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Oridonin A 14-o-substituted nitrogen mustard derivative, preparation method and use

A technology of Rubescensine A and its derivatives, which can be applied in pharmaceutical formulations, drug combinations, and medical preparations containing active ingredients, etc., can solve problems such as large toxic and side effects, low antitumor activity, and drug resistance failure.

Active Publication Date: 2017-01-11
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

With the deepening of its research in the past 30 years, scholars at home and abroad have found that it has certain therapeutic effects on esophageal cancer, gastric cancer, liver cancer, lung cancer, nasopharyngeal cancer, colon cancer, bladder cancer, cervical cancer and leukemia. Attracted attention, but its anti-tumor activity is not outstanding, there is a lot of room for improvement and optimization
[0005] The anti-tumor drugs currently used clinically are usually cytotoxic drugs, which have the disadvantages of large toxic side effects and serious damage to the human immune system.
Studies have found that many drugs used in chemotherapy achieve therapeutic purposes by interfering with cell growth, metabolism and proliferation processes, and inducing tumor cell apoptosis, but often due to tumor suppressor gene P53 mutations, drug resistance appears and fail

Method used

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  • Oridonin A 14-o-substituted nitrogen mustard derivative, preparation method and use
  • Oridonin A 14-o-substituted nitrogen mustard derivative, preparation method and use
  • Oridonin A 14-o-substituted nitrogen mustard derivative, preparation method and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0080]

[0081] Dissolve oridonin (0.2mmol) in 15ml of dichloromethane, add benzoic acid mustard (0.22mmol), stir at room temperature for 18 hours, add appropriate amount of water (about 15ml), extract with ethyl acetate (10ml×3 times ), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to column chromatography (dichloromethane:methanol=300:1) to obtain a white powdery solid.

[0082] ent-1,6,7-trihydroxy-(14-O-(4-(bis(2-chloroethyl)amino)benzoyl))-15-oxo-7,20-oxo-16- Kaurene. 1 H NMR (CDCl 3 , 300MHz): δ (ppm) 7.78 (d, J = 9.0Hz, 2H, Ar-H), 6.62 (d, J = 9.0Hz, 2H, Ar-H), 6.17 (m, 2H), 6.03 (s , 1H), 5.47(s, 1H), 4.30(s, 1H), 4.08, 4.33(dd, J A =J B =10.2Hz, each1H), 3.78(m, 4H), 3.65(m, 4H), 3.57(m, 1H), 3.28(d, J=9.6Hz, 1H), 2.67(m, 1H), 2.39(m , 1H), 2.04(m, 1H), 1.78(m, 2H), 1.68(m, 3H), 1.49(m, 2H), 1.36(m, 2H), 1.13(s, 3H), 1.12(s, 3H); ESI-MS m / z608.4[M+H] + .

Embodiment 2

[0084]

[0085] ent-1,6,7-trihydroxy-(14-O-(4-(bis(2-chloroethyl)amino)phenylacetyl))-15-oxo-7,20-oxo-16- Kaurene. Referring to the synthetic method of Example 1. 1 H NMR (CDCl 3 , 300MHz): δ (ppm) 7.78 (d, J = 9.0Hz, 2H, Ar-H), 6.62 (d, J = 9.0Hz, 2H, Ar-H), 6.17 (m, 2H), 6.03 (s , 1H), 5.47(s, 1H), 4.30(s, 1H), 4.08, 4.33(dd, J A =J B =10.2Hz, each1H), 4.12(s, 2H), 3.78(m, 4H), 3.65(m, 4H), 3.57(m, 1H), 3.28(d, J=9.6Hz, 1H), 2.67(m , 1H), 2.39(m, 1H), 2.04(m, 3II), 1.78(m, 2H), 1.68(m, 3H), 1.49(m, 2H), 1.36(m, 2H), 1.13(s, 3H), 1.12(s, 3H); ESI-MS m / z622.2[M+H] + .

Embodiment 3

[0087]

[0088] ent-1,6,7-trihydroxy-(14-O-(4-(bis(2-chloroethyl)amino)phenylbutyryl))-15-oxo-7,20-oxo-16- Kaurene. Referring to the synthetic method of Example 1. 1 H NMR (CDCl 3 , 300M Hz), δ(ppm): 6.92(d, J=8.4Hz, 2H, Ar-H), 6.53(d, J=8.4Hz, 2H, Ar-H), 6.07(s, 1H), 6.06 (d, J=6.0Hz, 1H), 5.75(s, 1H), 5.41(s, 1H), 4.25(s, 1H), 4.23, 4.01(dd, J A =J B =10.2Hz, each1H, 20-CH 2 ), 3.69(m, 1H), 3.63(m, 4H), 3.55(m, 4H), 3.43(m, 1H), 3.12(d, J=9.6 Hz, 1H), 2.65(m, 1H), 2.43 (t, J=7.2Hz, 2H), 2.20(t, J=7.2Hz, 2H), 1.91(m, 1H), 1.81(m, 2H), 1.73(m, 2H), 1.70(m, 2H) , 1.65(m, 3H), 1.37(m, 2H), 1.18(s, 3H, -CH 3 ), 1.05(s, 3H, -CH 3 ); ESI-MS m / z650.5[M+H] + .

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Abstract

The invention relates to the field of pharmaceutical chemistry, specifically to novel oridonin 14-0-sustituted nitrogen mustard derivatives with antineoplastic activity. The invention further discloses a preparation method for the oridonin 14-0-sustituted nitrogen mustard derivatives, a pharmaceutical composition containing the derivatives and application of the derivatives in treatment of neoplastic diseases and other related diseases or illness.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry, in particular to a new type of oridonin 14-O-substituted nitrogen mustard derivatives, in particular to the introduction of nitrogen mustard side chains on the oridonin mother nucleus by the splicing principle Oridonin 14-O-substituted nitrogen mustard derivatives. The invention also discloses the preparation method of these oridonine mustard derivatives and the anti-tumor application of these novel derivatives. Background technique [0002] Oridonin is a natural organic compound of ent-kaurene diterpenoid isolated from the Lamiaceae Rabdosia plant. The main plant sources are: fragrant tea Rabdosia amethystoides, Rabdosia nervosa, Rabdosia jabdsia, Rabdosia downsis, Rabdosia rubescens and Rabdosia rubescens (Isodon japonicus). [0003] Oridonin has anti-cell proliferation, inhibition of DNA, RNA and protein synthesis of cancer cells, induction of apoptosis, anti-mutation and β-recept...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D493/08A61K31/352A61P35/00A61P35/02
CPCC07D493/08
Inventor 徐进宜徐盛涛李达翃王诚倩姚鸿裴玲玲陈哲生张运闿张恒源张晨曦
Owner CHINA PHARM UNIV
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