, 1H...

Embodiment 3

[0027] Compound 2a

[0028] Substitute 115 mg of 2-methoxybenzoic acid for benzoic acid, and other operations are the same as in Example 2 to obtain a white solid product with a yield of 47%. 1 H NMR (400MHz, DMSO-d 6 )δ7.61(dd,J=7.9,1.8Hz,1H),7.58-7.55(m,1H),7.16-7.13(m,1H),7.04-7.01(m,1H),6.25(s,1H) ,5.91(s,1H),4.99(d,J=1.1Hz,1H),4.83(dd,J=4.1,1.8Hz,1H),3.77(d,J=2.5Hz,3H),3.46(d, J=8.4Hz, 1H), 3.28(s, 1H), 2.92(ddd, J=13.1, 8.0, 2.6Hz, 2H), 2.81(d, J=8.2Hz, 1H), 2.71(d, J=16.4 Hz, 1H), 1.89–1.84 (m, 1H), 1.69–1.65 (m, 1H), 1.41 (d, J=3.9Hz, 1H), 1.37 (s, 1H), 1.23 (s, 1H), 1.11 (d, J=3.8Hz, 1H), 1.09–1.07(m, 1H), 0.83(s, 3H), 0.73(s, 3H). 13 C NMR (101MHz, DMSO-d 6)δ203.48,198.47,174.02,164.49,158.56,146.22,134.56,131.10,122.73,120.25,118.25,112.78,73.80,72.65,58.81,56.30,55.71,46.55,45.32,43.16,39.76,38.55,33.83,30.49,28.16 , 23.13, 18.97, 18.15.HR-MS(ESI): Calculated for C 28 H 30 O 7. [M+NH 4 ] + :496.2335.found:496.2328.

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Abstract

The invention relates to the field of natural products and medicinal chemistry, and discloses 11,20-dicarbonyl Jiyuan oridonin A 14-O-benzoate derivative and a preparation method and application thereof. Its preparation method: taking Jiyuan Rubescensine A (JOA) as a starting material, oxidizing it to obtain 11,20-dicarbonyl Jiyuan Rubescensine A, and then without destroying its active center α-methylene group. Under the premise of cyclopentanone, benzoic acid or substituted benzoic acid and its 14-OH undergo esterification to obtain a series of 11,20-dicarbonyl Jiyuan Rubescensine A 14-O-benzoate derivatives. The compounds have good anti-tumor activity and can be used for preparing anti-cancer drugs and treating diseases such as esophageal cancer, gastric cancer, liver cancer, breast cancer, pancreatic cancer and the like. Its general structural formula is as follows:

Description

technical field [0001] The invention relates to the field of natural products and medicinal chemistry, in particular to 11,20-dicarbonyl Jiyuan Rubescensine A 14-O-benzoate derivative and a preparation method and application thereof. Background technique [0002] Rubescensica is a plant of the genus Lamiaceae, and its medicinal parts are dry aerial parts. Its effects are to clear heat and detoxify, promote blood circulation and relieve pain. A large number of studies have shown that the main anti-tumor active components in Rubescens are diterpenoids, and the enantiokaurene-type diterpenes are a class of natural compounds with good anti-tumor effects. The active center mainly depends on its molecular configuration and the structure of cyclopentanone conjugated with exocyclic methylene groups, such as Rubescensine A, Rubescensine B, and rubescensine A, etc. A variety of tumor cells have anti-proliferative effects, such as esophageal cancer, gastric cancer, breast cancer, cerv...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D311/96A61P35/00
CPCC07D311/96A61P35/00
Inventor 可钰李富欣王妮贾小苹赵梦圆
Owner ZHENGZHOU UNIV
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