Synthesis of berberine derivatives and application of berberine derivatives in preparing anti-tumor drug and anti-tumor drug composition in combination with adriamycin

A technology of berberine and its derivatives, applied in the field of medicinal chemistry, can solve the problems of insignificant anti-tumor effect and toxic and side effects of doxorubicin

Active Publication Date: 2014-10-29
SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This mixed preparation has a certain inhibitory effect on doxorubicin-induced cardiotoxicity, but the antitumor effect of berberine and doxorubicin alone is not obvious
[0006] However, doxorubicin has toxic and side effects on the body, therefore, it is very necessary to improve the anti-tumor effect of berberine alone and synergistically with doxorubicin to achieve the purpose of synergistic effect and attenuation

Method used

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  • Synthesis of berberine derivatives and application of berberine derivatives in preparing anti-tumor drug and anti-tumor drug composition in combination with adriamycin
  • Synthesis of berberine derivatives and application of berberine derivatives in preparing anti-tumor drug and anti-tumor drug composition in combination with adriamycin
  • Synthesis of berberine derivatives and application of berberine derivatives in preparing anti-tumor drug and anti-tumor drug composition in combination with adriamycin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Embodiment 1, the synthesis of berberine chloride (II)

[0049] Weigh 8g (0.0216mol) of berberine chloride, put it into a 250ml flask, add DMF120ml, reflux in an oil bath at 190°C for 25-30min, TLC (dichloromethane:methanol=10:1) detects that the raw material point just disappears and the impurity point The reaction was stopped when it did not appear (product Rf value about 0.4, red). The solvent was evaporated to dryness to obtain 7 g of crude product BBR-1 with a yield of 85%, which could be directly used in the next reaction.

Embodiment 2

[0050] Example 2 Synthesis of 9-O-propynyl berberine (compound III)

[0051] Weigh 0.54g (1.67mmol) of berbererythrine chloride (compound II) into a 100ml flask, add 0.24g (2.03mmol) of propargyl bromide, 60ml of acetonitrile, and reflux at 70-80°C for 2.5h. TLC detection (dichloromethane:methanol=10:1), visible product spot (Rf value about 0.45, yellow), and product yellow precipitate appeared at the bottom of the flask. Column chromatography (dichloromethane:methanol=25:1) yielded 0.35 g of the product with a yield of 65%.

Embodiment 3

[0052] Example 3 Synthesis of compound 1-propyl-4-(9-O-methylene berberine)-1 hydrogen-1,2,3-triazole (compound 3 in Table 1)

[0053] Add 50mgNaN to the 50ml flask 3 (0.77mmol), 76mg1-bromo-n-propane (0.6mmol) 10ml DMF70 ℃ stirring 3h, cooling, put in 9-O-propynyl berberine (II) 160mg (0.4mmol), the CuSO 4 .5H 2 O30mg and sodium ascorbate 50mg were prepared into 5ml aqueous solutions respectively, and added to the reaction system. Continue to react for 3h, TCL detection (dichloromethane:methanol=10:1), the product point yellow (Rf value about 0.45). Add 10% ammonia water to the reaction solution, extract three times with 100ml of dichloromethane, wash the extract twice with 5ml of 12% hydrochloric acid, concentrate and separate by column chromatography (dichloromethane:methanol:triethylamine=25:1:trace amount) , to obtain 40mg of compound 3. 1 H NMR (300MHz, DMSO) δ9.72(s, 1H), 8.95(s, 1H), 8.40(s, 1H), 8.20(dd, J=9.2, 3.8Hz, 1H), 8.00(d, J= 9.1Hz, 1H), 7.78(d, J=3.3Hz, ...

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Abstract

The invention relates to berberine derivatives as well as a preparation method and an application of the berberine derivatives. The general formula of the berberine derivatives is shown in the specification, where R is alkyl, benzyl, substituted benzyl, phenyl, substituted phenyl, a heterocyclic group or a substituted heterocyclic group. The invention also relates to a composition of the berberine derivatives and adriamycin and an application of the compositions in preparation of an anti-tumor drug. The berberine derivatives disclosed by the invention have not only anti-tumor effects alone and in combination with adriamycin and but also have a certain protective effect on myocardial damage, weight loss and intestinal epithelial cells induced by the treatment, thereby being an ideal synergistic combination drug during the treatment of cancer by virtue of adriamycin.

Description

【Technical field】 [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to a berberine derivative, a preparation method and application thereof, a pharmaceutical composition composed of a berberine derivative and doxorubicin, and an application thereof. 【Background technique】 [0002] Malignant tumors, often called cancer, are frequently-occurring and common diseases that seriously threaten human health. At present, the main three methods for treating malignant tumors include chemotherapy (abbreviated as chemotherapy), surgical treatment and radiotherapy. Chemotherapy with traditional cytotoxic antineoplastic or anticancer drugs still occupies a very important position in the comprehensive treatment of tumors. Some malignant tumors such as choriocarcinoma and malignant lymphoma may be cured by chemotherapy. The targeted therapy emerging in recent years provides us with new methods and ideas for curing cancer. However, the treatment of mo...

Claims

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Application Information

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IPC IPC(8): C07D455/03A61K31/704A61K31/4375A61K31/444A61K31/4709A61K31/513A61P35/00
CPCC07D455/03
Inventor 曹永兵孙青金鑫李新民
Owner SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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