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Flavone-ligustrazine compounds CH-X having selective anti-liver cancer effect, preparation method and applications thereof

A compound and anti-liver cancer technology, applied in medical preparations containing active ingredients, organic chemistry, organic active ingredients, etc., can solve problems such as vascular side effects

Active Publication Date: 2020-03-03
薪火炙药(北京)科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, many chemotherapy drugs currently used clinically, such as cisplatin and paclitaxel, have serious vascular side effects, including anemia and hemoptysis, etc.

Method used

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  • Flavone-ligustrazine compounds CH-X having selective anti-liver cancer effect, preparation method and applications thereof
  • Flavone-ligustrazine compounds CH-X having selective anti-liver cancer effect, preparation method and applications thereof
  • Flavone-ligustrazine compounds CH-X having selective anti-liver cancer effect, preparation method and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0104] The preparation of embodiment 1 intermediate tetramethylpyrazine bromide (TMP-Br)

[0105] Weigh TMP·3H 2 An appropriate amount of O was stirred and dissolved in 2-3 times the amount of toluene, heated to reflux for 10-12 hours, and dehydrated in a water separator to obtain anhydrous TMP. Dissolve an appropriate amount of anhydrous TMP in CCl 4 Stir in medium to dissolve, and then add NBS according to the molar ratio TMP:NBS=1:0.7-0.9. Under the full irradiation of an incandescent lamp, heat and reflux for 10 hours. When the reaction is completed, the reaction liquid is purple-red, and the generated succinimide is suspended on it. Cool, filter, concentrate under reduced pressure in a water bath at 60-80°C and take it away. Excessive ligustrazine yields purple-red semi-oil TMP-Br, Yield: 70%.

Embodiment 2

[0106] Example 2 Preparation of Ligustrazine and Chrysin Derivatives (CH-1)

[0107] Weigh 0.50g of chrysin into a 100mL round bottom flask, put into TMP-Br at a molar ratio of 1:1, add an appropriate amount of anhydrous DMF to the reaction flask and stir to dissolve, then add an appropriate amount of K 2 CO 3 Finally, under the protection of nitrogen, the reaction bottle was placed in an oil bath at 75° C. for a heating reaction for 2 h (TLC followed the reaction). After the reaction is complete, cool and filter. The filtrate was heated in a water bath at 55 °C, and DMF was removed with a rotary evaporator. After reconstitution with dichloromethane, add silica gel to mix the sample, separate and purify on silica gel column, eluting with dichloromethane / acetone=10:1-3:1, improve the color development of potassium bismuth iodide, detect by TLC, and obtain white The solid object is compound CH-1. M.p.: 156.2-157.1℃, yield 58%. 1 H-NMR (CDCl 3 )(ppm): δ12.72(s, 1H), 7.88-7....

Embodiment 3

[0108] Example 3 Preparation of Ligustrazine and Chrysin Derivatives (CH-2)

[0109] Weigh 0.50g of chrysin into a 100mL round bottom flask, put into TMP-Br at a molar ratio of 1:2, add an appropriate amount of anhydrous DMF to the reaction flask and stir to dissolve, then add an appropriate amount of K 2 CO 3 Finally, under the protection of nitrogen, the reaction bottle was placed in an oil bath at 75° C. for a heating reaction for 2 h (TLC followed the reaction). After the reaction is complete, cool and filter. The filtrate was heated in a water bath at 55 °C, and DMF was removed with a rotary evaporator. After reconstitution with dichloromethane, add silica gel to mix the sample, separate and purify on silica gel column, eluting with dichloromethane / acetone=10:1-3:1, improve the color development of potassium bismuth iodide, detect by TLC, and obtain white The powdery solid target, namely compound CH-2. M.p.: 223.1-224.2℃, yield 60%. 1 H-NMR (CDCl 3 )(ppm) δ7.83-7.81...

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Abstract

The invention provides a preparation method of a class of flavone-ligustrazine series derivatives, and applications of the flavone-ligustrazine series derivatives in preparation of antitumor drugs. According to the invention, the compound has obvious inhibition activity on the growth of tumor cell lines (HepG-2, Bel-7402, MCF-7, HT-29 and Hela), and almost does not affect a human normal vascular endothelial cell (HUVEC-12) line, the antitumor activity of part of the compounds is similar to the antitumor activity of a positive drug cis-platinum; the compound CH-5 has high selectivity between tumors and between tumors and normal cell lines, and has the strongest inhibition effect on liver cancer (Bel-7402), wherein the IC50s of the compound to HepG-2, Bel-7402, HT-29, MCF-7 and Hela respectively are 17.31+ / -0.47 [mu]M, 10.74+ / -1.12 [mu]M, 31.88+ / -1.96 [mu]M, 29.79+ / -2.18 [mu]M and 25.11+ / -1.80 [mu]M; and the compound CH-5 has no killing effect on HUVEC-12 cells while inhibiting cancer cells, and shows a certain proliferation promoting activity.

Description

technical field [0001] The invention relates to a compound and its preparation method and application, specifically a compound with selective anti-liver cancer activity and its preparation method and application, belonging to the field of medicinal chemistry. Background technique [0002] Malignant tumor is a frequently-occurring disease that seriously threatens human health and is a major public health problem all over the world. According to the 2018 cancer statistics published by the American Cancer Society in CA: A Cancer Journal for Clinicians: In the United States, there were 1.73 million new cancer patients in 2018, and 610,000 people died of cancer. In recent decades, many highly cytotoxic chemotherapeutic drugs have been discovered one after another, and they are used as first-line drugs for the treatment of various cancers in clinic. However, many chemotherapeutic drugs currently used clinically, such as cisplatin and paclitaxel, have serious vascular side effects...

Claims

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Application Information

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IPC IPC(8): C07D405/12C07D405/14C07D241/12A61K31/497A61K45/06A61P35/00
CPCA61P35/00C07D241/12C07D405/12C07D405/14
Inventor 郭文博王辉程亚涛王鹏龙成钢
Owner 薪火炙药(北京)科技有限公司
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