Nitrogen monoxide donor-type oridonin 1,4-hydroxyl-modified derivative, and its preparation method and application

A technology of oridonin A and nitric oxide, applied in the field of natural medicine and medicinal chemistry, can solve problems such as limited application

Active Publication Date: 2013-01-02
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 is insoluble in water, which limits its clinical application

Method used

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  • Nitrogen monoxide donor-type oridonin 1,4-hydroxyl-modified derivative, and its preparation method and application
  • Nitrogen monoxide donor-type oridonin 1,4-hydroxyl-modified derivative, and its preparation method and application
  • Nitrogen monoxide donor-type oridonin 1,4-hydroxyl-modified derivative, and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0159] ent-1α,6β,7β-trihydroxy-(14β-O-(2-formylbenzoic acid-(3-benzenesulfonyl-1,2,5-oxadiazole-2-oxide-4)-oxygen Ethyl ester))-15-oxo-7,20-oxo-16-kaurene

[0160] The compound 4-(2-(2-carboxybenzoyloxy)ethoxy)-3-benzenesulfonyl-1,2,5-oxadiazole-2-oxide was dissolved in anhydrous dichloromethane, Add oridonin (72mg, 0.2mmol), EDC (93mg, 0.6mmol) and a catalytic amount of DMAP, and stir at room temperature for 12h. Wash with water, dry over anhydrous sodium sulfate, filter, concentrate, and column chromatography (dichloromethane:methanol=200:1) to obtain 54mg of white solid (yield 53.2%): mp.123-125°C; IR(KBr)υ max 3392, 2951, 2025, 1714, 1618, 1553, 1451, 1363, 739, 685cm -1 ; 1 H NMR (CDCl 3 , 300MHz), δ (ppm) 1.09 (6H, s, -CH 3 ), 3.37 (1H, d, J=9.6Hz, 13-CH), 3.50 (1H, m, 1-CH), 3.72 (1H, m, 6-CH), 4.05 (1H, s, 1-OH) , 4.07, 4.36 (each 1H, dd, J A =J B =10.2HZ, 20-CH 2 ), 4.67 (2H, m, -CH 2 ), 4.76 (2H, m, -CH 2 ), 5.54 (1H, s, 17-CH 2 ), 6.04 (1H, d, J=12.0Hz,...

Embodiment 2

[0162] ent-1α,6β,7β-trihydroxy-(14β-O-(2-formylbenzoic acid-(3-benzenesulfonyl-1,2,5-oxadiazole-2-oxide-4)-oxygen Propyl ester))-15-oxo-7,20-oxo-16-kaurene

[0163] With reference to the synthetic method of Example 1, 52 mg (yield 47.6%) of white solid was obtained: mp.113-115 ° C; IR (KBr) υ max 3418, 2954, 2025, 1714, 1616, 1554, 1451, 1384, 736, 685cm -1 ; 1 H NMR (CDCl 3 , 300MHz), δ (ppm) 1.11 (6H, s, -CH 3 ), 3.39 (1H, d, J=9.9Hz, 13-CH), 3.50 (1H, m, 1-CH), 3.76 (1H, m, 6-CH), 4.06 (1H, s, 1-OH) , 4.08, 4.34 (each 1H, dd, J A =J B =10.2Hz, 20-CH 2 ), 4.46 (1H, m, -CH 2 ), 4.57 (1H, m, -CH 2 ), 4.58 (2H, m, -CH 2 ), 5.56 (1H, s, 17-CH 2 ), 6.05 (1H, d, J=10.5Hz, 6-OH), 6.07 (1H, s, 14-CH), 6.17 (1H, s, 17-CH 2 ), 7.52 (2H, m, Ar-H), 7.57 (3H, m, Ar-H), 7.75 (2H, m, Ar-H), 8.06 (2H, d, J=7.5Hz, Ar-H) ; MS (ESI) m / z: 812.3 [M+NH 4 ] + , 795.3[M+H] + , 829.4[M+Cl] - .

Embodiment 3

[0165] ent-1α,6β,7β-trihydroxy-(14β-O-(2-formylbenzoic acid-(3-benzenesulfonyl-1,2,5-oxadiazole-2-oxide-4)-oxygen Butyl ester))-15-oxo-7,20-oxo-16-kaurene

[0166] With reference to the synthesis method of Example 1, 52 mg of white solid (yield 50.1%) was obtained: mp.108-110° C.; IR (KBr) υ max 3384, 2952, 2025, 1715, 1615, 1553, 1450, 1368, 734, 685cm -1 ; 1 H NMR (CDCl 3 , 300MHz), δ (ppm) 1.10 (6H, s, -CH 3 ), 3.32 (1H, d, J=9.9Hz, 13-CH), 3.50 (1H, m, 1-CH), 3.76 (1H, m, 6-CH), 4.08, 4.34 (each 1H, dd, J A =J B =8.4HZ, 20-CH 2 ), 4.44 (2H, m, -CH 2 ), 4.50 (2H, t, J=5.4Hz, -CH 2 ), 5.30 (1H, s, 1-OH), 5.56 (1H, s, 17-CH 2), 6.04 (1H, d, J=10.5Hz, 6-OH), 6.09 (1H, s, 14-CH), 6.61 (1H, s, 17-CH 2 ), 7.53 (3H, m, Ar-H), 7.61 (2H, m, Ar-H), 7.76 (2H, m, Ar-H), 8.06 (2H, d, J=7.8Hz, Ar-H) ; MS (ESI) m / z: 826.1 [M+NH 4 ] + , 809.0[M+H] + , 843.3[M+Cl] - .

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Abstract

The invention relates to pharmaceutical chemistry field, and especially relates to a nitrogen monoxide donor-type oridonin 1,4-hydroxyl-modified derivative. The invention also discloses a preparation method for the nitrogen monoxide donor-type oridonin 1,4-hydroxyl-modified derivative and application of the compound in anti-tumor.

Description

technical field [0001] The invention relates to the fields of natural medicine and medicinal chemistry, in particular to a derivative of nitric oxide donor-type oridonin A modified at the 14-position hydroxyl. The invention also discloses the preparation method of these nitric oxide donating type oridonin A derivatives and the anti-tumor application of these nitric oxide donating type oridonin A derivatives. Background technique [0002] Oridonin (oridonin) is a natural organic compound of ent-kaurene diterpenoid isolated from Lamiaceae (Rabdosia) plant Rabdosia. Removing blood stasis, antibacterial and anti-inflammatory, anti-tumor and other effects. In vitro activity studies have shown that Rubescensine A has the functions of inhibiting tumor cell proliferation, inducing cell apoptosis, regulating tumor cell signaling pathways, scavenging intracellular free radicals and inhibiting toxic substances from mutagenizing cellular DNA (Wang Zhenni, Wo Xing De, China Medical Her...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D493/08C07D493/10C07D271/08A61K31/4245A61P35/00
Inventor 徐进宜王磊张奕华姚和权李达翝徐盛涛黄晓静张恒源李德尧郭建曼王国财
Owner CHINA PHARM UNIV
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