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Ent-6,7-open-cycle kaurene type rubescensine a derivative with Anti-tumor activity and preparation method and use thereof

A technology of ent-6 and kaurene, which is applied in the fields of natural medicine and medicinal chemistry, and can solve problems such as limited applications

Active Publication Date: 2011-04-06
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Oridonin belongs to diterpenoids, and its clinical application is limited due to its insolubility in water

Method used

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  • Ent-6,7-open-cycle kaurene type rubescensine a derivative with Anti-tumor activity and preparation method and use thereof
  • Ent-6,7-open-cycle kaurene type rubescensine a derivative with Anti-tumor activity and preparation method and use thereof
  • Ent-6,7-open-cycle kaurene type rubescensine a derivative with Anti-tumor activity and preparation method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0107] ent-6,14-dihydroxy-7,15-dioxo-1,7-lactone-6,20-hemiketal-6,7-cyclo-16-kaurene

[0108] Oridonin (72mg, 0.2mmol) was dissolved in 10ml of water, sodium periodate (644g, 3mmol) was added, stirred at room temperature for 24 hours, extracted three times with dichloromethane, each 10ml, washed twice with saturated saline, without Dry over sodium sulfate, filter, concentrate (the crude product can be directly used in the next reaction), and column chromatography (dichloromethane:methanol=80:1) gives a white powdery solid (65 mg, 91.4%). 1 H-NMR (DMSO, 500MHz), δ (ppm): 6.17 (1H, d, J = 3.3Hz, 6-OH), 5.92 (1H, s, 17-CH 2 ), 5.52 (1H, s, 17-CH 2), 5.38 (1H, d, J = 2.1Hz, 14-OH), 5.17 (1H, d, J = 2.1Hz, 6-CH), 4.67 (1H, s, 14-CH), 4.65 (1H, m , 1-CH), 3.87, 3.58 (each1H, dd, J A =J B =9.1Hz, 20-CH 2 ), 2.95 (1H, d, J=9.1Hz, 13-CH), 2.49 (2H, m, 12-CH 2 ), 1.67 (2H, m, 2-CH 2 ), 1.36 (2H, m, 11-CH 2 ), 1.26 (1H, m, 9-CH), 0.93 (3H, s, 18-CH 3 ), 0.88 (3H, s, 19-CH 3 ). ...

Embodiment 2

[0110] ent-6,7,15-trioxo-1,7-lactone-6,20-lactone-14-hydroxy-6,7-cyclo-16-kaurene

[0111] Ent-6,14-dihydroxy-7,15-dioxo-1,7-lactone-6,20-hemiketal-6,7-cyclo-16-kaurene (72mg, 0.2mmol ) was dissolved in 10ml of acetone, added 0.5ml of Jones’ reagent and stirred at room temperature for 10min, added 0.3ml of isopropanol, evaporated the acetone under reduced pressure, extracted three times with 10ml of dichloromethane, washed twice with saturated saline, dried over anhydrous sodium sulfate , filtered, concentrated (the crude product can be directly used in the next reaction), and column chromatography (dichloromethane:methanol=100:1) gave a white powdery solid (63mg, 87.8%). 1 H-NMR (CDCl 3 , 300MHz), δ (ppm): 6.41 (1H, s, 17-CH 2 ), 5.69 (1H, s, 17-CH 2 ), 4.55 (1H, s, 14-CH), 4.45 (1H, m, 1-CH), 4.35, 4.01 (each1H, dd, J A =J B =10.2Hz, 20-CH 2 ), 3.19 (1H, d, J=9.3Hz, 13-CH), 1.21 (3H, s, 18-CH 3 ), 1.07 (3H, s, 19-CH 3 ). MS-ESI(m / z): 719.1[2M-H] - , 359.1[M-H] - ,...

Embodiment 3

[0113] ent-6-hydroxy-7,15-dioxo-1,7-lactone-6,20-hemiketal-(14-O-pentanoyl)-6,7-cyclo-16-kaurene

[0114] Ent-6,14-dihydroxy-7,15-dioxo-1,7-lactone-6,20-hemiketal-6,7-cyclo-16-kaurene (72mg, 0.2mmol ) was dissolved in 10 ml of anhydrous dichloromethane, and 0.5 ml of triethylamine was added dropwise under ice-cooling. After stirring for 10 minutes, 0.5 ml of valeryl chloride was added dropwise and reacted for 15 minutes. Washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatography (dichloromethane:methanol=300:1) gave a pale yellow solid (73mg, 83.3%). 1 H-NMR (CDCl 3 , 300MHz), δ (ppm): 6.27 (1H, s, 17-CH 2 ), 6.15 (1H, s, 6-CH), 5.63 (1H, s, 17-CH 2 ), 4.56 (1H, s, 14-CH), 4.44 (1H, m, 1-CH), 4.41, 4.031 (each1H, dd, J A =J B =9.3Hz, 20-CH 2 ), 3.19 (1H, d, J=8.1Hz, 13-CH), 1.25 (3H, s, 18-CH 3 ), 1.02 (3H, s, 19-CH 3 ), 0.88 (3H, s, -CH 3 ). MS-ESI(m / z): 464.1[M+NH4] + , 447.1[M+H] + , 4...

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Abstract

The invention relates to the fields of natural medicaments and medicinal chemistry, in particular to a 14-position modified ent-6,7-open-cycle kaurene type rubescensine A derivative with anti-tumor activity. The invention also discloses a method for preparing the 14-position modified ent-6,7-open-cycle rubescensine A derivative and application of a medicinal composition comprising the compound and the compound for treating tumor diseases.

Description

technical field [0001] The invention relates to the fields of natural medicine and medicinal chemistry, in particular to a class of 14-modified ent-6,7-ring oridonin derivatives. The invention also discloses the preparation method of these ent-6,7-opening-ring oridonin derivatives and the application for preparing medicines for treating tumor diseases. Background technique [0002] In 1977, Chinese scientists first isolated oridonin, a natural organic compound of ent-kaurene diterpenoid, from the Lamiaceae Rabdosia plant Oridonin. Clearing heat and detoxifying, promoting blood circulation and removing blood stasis, antibacterial and anti-inflammatory, anti-tumor and other effects. In vitro activity studies have shown that Rubescensine A has an effect on human esophageal cancer 109 cell line, human liver cancer BEL-7402 cell line, human esophageal squamous cell line CaEs-17, liver cancer and histiocytic sarcoma solid cell line, L1210 cells, cells Strain P388, Ehrlich ascite...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D493/10C07D311/96A61K31/366A61P35/00A61P35/02
Inventor 徐进宜王磊张奕华姚和权李达翝徐盛涛王超磊刘琴李德尧郭建曼王国财
Owner CHINA PHARM UNIV
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